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1
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Zhou W, Bandara SR, Ko K, Akinrotimi O, Hernández-Saavedra D, Richter E, Brauer N, Woodward TJ, Bradshaw HB, Leal C, Anakk S. Deleting adipose FXR exacerbates metabolic defects and induces endocannabinoid lipid, 2-oleoyl glycerol, in obesity. J Lipid Res 2025; 66:100754. [PMID: 39938865 PMCID: PMC11946508 DOI: 10.1016/j.jlr.2025.100754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 01/26/2025] [Accepted: 02/06/2025] [Indexed: 02/14/2025] Open
Abstract
The nutrient sensor farnesoid X receptor (FXR) transcriptionally regulates whole-body lipid and glucose homeostasis. Several studies examined targeting FXR as a modality to treat obesity with varying conflicting results, emphasizing the need to study tissue-specific roles of FXR. We show that deletion of adipocyte Fxr results in increased adipocyte hypertrophy and suppression of several metabolic genes that is akin to some of the changes noted in high-fat diet (HFD)-fed control mice. Moreover, upon HFD challenge, these effects are worsened in adipocyte-specific Fxr knockout mice. We uncover that FXR regulates fatty acid amide hydrolase (Faah) such that its deletion lowers Faah expression. Conversely, FXR activation by its ligand, chenodeoxycholic acid, induces Faah transcription. Notably, HFD results in the reduction of adipose Faah expression in control mice and that Faah inhibition or deletion is linked to obesity. We report that the adipocyte FXR-Faah axis controls local 2-oleoyl glycerol and systemic N-acyl ethanolamine levels. Taken together, these findings show that loss of adipose FXR may contribute to the pathogenesis of obesity and subsequent metabolic defects.
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Affiliation(s)
- Weinan Zhou
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Sarith R Bandara
- Department of Materials Science and Engineering, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Kyungwon Ko
- Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Oludemilade Akinrotimi
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Diego Hernández-Saavedra
- Department of Kinesiology and Community Health, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Emily Richter
- Department of Psychological and Brain Sciences, Indiana University Bloomington, Bloomington, IN, USA
| | - Noah Brauer
- Department of Psychological and Brain Sciences, Indiana University Bloomington, Bloomington, IN, USA
| | - Taylor J Woodward
- Department of Psychological and Brain Sciences, Indiana University Bloomington, Bloomington, IN, USA
| | - Heather B Bradshaw
- Department of Psychological and Brain Sciences, Indiana University Bloomington, Bloomington, IN, USA
| | - Cecilia Leal
- Department of Materials Science and Engineering, University of Illinois Urbana-Champaign, Urbana, IL, USA; Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL, USA; Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA.
| | - Sayeepriyadarshini Anakk
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA; Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL, USA; Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA.
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2
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Nikolova V, Mitchell AL, Bellafante E, Jansen E, Papacleovoulou G, Bergh P, Marshall H, Williamson C. Gestational hypercholanemia suppresses pregnancy-associated adipose mass increase and stimulates a pro-inflammatory environment in mice. Physiol Rep 2024; 12:e70141. [PMID: 39667808 PMCID: PMC11637612 DOI: 10.14814/phy2.70141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/15/2024] [Accepted: 11/21/2024] [Indexed: 12/14/2024] Open
Abstract
Women with intrahepatic cholestasis of pregnancy (ICP) have hypercholanemia alongside an increased risk of dyslipidemia. We investigated how cholic acid (CA) supplementation in murine pregnancy impacts adipose tissue function. Mice were fed normal or 0.5% CA-supplemented chow from identification of copulatory plug until gestational day 14 or 15 (n = 10-11/group) and were matched experimentally with nonpregnant mice (n = 7/group). Tissue weights were measured alongside plasma bile acids, glucose, lipids, reactive oxygen metabolites (ROM), and adipokines. Subcutaneous and gonadal adipocyte mRNA expression was evaluated. CA supplementation inhibited pregnancy-associated adipose tissue expansion and decreased fetal weight. CA diet in pregnancy increased LDL-cholesterol and reduced HDL-cholesterol. Pregnancy and CA diet reduced lipid metabolism transcript expression in adipocytes. CA supplementation during pregnancy increased plasma ROM by 1.24-fold and suppressed inflammatory-modulating pentraxin-2/3 and insulin-like growth factor 1 (IGF-1) levels by >50% and >80%, respectively. Together, we show that hypercholanemia disturbs pregnancy-associated adipose tissue expansion and mRNA expression in late gestation concomitant with reduced IGF-1, altered lipid availability and increased inflammation and oxidation, which could impact fetal growth. This work highlights the need to better understand adipose tissue and redox stress changes in ICP pregnancies and the potential implications for fetal health.
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Affiliation(s)
- Vanya Nikolova
- Department of Women and Children's Health, Guy's CampusKing's College LondonLondonUK
| | - Alice L. Mitchell
- Department of Women and Children's Health, Guy's CampusKing's College LondonLondonUK
- Department of Metabolism, Digestion and Reproduction, Hammersmith CampusImperial College LondonLondonUK
| | - Elena Bellafante
- Department of Women and Children's Health, Guy's CampusKing's College LondonLondonUK
| | - Eugene Jansen
- Centre for Health Protection, National Institute for Public Health and the EnvironmentBilthovenThe Netherlands
| | | | - Per‐Olof Bergh
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Hanns‐Ulrich Marshall
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Catherine Williamson
- Department of Women and Children's Health, Guy's CampusKing's College LondonLondonUK
- Department of Metabolism, Digestion and Reproduction, Hammersmith CampusImperial College LondonLondonUK
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3
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Sekimoto A, Takaso Y, Saruyama H, Ookawa M, Yamamoto M, Toyohara T, Saigusa D, Fukuuchi T, Otsuka M, Fushiki Y, Yamakoshi S, Tanaka K, Ikeda T, Tanaka T, Takahashi N, Mishima E, Sato E. Impacts of low birthweight on kidney development and intergenerational growth of the offspring. iScience 2024; 27:111159. [PMID: 39524353 PMCID: PMC11546680 DOI: 10.1016/j.isci.2024.111159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 07/10/2024] [Accepted: 10/09/2024] [Indexed: 11/16/2024] Open
Abstract
Low birthweight (LBW) increases the risk of adult-onset diseases, including kidney diseases, with intergenerational consequences; however, the underlying mechanisms and effective interventions are unclear. To examine the cross-generational effects of LBW, we established an LBW mouse model through reduced uterine perfusion pressure (RUPP) and investigated the therapeutic potential of tadalafil, a phosphodiesterase 5 inhibitor, on LBW-associated consequences. RUPP-pups (R1) had lower fetal and birth weights, delayed renal development, and fewer glomeruli than Sham-pups. In adulthood, R1 mice exhibited persistently fewer glomeruli and elevated blood pressure, while Tadalafil-R1 mice showed reduced hypertension in both sexes and improved renal pathological changes in males. Additionally, pregnant R1 mice displayed inadequate gestational liver hypertrophy, impaired hepatic purine metabolism, and diminished placental angiogenesis, resulting in fetal growth restriction in the subsequent generation. These findings underscore the lasting impact of LBW on adult health and future generations and suggest tadalafil's potential to mitigate LBW-associated risks.
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Affiliation(s)
- Akiyo Sekimoto
- Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan
- Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Yoko Takaso
- Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan
| | - Haruka Saruyama
- Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan
| | - Masataka Ookawa
- Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan
| | - Mari Yamamoto
- Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan
| | - Takafumi Toyohara
- Department of Nephrology, Tohoku University Graduate School of Medicine, Sendai 983-8536, Japan
| | - Daisuke Saigusa
- Laboratory of Biomedical and Analytical Sciences, Faculty of Pharma-Science, Teikyo University, Tokyo 173-8605, Japan
| | - Tomoko Fukuuchi
- Laboratory of Biomedical and Analytical Sciences, Faculty of Pharma-Science, Teikyo University, Tokyo 173-8605, Japan
| | - Mayu Otsuka
- Laboratory of Biomedical and Analytical Sciences, Faculty of Pharma-Science, Teikyo University, Tokyo 173-8605, Japan
| | - Yui Fushiki
- Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan
| | - Seiko Yamakoshi
- Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan
| | - Kayo Tanaka
- Department of Obstetrics and Gynecology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Tomoaki Ikeda
- Department of Obstetrics and Gynecology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Tetsuhiro Tanaka
- Department of Nephrology, Tohoku University Graduate School of Medicine, Sendai 983-8536, Japan
| | - Nobuyuki Takahashi
- Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan
- Department of Nephrology, Tohoku University Graduate School of Medicine, Sendai 983-8536, Japan
| | - Eikan Mishima
- Department of Nephrology, Tohoku University Graduate School of Medicine, Sendai 983-8536, Japan
- Institute of Metabolism and Cell Death, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Emiko Sato
- Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan
- Department of Nephrology, Tohoku University Graduate School of Medicine, Sendai 983-8536, Japan
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Sousa D, Magalhães C, Matafome P, Pereira S. Adipose tissue-liver cross-talk: a route to hepatic dysfunction in pregnant women with obesity. Biosci Rep 2024; 44:BSR20231679. [PMID: 39083072 PMCID: PMC11327218 DOI: 10.1042/bsr20231679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 05/24/2024] [Accepted: 07/31/2024] [Indexed: 08/15/2024] Open
Abstract
Obesity during pregnancy has been escalating, becoming a huge problem that poses consequences not only for the health of the offspring but also for the maternal well-being. Women's adipose and hepatic tissue metabolism undergoes significant changes during the gestational period. During pregnancy, obesity is a primary instigator of steatosis, increasing the risk of non-alcholic fatty liver disease (NAFLD), now recognized under the updated nomenclature metabolic dysfunction-associated steatotic liver disease (MASLD). Pregnant women with obesity present higher levels of free fatty acids and glucose, reduction in insulin sensitivity, and adipose tissue endocrine dysregulation. Furthermore, obesity-induced modifications in clock genes and lipid-associated gene expression within adipose tissue disrupt crucial metabolic adaptations, potentially culminating in adipose tissue dysfunction. Thus, the liver experiences increased exposure to free fatty acids through the portal vein. Higher uptake of free fatty acids into the liver disrupts hepatic lipid oxidation while enhances lipogenesis, thereby predisposing to ectopic fat deposition within the liver. This review focuses on the obesity-induced changes during pregnancy in both liver and adipose tissue metabolism, elucidating how the metabolic crosstalk between these two organs can be dysregulated in pregnant women living with obesity.
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Affiliation(s)
- Diana Sousa
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- CIBB—Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3004-561 Coimbra, Portugal
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal
- Ph.D. Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal
| | - Carina C. Magalhães
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- CIBB—Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3004-561 Coimbra, Portugal
| | - Paulo Matafome
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- CIBB—Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3004-561 Coimbra, Portugal
- Polytechnic University of Coimbra, Coimbra Health School, Rua 5 de Outubro—S. Martinho do Bispo, 3046-854 Coimbra, Portugal
| | - Susana P. Pereira
- CNC-UC—Center for Neuroscience and Cell Biology, University of Coimbra,3004-504 Coimbra, Portugal
- CIBB—Centre for Innovative Biomedicine and Biotechnology, University of Coimbra; 3004-517 Coimbra, Portugal
- Laboratory of Metabolism and Exercise (LaMetEx), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Laboratory of for Integrative and Translational Research in Population Health (ITR), Faculty of Sports, University of Porto, 4200-450 Porto, Portugal
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Molinuevo R, Menendez J, Cadle K, Ariqat N, Choy MK, Lagousis C, Thomas G, Strietzel C, Bubolz JW, Hinck L. Physiological DNA damage promotes functional endoreplication of mammary gland alveolar cells during lactation. Nat Commun 2024; 15:3288. [PMID: 38627401 PMCID: PMC11021458 DOI: 10.1038/s41467-024-47668-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 04/08/2024] [Indexed: 04/19/2024] Open
Abstract
Lactation insufficiency affects many women worldwide. During lactation, a large portion of mammary gland alveolar cells become polyploid, but how these cells balance the hyperproliferation occurring during normal alveologenesis with terminal differentiation required for lactation is unknown. Here, we show that DNA damage accumulates due to replication stress during pregnancy, activating the DNA damage response. Modulation of DNA damage levels in vivo by intraductal injections of nucleosides or DNA damaging agents reveals that the degree of DNA damage accumulated during pregnancy governs endoreplication and milk production. We identify a mechanism involving early mitotic arrest through CDK1 inactivation, resulting in a heterogeneous alveolar population with regards to ploidy and nuclei number. The inactivation of CDK1 is mediated by the DNA damage response kinase WEE1 with homozygous loss of Wee1 resulting in decreased endoreplication, alveologenesis and milk production. Thus, we propose that the DNA damage response to replication stress couples proliferation and endoreplication during mammary gland alveologenesis. Our study sheds light on mechanisms governing lactogenesis and identifies non-hormonal means for increasing milk production.
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Affiliation(s)
- Rut Molinuevo
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA, 95064, USA
- Institute for the Biology of Stem Cells, University of California, Santa Cruz, CA, 95064, USA
| | - Julien Menendez
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA, 95064, USA
- Institute for the Biology of Stem Cells, University of California, Santa Cruz, CA, 95064, USA
| | - Kora Cadle
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA, 95064, USA
| | - Nabeela Ariqat
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA, 95064, USA
| | - Marie Klaire Choy
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA, 95064, USA
| | - Cayla Lagousis
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA, 95064, USA
| | - Gwen Thomas
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA, 95064, USA
| | | | - J W Bubolz
- Zoetis Inc., 333 Portage Street, Building 300, Kalamazoo, MI, 49007, USA
| | - Lindsay Hinck
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA, 95064, USA.
- Institute for the Biology of Stem Cells, University of California, Santa Cruz, CA, 95064, USA.
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6
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Alves-Silva T, Húngaro TG, Freitas-Lima LC, de Melo Arthur G, Arruda AC, Santos RB, Oyama LM, Mori MA, Bader M, Araujo RC. Kinin B1 receptor controls maternal adiponectin levels and influences offspring weight gain. iScience 2023; 26:108409. [PMID: 38058311 PMCID: PMC10696114 DOI: 10.1016/j.isci.2023.108409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 06/16/2023] [Accepted: 11/03/2023] [Indexed: 12/08/2023] Open
Abstract
Given the importance of the kinin B1 receptor in insulin and leptin hormonal regulation, which in turn is crucial in maternal adaptations to ensure nutrient supply to the fetus, we investigated the role of this receptor in maternal metabolism and fetoplacental development. Wild-type and kinin B1 receptor-deficient (B1KO) female mice were mated with male mice of the opposite genotype. Consequently, the entire litter was heterozygous for kinin B1 receptor, ensuring that there would be no influence of offspring genotype on the maternal phenotype. Maternal kinin B1 receptor blockade reduces adiponectin secretion by adipose tissue ex vivo, consistent with lower adiponectin levels in pregnant B1KO mice. Furthermore, fasting insulinemia also increased, which was associated with placental insulin resistance, reduced placental glycogen accumulation, and heavier offspring. Therefore, we propose the combination of chronic hyperinsulinemia and reduced adiponectin secretion in B1KO female mice create a maternal obesogenic environment that results in heavier pups.
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Affiliation(s)
- Thaís Alves-Silva
- Laboratory of Genetics and Exercise Metabolism, Molecular Biology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
- Max-Delbrück Center for Molecular Medicine (MDC), Campus Berlin-Buch, 13125 Berlin, Germany
| | - Talita G.R. Húngaro
- Laboratory of Genetics and Exercise Metabolism, Nephrology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
| | - Leandro C. Freitas-Lima
- Laboratory of Genetics and Exercise Metabolism, Molecular Biology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
| | - Gabriel de Melo Arthur
- Laboratory of Genetics and Exercise Metabolism, Molecular Biology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
| | - Adriano C. Arruda
- Laboratory of Genetics and Exercise Metabolism, Nephrology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
| | - Raisa B. Santos
- Laboratory of Genetics and Exercise Metabolism, Nephrology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
| | - Lila M. Oyama
- Laboratory of Nutrition and Endocrine Physiology, Physiology Department, Federal University of São Paulo (UNIFESP), São Paulo 04023-901, Brazil
| | - Marcelo A.S. Mori
- Laboratory of Aging Biology, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), São Paulo 13083-862, Brazil
| | - Michael Bader
- Max-Delbrück Center for Molecular Medicine (MDC), Campus Berlin-Buch, 13125 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Institute for Biology, University of Lübeck, Lübeck, Germany
- Charité University Medicine Berlin, Berlin, Germany
| | - Ronaldo C. Araujo
- Laboratory of Genetics and Exercise Metabolism, Molecular Biology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
- Laboratory of Genetics and Exercise Metabolism, Nephrology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
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Maiti S, Bhattacharya K, Wider D, Hany D, Panasenko O, Bernasconi L, Hulo N, Picard D. Hsf1 and the molecular chaperone Hsp90 support a 'rewiring stress response' leading to an adaptive cell size increase in chronic stress. eLife 2023; 12:RP88658. [PMID: 38059913 PMCID: PMC10703448 DOI: 10.7554/elife.88658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2023] Open
Abstract
Cells are exposed to a wide variety of internal and external stresses. Although many studies have focused on cellular responses to acute and severe stresses, little is known about how cellular systems adapt to sublethal chronic stresses. Using mammalian cells in culture, we discovered that they adapt to chronic mild stresses of up to two weeks, notably proteotoxic stresses such as heat, by increasing their size and translation, thereby scaling the amount of total protein. These adaptations render them more resilient to persistent and subsequent stresses. We demonstrate that Hsf1, well known for its role in acute stress responses, is required for the cell size increase, and that the molecular chaperone Hsp90 is essential for coupling the cell size increase to augmented translation. We term this translational reprogramming the 'rewiring stress response', and propose that this protective process of chronic stress adaptation contributes to the increase in size as cells get older, and that its failure promotes aging.
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Affiliation(s)
- Samarpan Maiti
- Département de Biologie Moléculaire et Cellulaire, Université de GenèveGenèveSwitzerland
| | - Kaushik Bhattacharya
- Département de Biologie Moléculaire et Cellulaire, Université de GenèveGenèveSwitzerland
| | - Diana Wider
- Département de Biologie Moléculaire et Cellulaire, Université de GenèveGenèveSwitzerland
| | - Dina Hany
- Département de Biologie Moléculaire et Cellulaire, Université de GenèveGenèveSwitzerland
- On leave from: Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in AlexandriaAlexandriaEgypt
| | - Olesya Panasenko
- BioCode: RNA to Proteins Core Facility, Département de Microbiologie et Médecine Moléculaire, Faculté de Médecine, Université de GenèveGenèveSwitzerland
| | - Lilia Bernasconi
- Département de Biologie Moléculaire et Cellulaire, Université de GenèveGenèveSwitzerland
| | - Nicolas Hulo
- Institute of Genetics and Genomics of Geneva, Université de GenèveGenèveSwitzerland
| | - Didier Picard
- Département de Biologie Moléculaire et Cellulaire, Université de GenèveGenèveSwitzerland
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Kozuki S, Kabata M, Sakurai S, Iwaisako K, Nishimura T, Toi M, Yamamoto T, Toyoshima F. Periportal hepatocyte proliferation at midgestation governs maternal glucose homeostasis in mice. Commun Biol 2023; 6:1226. [PMID: 38049528 PMCID: PMC10695921 DOI: 10.1038/s42003-023-05614-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 11/20/2023] [Indexed: 12/06/2023] Open
Abstract
The maternal liver is challenged by metabolic demands throughout pregnancy. However, hepatocyte dynamics and their physiological significance in pregnancy remain unclear. Here, we show in mice that hepatocyte proliferation is spatiotemporally regulated in each liver lobular zone during pregnancy, with transient proliferation of periportal and pericentral hepatocytes during mid and late gestation, respectively. Using adeno-associated virus (AAV)-8-mediated expression of the cell cycle inhibitor p21 in hepatocytes, we show that inhibition of hepatocyte proliferation during mid, but not late, gestation impairs liver growth. Transcriptionally, genes involved in glucose/glycogen metabolism are downregulated in late pregnancy when midgestational hepatocyte proliferation is attenuated. In addition, hepatic glycogen storage is abolished, with concomitant elevated blood glucose concentrations, glucose intolerance, placental glycogen deposition, and fetal overgrowth. Laser capture microdissection and RNA-seq analysis of each liver lobular zone show zone-specific changes in the transcriptome during pregnancy and identify genes that are periportally expressed at midgestation, including the hyaluronan-mediated motility receptor (Hmmr). Knockdown of Hmmr in hepatocytes by AAV8-shHmmr suppresses periportal hepatocyte proliferation at midgestation and induces impaired hepatic glycogen storage, glucose intolerance, placental glycogen deposition and fetal overgrowth. Our results suggest that periportal hepatocyte proliferation during midgestation is critical for maternal glycogen metabolism and fetal size.
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Affiliation(s)
- Satoshi Kozuki
- Department of Biosystems Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan
- Department of Mammalian and Regulatory Networks, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8502, Japan
| | - Mio Kabata
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan
| | - Satoko Sakurai
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan
| | - Keiko Iwaisako
- Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, 610-0394, Japan
- Department of Target Therapy Oncology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan
| | - Tomomi Nishimura
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan
| | - Masakazu Toi
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan
| | - Takuya Yamamoto
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
- Medical Risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, 606-8507, Japan
| | - Fumiko Toyoshima
- Department of Biosystems Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.
- Department of Mammalian and Regulatory Networks, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8502, Japan.
- Department of Homeostatic Medicine, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Yushima Bunkyo-ku, Tokyo, 113-8510, Japan.
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9
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He S, Guo Z, Zhou M, Wang H, Zhang Z, Shi M, Li X, Yang X, He L. Spatial-temporal proliferation of hepatocytes during pregnancy revealed by genetic lineage tracing. Cell Stem Cell 2023; 30:1549-1558.e5. [PMID: 37794588 DOI: 10.1016/j.stem.2023.09.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 08/04/2023] [Accepted: 09/05/2023] [Indexed: 10/06/2023]
Abstract
The maternal liver undergoes dramatic enlargement to adapt to the increased metabolic demands during pregnancy. However, the cellular sources for liver growth during pregnancy remain largely elusive. Here, we employed a proliferation recording system, ProTracer, to examine the spatial-temporal proliferation of hepatocytes during pregnancy. We discovered that during early to late pregnancy, hepatocyte proliferation initiated from zone 1, to zone 2, and lastly to zone 3, with the majority of new hepatocytes being generated in zone 2. Additionally, using single-cell RNA sequencing, we observed that Ccnd1 was highly enriched in zone 2 hepatocytes. We further applied dual-recombinase-mediated genetic lineage tracing to reveal that Ccnd1+ hepatocytes expanded preferentially during pregnancy. Moreover, we demonstrated that estrogen induces liver enlargement during pregnancy, which was abolished in Ccnd1 knockout mice. Our work revealed a unique spatial-temporal hepatocyte proliferation pattern during pregnancy, with Ccnd1+ hepatocytes in zone 2 serving as the major cellular source for hepatic enlargement.
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Affiliation(s)
- Shun He
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310030, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou 310030, Zhejiang, China; Westlake Institute for Advanced Study, Hangzhou 310030, Zhejiang, China
| | - Zhihou Guo
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310030, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou 310030, Zhejiang, China; Westlake Institute for Advanced Study, Hangzhou 310030, Zhejiang, China
| | - Mingshan Zhou
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310030, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou 310030, Zhejiang, China; Westlake Institute for Advanced Study, Hangzhou 310030, Zhejiang, China
| | - Haichang Wang
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310030, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou 310030, Zhejiang, China; Westlake Institute for Advanced Study, Hangzhou 310030, Zhejiang, China
| | - Zhuonan Zhang
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310030, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou 310030, Zhejiang, China; Westlake Institute for Advanced Study, Hangzhou 310030, Zhejiang, China
| | - Mengyang Shi
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academic of Sciences, Shanghai 200031, China
| | - Xufeng Li
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, Zhejiang, China
| | - Xueying Yang
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, Zhejiang, China
| | - Lingjuan He
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310030, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou 310030, Zhejiang, China; Westlake Institute for Advanced Study, Hangzhou 310030, Zhejiang, China.
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10
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Grilo LF, Martins JD, Diniz MS, Tocantins C, Cavallaro CH, Baldeiras I, Cunha-Oliveira T, Ford S, Nathanielsz PW, Oliveira PJ, Pereira SP. Maternal hepatic adaptations during obese pregnancy encompass lobe-specific mitochondrial alterations and oxidative stress. Clin Sci (Lond) 2023; 137:1347-1372. [PMID: 37565250 DOI: 10.1042/cs20230048] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 08/02/2023] [Accepted: 08/10/2023] [Indexed: 08/12/2023]
Abstract
Maternal obesity (MO) is rising worldwide, affecting half of all gestations, constituting a possible risk-factor for some pregnancy-associated liver diseases (PALD) and hepatic diseases. PALD occur in approximately 3% of pregnancies and are characterized by maternal hepatic oxidative stress (OS) and mitochondrial dysfunction. Maternal hepatic disease increases maternal and fetal morbidity and mortality. Understanding the role of MO on liver function and pathophysiology could be crucial for better understanding the altered pathways leading to PALD and liver disease, possibly paving the way to prevention and adequate management of disease. We investigated specific hepatic metabolic alterations in mitochondria and oxidative stress during MO at late-gestation. Maternal hepatic tissue was collected at 90% gestation in Control and MO ewes (fed 150% of recommended nutrition starting 60 days before conception). Maternal hepatic redox state, mitochondrial respiratory chain (MRC), and OS markers were investigated. MO decreased MRC complex-II activity and its subunits SDHA and SDHB protein expression, increased complex-I and complex-IV activities despite reduced complex-IV subunit mtCO1 protein expression, and increased ATP synthase ATP5A subunit. Hepatic MO-metabolic remodeling was characterized by decreased adenine nucleotide translocator 1 and 2 (ANT-1/2) and voltage-dependent anion channel (VDAC) protein expression and protein kinase A (PKA) activity (P<0.01), and augmented NAD+/NADH ratio due to reduced NADH levels (P<0.01). MO showed an altered redox state with increased OS, increased lipid peroxidation (P<0.01), decreased GSH/GSSG ratio (P=0.005), increased superoxide dismutase (P=0.03) and decreased catalase (P=0.03) antioxidant enzymatic activities, lower catalase, glutathione peroxidase (GPX)-4 and glutathione reductase protein expression (P<0.05), and increased GPX-1 abundance (P=0.03). MO-related hepatic changes were more evident in the right lobe, corroborated by the integrative data analysis. Hepatic tissue from obese pregnant ewes showed alterations in the redox state, consistent with OS and MRC and metabolism remodeling. These are hallmarks of PALD and hepatic disease, supporting MO as a risk-factor and highlighting OS and mitochondrial dysfunction as mechanisms responsible for liver disease predisposition.
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Affiliation(s)
- Luís F Grilo
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal
- Ph.D. Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal
| | - João D Martins
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal
| | - Mariana S Diniz
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal
| | - Carolina Tocantins
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal
| | - Chiara H Cavallaro
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal
| | - Inês Baldeiras
- Neurological Clinic, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Teresa Cunha-Oliveira
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal
| | - Stephen Ford
- Department of Animal Science, University of Wyoming, Laramie, WY, U.S.A
| | | | - Paulo J Oliveira
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal
| | - Susana P Pereira
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal
- Laboratory of Metabolism and Exercise (LametEx), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Laboratory for Integrative and Translational Research in Population Health (ITR), Faculty of Sport, University of Porto, Porto, Portugal
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11
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Yang L, Meng Y, Shi Y, Fang H, Zhang L. Maternal hepatic immunology during pregnancy. Front Immunol 2023; 14:1220323. [PMID: 37457700 PMCID: PMC10348424 DOI: 10.3389/fimmu.2023.1220323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 06/20/2023] [Indexed: 07/18/2023] Open
Abstract
The liver plays pivotal roles in immunologic responses, and correct hepatic adaptations in maternal immunology are required during pregnancy. In this review, we focus on anatomical and immunological maternal hepatic adaptations during pregnancy, including our recent reports in this area. Moreover, we summarize maternal pregnancy-associated liver diseases, including hyperemesis gravidarum; intrahepatic cholestasis of pregnancy; preeclampsia, specifically hemolysis, elevated liver enzymes, and low platelet count syndrome; and acute fatty liver of pregnancy. In addition, the latest information about the factors that regulate hepatic immunology during pregnancy are reviewed for the first time, including human chorionic gonadotropin, estrogen, progesterone, growth hormone, insulin like growth factor 1, oxytocin, adrenocorticotropic hormone, adrenal hormone, prolactin, melatonin and prostaglandins. In summary, the latest progress on maternal hepatic anatomy and immunological adaptations, maternal pregnancy-associated diseases and the factors that regulate hepatic immunology during pregnancy are discussed, which may be used to prevent embryo loss and abortion, as well as pregnancy-associated liver diseases.
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12
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Nambiar SM, Lee J, Yanum JA, Garcia V, Jiang H, Dai G. Maternal hepatocytes heterogeneously and dynamically exhibit developmental phenotypes partially via yes-associated protein 1 during pregnancy. Am J Physiol Gastrointest Liver Physiol 2023; 324:G38-G50. [PMID: 36283963 PMCID: PMC9799147 DOI: 10.1152/ajpgi.00197.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 10/11/2022] [Accepted: 10/21/2022] [Indexed: 02/08/2023]
Abstract
Pregnancy induces reprogramming of maternal physiology to support fetal development and growth. Maternal hepatocytes undergo hypertrophy and hyperplasia to drive maternal liver growth and alter their gene expression profiles simultaneously. This study aimed to further understand maternal hepatocyte adaptation to pregnancy. Timed pregnancies were generated in mice. In a nonpregnant state, most hepatocytes expressed Cd133, α-fetal protein (Afp) and epithelial cell adhesion molecule (Epcam) mRNAs, whereas overall, at the protein level, they exhibited a CD133-/AFP- phenotype; however, pericentral hepatocytes were EpCAM+. As pregnancy advanced, although most maternal hepatocytes retained Cd133, Afp, and Epcam mRNA expression, they generally displayed a phenotype of CD133+/AFP+, and EpCAM protein expression was switched from pericentral to periportal maternal hepatocytes. In addition, we found that the Hippo/yes-associated protein (YAP) pathway does not respond to pregnancy. Yap1 gene deletion specifically in maternal hepatocytes did not affect maternal liver growth or metabolic zonation. However, the absence of Yap1 gene eliminated CD133 protein expression without interfering with Cd133 transcript expression in maternal livers. We demonstrated that maternal hepatocytes acquire heterogeneous and dynamic developmental phenotypes, resembling fetal hepatocytes, partially via YAP1 through a posttranscriptional mechanism. Moreover, maternal liver is a new source of AFP. In addition, maternal liver grows and maintains its metabolic zonation independent of the Hippo/YAP1 pathway. Our findings revealed a novel and gestation-dependent phenotypic plasticity in adult hepatocytes.NEW & NOTEWORTHY We found that maternal hepatocytes exhibit developmental phenotypes in a temporal and spatial manner, similarly to fetal hepatocytes. They acquire this new property partially via yes-associated protein 1.
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Affiliation(s)
- Shashank Manohar Nambiar
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Joonyong Lee
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Jennifer Abla Yanum
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Veronica Garcia
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Huaizhou Jiang
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Guoli Dai
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
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13
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Liu S, Tan C, Tyers M, Zetterberg A, Kafri R. What programs the size of animal cells? Front Cell Dev Biol 2022; 10:949382. [PMID: 36393871 PMCID: PMC9665425 DOI: 10.3389/fcell.2022.949382] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 09/07/2022] [Indexed: 01/19/2023] Open
Abstract
The human body is programmed with definite quantities, magnitudes, and proportions. At the microscopic level, such definite sizes manifest in individual cells - different cell types are characterized by distinct cell sizes whereas cells of the same type are highly uniform in size. How do cells in a population maintain uniformity in cell size, and how are changes in target size programmed? A convergence of recent and historical studies suggest - just as a thermostat maintains room temperature - the size of proliferating animal cells is similarly maintained by homeostatic mechanisms. In this review, we first summarize old and new literature on the existence of cell size checkpoints, then discuss additional advances in the study of size homeostasis that involve feedback regulation of cellular growth rate. We further discuss recent progress on the molecules that underlie cell size checkpoints and mechanisms that specify target size setpoints. Lastly, we discuss a less-well explored teleological question: why does cell size matter and what is the functional importance of cell size control?
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Affiliation(s)
- Shixuan Liu
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Program in Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, United States
| | - Ceryl Tan
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Program in Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Mike Tyers
- Institute for Research in Immunology and Cancer, University of Montréal, Montréal, QC, Canada
| | - Anders Zetterberg
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Ran Kafri
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Program in Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada
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14
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Sissala N, Myllymäki E, Mohr F, Halmetoja R, Kuvaja P, Dimova EY, Koivunen P. Hypoxia ameliorates maternal diet-induced insulin resistance during pregnancy while having a detrimental effect on the placenta. Physiol Rep 2022; 10:e15302. [PMID: 35535947 PMCID: PMC9088222 DOI: 10.14814/phy2.15302] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 03/29/2022] [Accepted: 04/03/2022] [Indexed: 06/14/2023] Open
Abstract
Maternal overweight/obesity contributes significantly to the development of gestational diabetes, which causes risks to both mother and fetus and is increasing sharply in prevalence worldwide. Since hypoxia reprograms energy metabolism and can alleviate weight gain, adiposity, insulin resistance (IR), and dyslipidemia, we set out to study the potential of sustained reduced ambient oxygen tension (15% O2 ) during pregnancy for alleviating the detrimental effects of diet-induced IR in C57Bl/6N mice, taking normal chow-fed and normoxia (21% O2 ) groups as controls. Our data show that hypoxic intervention reduced maternal weight gain, adiposity, and adipose tissue inflammation, and ameliorated maternal glucose metabolism and IR during gestation in diet-induced IR relative to normoxia. Where diet-induced IR reduced maternal hemoglobin and increased serum erythropoietin levels, hypoxic intervention compensated for these changes. Diet-induced IR reduced fetal growth in normoxia, and even more in hypoxia. Hypoxic intervention reduced liver weight gain during pregnancy in the dams with diet-induced IR, maternal liver weight being positively associated with embryo number. In case of diet-induced IR, the hypoxic intervention compromised placental energy metabolism and vascularization and increased end-pregnancy placental necrosis. Altogether, these data show that although hypoxic intervention mediates several beneficial effects on maternal metabolism, the combination of it with diet-induced IR is even more detrimental to the placental and fetal outcome than diet-induced IR alone.
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Affiliation(s)
- Niina Sissala
- Biocenter Oulu and Faculty of Biochemistry and Molecular MedicineOulu Center for Cell‐Matrix ResearchUniversity of OuluOuluFinland
| | - Elisa Myllymäki
- Biocenter Oulu and Faculty of Biochemistry and Molecular MedicineOulu Center for Cell‐Matrix ResearchUniversity of OuluOuluFinland
| | - Florian Mohr
- Biocenter Oulu and Faculty of Biochemistry and Molecular MedicineOulu Center for Cell‐Matrix ResearchUniversity of OuluOuluFinland
| | - Riikka Halmetoja
- Biocenter Oulu and Faculty of Biochemistry and Molecular MedicineOulu Center for Cell‐Matrix ResearchUniversity of OuluOuluFinland
| | - Paula Kuvaja
- Finnish Institute for Health and WelfareOuluFinland
| | - Elitsa Y. Dimova
- Biocenter Oulu and Faculty of Biochemistry and Molecular MedicineOulu Center for Cell‐Matrix ResearchUniversity of OuluOuluFinland
| | - Peppi Koivunen
- Biocenter Oulu and Faculty of Biochemistry and Molecular MedicineOulu Center for Cell‐Matrix ResearchUniversity of OuluOuluFinland
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15
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Zhao P, Fan S, Gao Y, Huang M, Bi H. Nuclear Receptor-Mediated Hepatomegaly and Liver Regeneration: An Update. Drug Metab Dispos 2022; 50:636-645. [PMID: 35078806 DOI: 10.1124/dmd.121.000454] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 01/04/2022] [Indexed: 02/13/2025] Open
Abstract
Nuclear receptors (NRs), a superfamily of ligand-activated transcription factors, are critical in cell growth, proliferation, differentiation, metabolism, and numerous biologic events. NRs have been reported to play important roles in hepatomegaly (liver enlargement) and liver regeneration by regulating target genes or interacting with other signals. In this review, the roles and involved molecular mechanisms of NRs in hepatomegaly and liver regeneration are summarized and the future perspectives of NRs in the treatment of liver diseases are discussed. SIGNIFICANCE STATEMENT: NRs play critical roles in hepatomegaly and liver regeneration, indicating the potential of NRs as targets to promote liver repair after liver injury. This paper reviews the characteristics and molecular mechanisms of NRs in regulating hepatomegaly and liver regeneration, providing more evidence for NRs in the treatment of related liver diseases.
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Affiliation(s)
- Pengfei Zhao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (P.Z., S.F., Y.G., M.H., H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China (H.B.)
| | - Shicheng Fan
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (P.Z., S.F., Y.G., M.H., H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China (H.B.)
| | - Yue Gao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (P.Z., S.F., Y.G., M.H., H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China (H.B.)
| | - Min Huang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (P.Z., S.F., Y.G., M.H., H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China (H.B.)
| | - Huichang Bi
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (P.Z., S.F., Y.G., M.H., H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China (H.B.)
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16
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Fan HM, Mitchell AL, Bellafante E, McIlvride S, Primicheru LI, Giorgi M, Eberini I, Syngelaki A, Lövgren-Sandblom A, Jones P, McCance D, Sukumar N, Periyathambi N, Weldeselassie Y, Hunt KF, Nicolaides KH, Andersson D, Bevan S, Seed PT, Bewick GA, Bowe JE, Fraternali F, Saravanan P, Marschall HU, Williamson C. Sulfated Progesterone Metabolites That Enhance Insulin Secretion via TRPM3 Are Reduced in Serum From Women With Gestational Diabetes Mellitus. Diabetes 2022; 71:837-852. [PMID: 35073578 PMCID: PMC8965673 DOI: 10.2337/db21-0702] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 01/19/2022] [Indexed: 12/02/2022]
Abstract
Serum progesterone sulfates were evaluated in the etiology of gestational diabetes mellitus (GDM). Serum progesterone sulfates were measured using ultra-performance liquid chromatography-tandem mass spectrometry in four patient cohorts: 1) the Hyperglycemia and Adverse Pregnancy Outcomes study; 2) London-based women of mixed ancestry and 3) U.K.-based women of European ancestry with or without GDM; and 4) 11-13 weeks pregnant women with BMI ≤25 or BMI ≥35 kg/m2 with subsequent uncomplicated pregnancies or GDM. Glucose-stimulated insulin secretion (GSIS) was evaluated in response to progesterone sulfates in mouse islets and human islets. Calcium fluorescence was measured in HEK293 cells expressing transient receptor potential cation channel subfamily M member 3 (TRPM3). Computer modeling using Molecular Operating Environment generated three-dimensional structures of TRPM3. Epiallopregnanolone sulfate (PM5S) concentrations were reduced in GDM (P < 0.05), in women with higher fasting plasma glucose (P < 0.010), and in early pregnancy samples from women who subsequently developed GDM with BMI ≥35 kg/m2 (P < 0.05). In islets, 50 µmol/L PM5S increased GSIS by at least twofold (P < 0.001); isosakuranetin (TRPM3 inhibitor) abolished this effect. PM5S increased calcium influx in TRPM3-expressing HEK293 cells. Computer modeling and docking showed identical positioning of PM5S to the natural ligand in TRPM3. PM5S increases GSIS and is reduced in GDM serum. The activation of GSIS by PM5S is mediated by TRPM3 in both mouse and human islets.
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Affiliation(s)
- Hei Man Fan
- School of Life Course Sciences, King’s College London, London, U.K
| | | | - Elena Bellafante
- School of Life Course Sciences, King’s College London, London, U.K
| | - Saraid McIlvride
- School of Life Course Sciences, King’s College London, London, U.K
| | - Laura I. Primicheru
- Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, U.K
| | - Mirko Giorgi
- Randall Division of Cell and Molecular Biophysics, King’s College London, London, U.K
| | - Ivano Eberini
- Department of Pharmacological and Biomolecular Sciences, University of Milan La Statale, Milan, Italy
| | - Argyro Syngelaki
- School of Life Course Sciences, King’s College London, London, U.K
| | | | - Peter Jones
- School of Life Course Sciences, King’s College London, London, U.K
| | - David McCance
- Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, U.K
| | - Nithya Sukumar
- Department of Diabetes, Endocrinology and Metabolism, George Eliot Hospital, Nuneaton, U.K
- Populations, Evidence and Technologies, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, U.K
| | - Nishanthi Periyathambi
- Department of Diabetes, Endocrinology and Metabolism, George Eliot Hospital, Nuneaton, U.K
- Populations, Evidence and Technologies, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, U.K
| | - Yonas Weldeselassie
- Department of Diabetes, Endocrinology and Metabolism, George Eliot Hospital, Nuneaton, U.K
- Populations, Evidence and Technologies, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, U.K
| | | | | | - David Andersson
- Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, U.K
| | - Stuart Bevan
- Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, U.K
| | - Paul T. Seed
- School of Life Course Sciences, King’s College London, London, U.K
| | - Gavin A. Bewick
- School of Life Course Sciences, King’s College London, London, U.K
| | - James E. Bowe
- School of Life Course Sciences, King’s College London, London, U.K
| | - Franca Fraternali
- Randall Division of Cell and Molecular Biophysics, King’s College London, London, U.K
| | - Ponnusamy Saravanan
- Department of Diabetes, Endocrinology and Metabolism, George Eliot Hospital, Nuneaton, U.K
- Populations, Evidence and Technologies, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, U.K
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Catherine Williamson
- School of Life Course Sciences, King’s College London, London, U.K
- Corresponding author: Catherine Williamson,
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17
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Kim EY, Lee JM. Transcriptional Control of Trpm6 by the Nuclear Receptor FXR. Int J Mol Sci 2022; 23:ijms23041980. [PMID: 35216094 PMCID: PMC8874704 DOI: 10.3390/ijms23041980] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/03/2022] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
Farnesoid x receptor (FXR) is a nuclear bile acid receptor that belongs to the nuclear receptor superfamily. It plays an essential role in bile acid biosynthesis, lipid and glucose metabolism, liver regeneration, and vertical sleeve gastrectomy. A loss of the FXR gene or dysregulations of FXR-mediated gene expression are associated with the development of progressive familial intrahepatic cholestasis, tumorigenesis, inflammation, and diabetes mellitus. Magnesium ion (Mg2+) is essential for mammalian physiology. Over 600 enzymes are dependent on Mg2+ for their activity. Here, we show that the Trpm6 gene encoding a Mg2+ channel is a direct FXR target gene in the intestinal epithelial cells of mice. FXR expressed in the intestinal epithelial cells is absolutely required for sustaining a basal expression of intestinal Trpm6 that can be robustly induced by the treatment of GW4064, a synthetic FXR agonist. Analysis of FXR ChIP-seq data revealed that intron regions of Trpm6 contain two prominent FXR binding peaks. Among them, the proximal peak from the transcription start site contains a functional inverted repeat 1 (IR1) response element that directly binds to the FXR-RXRα heterodimer. Based on these results, we proposed that an intestinal FXR-TRPM6 axis may link a bile acid signaling to Mg2+ homeostasis.
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Affiliation(s)
- Eun Young Kim
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Korea;
| | - Jae Man Lee
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Korea;
- BK21 FOUR KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu 41944, Korea
- Correspondence: ; Tel.: +82-53-420-4826
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18
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Kozuki S, Sakurai S, Suzuki A, Yamamoto T, Toyoshima F. Delineation of biliary epithelial cell dynamics in maternal liver during pregnancy. Genes Cells 2021; 27:192-201. [PMID: 34967957 DOI: 10.1111/gtc.12918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 12/28/2021] [Accepted: 12/28/2021] [Indexed: 11/29/2022]
Abstract
In pregnant mice, the maternal liver expands drastically during gestation, which is believed to be essential to accommodate various metabolic demands caused by physiological changes and fetal growth. Although hepatocyte proliferation and hypertrophy have been reported, little is known about the dynamics of biliary epithelial cells (BECs), which comprise the bile duct epithelium in the liver. Here, we show that BECs transiently proliferate during the early stage of gestation. Lineage tracing revealed that BEC progeny were retained in the bile duct epithelium and did not differentiate into hepatocytes, indicating BEC self-replication during pregnancy. RNA-sequencing analysis of BECs identified their early pregnancy-signature transcriptomes, which highlighted Yes-associated protein (YAP) signaling-related genes. Nuclear accumulation of YAP was enhanced in BECs during pregnancy but was barely detectable in hepatocytes. In addition, the pharmacological inhibition of YAP attenuated BEC proliferation and liver weight gain during pregnancy. Our results delineate the proliferation and transcriptomic dynamics of BECs during pregnancy and suggest the relevance of YAP-mediated signals.
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Affiliation(s)
- Satoshi Kozuki
- Department of Biosystems Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.,Department of Mammalian and Regulatory Networks, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8502, Japan
| | - Satoko Sakurai
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan
| | - Atsushi Suzuki
- Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
| | - Takuya Yamamoto
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.,Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.,Medical Risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, 606-8507, Japan
| | - Fumiko Toyoshima
- Department of Biosystems Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.,Department of Mammalian and Regulatory Networks, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8502, Japan
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19
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Kobayashi S. Hepatic pseudolesions caused by alterations in intrahepatic hemodynamics. World J Gastroenterol 2021; 27:7894-7908. [PMID: 35046619 PMCID: PMC8678815 DOI: 10.3748/wjg.v27.i46.7894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/23/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatic pseudolesion may occur in contrast-enhanced computed tomography and magnetic resonance imaging due to the unique haemodynamic characteristics of the liver. The concept of hepatic arterial buffer response (HABR) has become mainstream for the understanding of the mechanism of the reciprocal effect between hepatic arterial and portal venous flow. And HABR is thought to be significantly related to the occurrence of the abnormal imaging findings on arterial phase of contrast enhanced images, such as hepatic arterial-portal vein shunt and transient hepatic attenuation difference, which mimic hypervascular tumor and may cause clinical problems. Third inflow to the liver also cause hepatic pseudolesion, and some of the cases may show histopathologic change such as focal hyperplasia, focal fatty liver, and focal sparing of fatty liver, and called pseudotumor. To understand these phenomena might be valuable for interpreting the liver imaging findings.
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Affiliation(s)
- Satoshi Kobayashi
- Department of Quantum Medical Technology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 9200942, Ishikawa, Japan
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20
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Pregnancy and weaning regulate human maternal liver size and function. Proc Natl Acad Sci U S A 2021; 118:2107269118. [PMID: 34815335 PMCID: PMC8640831 DOI: 10.1073/pnas.2107269118] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2021] [Indexed: 12/19/2022] Open
Abstract
During pregnancy, the rodent liver undergoes hepatocyte proliferation and increases in size, followed by weaning-induced involution via hepatocyte cell death and stromal remodeling, creating a prometastatic niche. These data suggest a mechanism for increased liver metastasis in breast cancer patients with recent childbirth. It is unknown whether the human liver changes in size and function during pregnancy and weaning. In this study, abdominal imaging was obtained in healthy women at early and late pregnancy and postwean. During pregnancy time points, glucose production and utilization and circulating bile acids were measured. Independently of weight gain, most women's livers increased in size with pregnancy, then returned to baseline postwean. Putative roles for bile acids in liver growth and regression were observed. Together, the data support the hypothesis that the human liver is regulated by reproductive state with growth during pregnancy and volume loss postwean. These findings have implications for sex-specific liver diseases and for breast cancer outcomes.
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21
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Ijssennagger N, van Rooijen KS, Magnúsdóttir S, Ramos Pittol JM, Willemsen ECL, de Zoete MR, Baars MJD, Stege PB, Colliva C, Pellicciari R, Youssef SA, de Bruin A, Vercoulen Y, Kuipers F, van Mil SWC. Ablation of liver Fxr results in an increased colonic mucus barrier in mice. JHEP Rep 2021; 3:100344. [PMID: 34604725 PMCID: PMC8463863 DOI: 10.1016/j.jhepr.2021.100344] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/16/2021] [Accepted: 07/22/2021] [Indexed: 12/12/2022] Open
Abstract
Background & Aims The interorgan crosstalk between the liver and the intestine has been the focus of intense research. Key in this crosstalk are bile acids, which are secreted from the liver into the intestine, interact with the microbiome, and upon absorption reach back to the liver. The bile acid-activated farnesoid X receptor (Fxr) is involved in the gut-to-liver axis. However, liver-to-gut communication and the roles of bile acids and Fxr remain elusive. Herein, we aim to get a better understanding of Fxr-mediated liver-to-gut communication, particularly in colon functioning. Methods Fxr floxed/floxed mice were crossed with cre-expressing mice to yield Fxr ablation in the intestine (Fxr-intKO), liver (Fxr-livKO), or total body (Fxr-totKO). The effects on colonic gene expression (RNA sequencing), the microbiome (16S sequencing), and mucus barrier function by ex vivo imaging were analysed. Results Despite relatively small changes in biliary bile acid concentration and composition, more genes were differentially expressed in the colons of Fxr-livKO mice than in those of Fxr-intKO and Fxr-totKO mice (3272, 731, and 1824, respectively). The colons of Fxr-livKO showed increased expression of antimicrobial genes, Toll-like receptors, inflammasome-related genes and genes belonging to the ‘Mucin-type O-glycan biosynthesis’ pathway. Fxr-livKO mice have a microbiome profile favourable for the protective capacity of the mucus barrier. The thickness of the inner sterile mucus layer was increased and colitis symptoms reduced in Fxr-livKO mice. Conclusions Targeting of FXR is at the forefront in the battle against metabolic diseases. We show that ablation of Fxr in the liver greatly impacts colonic gene expression and increased the colonic mucus barrier. Increasing the mucus barrier is of utmost importance to battle intestinal diseases such as inflammatory bowel disease, and we show that this might be done by antagonising FXR in the liver. Lay summary This study shows that the communication of the liver to the intestine is crucial for intestinal health. Bile acids are key players in this liver-to-gut communication, and when Fxr, the master regulator of bile acid homoeostasis, is ablated in the liver, colonic gene expression is largely affected, and the protective capacity of the mucus barrier is increased.
Fxr ablation in the mouse liver has a major impact on colonic gene expression. Fxr signalling is induced in the colons of liver Fxr knockout (Fxr-livKO) mice. In Fxr-livKO colons, expression of antimicrobial and mucus genes is increased. Microbiome of Fxr-livKO mice is indicative of enhanced mucus barrier function. Fxr-livKO mice have an increased mucus barrier.
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Key Words
- BAs, bile acids
- Colon
- DSS, dextran sodium sulfate
- FITC, fluorescein isothiocyanate
- Farnesoid X receptor
- Fgfr4, fibroblast growth factor receptor 4
- Fxr, farnesoid X receptor
- Fxr-intKO, intestine-specific Fxr knockout
- Fxr-livKO, liver-specific Fxr knockout
- Fxr-totKO, whole body Fxr knockout
- GO, Gene Ontology
- Gut microbiome
- HID, high-iron diamine
- IBD, inflammatory bowel disease
- Intestine-specific Fxr-KO mouse
- KEGG, Kyoto Encyclopedia of Genes and Genomes
- Liver-specific Fxr-KO mouse
- Liver–gut axis
- Mucus layer
- RT qPCR, real-time quantitative PCR
- fpkm, fragments per kilobase of transcript per million mapped reads
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Affiliation(s)
- Noortje Ijssennagger
- Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Kristel S van Rooijen
- Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Stefanía Magnúsdóttir
- Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - José M Ramos Pittol
- Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.,Institute of Biochemistry, University of Innsbruck, Innsbruck, Austria
| | - Ellen C L Willemsen
- Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Marcel R de Zoete
- Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Matthijs J D Baars
- Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Paul B Stege
- Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | | | - Sameh A Youssef
- Non-Clinical Safety, Department of Pathology, Janssen Pharmaceutica Research and Development, Beerse, Belgium
| | - Alain de Bruin
- Departments of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.,Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | - Yvonne Vercoulen
- Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Folkert Kuipers
- Departments of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Saskia W C van Mil
- Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
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22
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Garczyńska K, Tzschätzsch H, Kühl AA, Morr AS, Lilaj L, Häckel A, Schellenberger E, Berndt N, Holzhütter HG, Braun J, Sack I, Guo J. Changes in Liver Mechanical Properties and Water Diffusivity During Normal Pregnancy Are Driven by Cellular Hypertrophy. Front Physiol 2020; 11:605205. [PMID: 33329058 PMCID: PMC7719759 DOI: 10.3389/fphys.2020.605205] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 10/29/2020] [Indexed: 12/27/2022] Open
Abstract
During pregnancy, the body’s hyperestrogenic state alters hepatic metabolism and synthesis. While biochemical changes related to liver function during normal pregnancy are well understood, pregnancy-associated alterations in biophysical properties of the liver remain elusive. In this study, we investigated 26 ex vivo fresh liver specimens harvested from pregnant and non-pregnant rats by diffusion-weighted imaging (DWI) and magnetic resonance elastography (MRE) in a 0.5-Tesla compact magnetic resonance imaging (MRI) scanner. Water diffusivity and viscoelastic parameters were compared with histological data and blood markers. We found livers from pregnant rats to have (i) significantly enlarged hepatocytes (26 ± 15%, p < 0.001), (ii) increased liver stiffness (12 ± 15%, p = 0.012), (iii) decreased viscosity (−23 ± 14%, p < 0.001), and (iv) increased water diffusivity (12 ± 11%, p < 0.001). In conclusion, increased stiffness and reduced viscosity of the liver during pregnancy are mainly attributable to hepatocyte enlargement. Hypertrophy of liver cells imposes fewer restrictions on intracellular water mobility, resulting in a higher hepatic water diffusion coefficient. Collectively, MRE and DWI have the potential to inform on structural liver changes associated with pregnancy in a clinical context.
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Affiliation(s)
- Karolina Garczyńska
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Heiko Tzschätzsch
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Anja A Kühl
- iPATH.Berlin Core Unit, Charitá - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Anna Sophie Morr
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Ledia Lilaj
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Akvile Häckel
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Eyk Schellenberger
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Nikolaus Berndt
- Institute for Imaging Science and Computational Modelling in Cardiovascular Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Computational Systems Biochemistry Group, Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Hermann-Georg Holzhütter
- Computational Systems Biochemistry Group, Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Jürgen Braun
- Institute of Medical Informatics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Ingolf Sack
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Jing Guo
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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23
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Perino A, Demagny H, Velazquez-Villegas L, Schoonjans K. Molecular Physiology of Bile Acid Signaling in Health, Disease, and Aging. Physiol Rev 2020; 101:683-731. [PMID: 32790577 DOI: 10.1152/physrev.00049.2019] [Citation(s) in RCA: 251] [Impact Index Per Article: 50.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Over the past two decades, bile acids (BAs) have become established as important signaling molecules that enable fine-tuned inter-tissue communication from the liver, their site of production, over the intestine, where they are modified by the gut microbiota, to virtually any organ, where they exert their pleiotropic physiological effects. The chemical variety of BAs, to a large extent determined by the gut microbiome, also allows for a complex fine-tuning of adaptive responses in our body. This review provides an overview of the mechanisms by which BA receptors coordinate several aspects of physiology and highlights new therapeutic strategies for diseases underlying pathological BA signaling.
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Affiliation(s)
- Alessia Perino
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Hadrien Demagny
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Laura Velazquez-Villegas
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Kristina Schoonjans
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
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24
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Pataia V, McIlvride S, Papacleovoulou G, Ovadia C, McDonald JAK, Wahlström A, Jansen E, Adorini L, Shapiro D, Marchesi JR, Marschall HU, Williamson C. Obeticholic acid improves fetal bile acid profile in a mouse model of gestational hypercholanemia. Am J Physiol Gastrointest Liver Physiol 2020; 319:G197-G211. [PMID: 32597707 PMCID: PMC7500267 DOI: 10.1152/ajpgi.00126.2020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated maternal circulating bile acid levels and associated dyslipidemia. ICP leads to accumulation of bile acids in the fetal compartment, and the elevated bile acid concentrations are associated with an increased risk of adverse fetal outcomes. The farnesoid X receptor agonist obeticholic acid (OCA) is efficient in the treatment of cholestatic conditions such as primary biliary cholangitis. We hypothesized that OCA administration during hypercholanemic pregnancy will improve maternal and fetal bile acid and lipid profiles. Female C57BL/6J mice were fed either a normal chow diet, a 0.5% cholic acid (CA)-supplemented diet, a 0.03% OCA-supplemented diet, or a 0.5% CA + 0.03% OCA-supplemented diet for 1 wk before mating and throughout pregnancy until euthanization on day 18. The effects of CA and OCA feeding on maternal and fetal morphometry, bile acid and lipid levels, and cecal microbiota were investigated. OCA administration during gestation did not alter the maternal or fetal body weight or organ morphometry. OCA treatment during hypercholanemic pregnancy reduced bile acid levels in the fetal compartment. However, fetal dyslipidemia was not reversed, and OCA did not impact maternal bile acid levels or dyslipidemia. In conclusion, OCA administration during gestation had no apparent detrimental impact on maternal or fetal morphometry and improved fetal hypercholanemia. Because high serum bile acid concentrations in ICP are associated with increased rates of adverse fetal outcomes, further investigations into the potential use of OCA during cholestatic gestation are warranted.NEW & NOTEWORTHY We used a mouse model of gestational hypercholanemia to investigate the use of obeticholic acid (OCA), a potent FXR agonist, as a treatment for the hypercholanemia of intrahepatic cholestasis of pregnancy (ICP). The results demonstrate that OCA can improve the fetal bile acid profile. This is relevant not only to women with ICP but also for women who become pregnant while receiving OCA treatment for other conditions such as primary biliary cholangitis and nonalcoholic steatohepatitis.
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Affiliation(s)
- Vanessa Pataia
- 1Department of Women and Children’s Health, King’s College London, London, United Kingdom
| | - Saraid McIlvride
- 1Department of Women and Children’s Health, King’s College London, London, United Kingdom
| | - Georgia Papacleovoulou
- 1Department of Women and Children’s Health, King’s College London, London, United Kingdom
| | - Caroline Ovadia
- 1Department of Women and Children’s Health, King’s College London, London, United Kingdom
| | - Julie A. K. McDonald
- 2MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
| | - Annika Wahlström
- 3Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Eugène Jansen
- 4Centre for Health Protection, National Institute for Public Health and the Environment, Bilthoven, The Netherlands
| | | | | | - Julian R. Marchesi
- 6Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom,7School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Hanns-Ulrich Marschall
- 3Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Catherine Williamson
- 1Department of Women and Children’s Health, King’s College London, London, United Kingdom
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25
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Bellafante E, McIlvride S, Nikolova V, Fan HM, Manna LB, Chambers J, Machirori M, Banerjee A, Murphy K, Martineau M, Schoonjans K, Marschall HU, Jones P, Williamson C. Maternal glucose homeostasis is impaired in mouse models of gestational cholestasis. Sci Rep 2020; 10:11523. [PMID: 32661285 PMCID: PMC7359298 DOI: 10.1038/s41598-020-67968-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 05/28/2020] [Indexed: 12/13/2022] Open
Abstract
Women with intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by raised serum bile acids, are at increased risk of developing gestational diabetes mellitus and have impaired glucose tolerance whilst cholestatic. FXR and TGR5 are modulators of glucose metabolism, and FXR activity is reduced in normal pregnancy, and further in ICP. We aimed to investigate the role of raised serum bile acids, FXR and TGR5 in gestational glucose metabolism using mouse models. Cholic acid feeding resulted in reduced pancreatic β-cell proliferation and increased apoptosis in pregnancy, without altering insulin sensitivity, suggesting that raised bile acids affect β-cell mass but are insufficient to impair glucose tolerance. Conversely, pregnant Fxr-/- and Tgr5-/- mice are glucose intolerant and have reduced insulin secretion in response to glucose challenge, and Fxr-/- mice are also insulin resistant. Furthermore, fecal bile acids are reduced in pregnant Fxr-/- mice. Lithocholic acid and deoxycholic acid, the principal ligands for TGR5, are decreased in particular. Therefore, we propose that raised serum bile acids and reduced FXR and TGR5 activity contribute to the altered glucose metabolism observed in ICP.
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MESH Headings
- Animals
- Bile Acids and Salts/blood
- Cholestasis, Intrahepatic/blood
- Cholestasis, Intrahepatic/genetics
- Cholestasis, Intrahepatic/metabolism
- Cholestasis, Intrahepatic/pathology
- Diabetes, Gestational/blood
- Diabetes, Gestational/genetics
- Diabetes, Gestational/metabolism
- Diabetes, Gestational/pathology
- Disease Models, Animal
- Female
- Glucose/metabolism
- Glucose Intolerance/genetics
- Glucose Intolerance/metabolism
- Glucose Intolerance/pathology
- Homeostasis/genetics
- Humans
- Insulin Resistance/genetics
- Insulin-Secreting Cells/metabolism
- Insulin-Secreting Cells/pathology
- Maternal Inheritance/genetics
- Mice
- Pregnancy
- Pregnancy Complications/blood
- Pregnancy Complications/genetics
- Pregnancy Complications/metabolism
- Pregnancy Complications/pathology
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, G-Protein-Coupled/genetics
- Risk Factors
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Affiliation(s)
- Elena Bellafante
- School of Life Course Sciences, King's College London, London, UK
| | - Saraid McIlvride
- School of Life Course Sciences, King's College London, London, UK
| | - Vanya Nikolova
- School of Life Course Sciences, King's College London, London, UK
| | - Hei Man Fan
- School of Life Course Sciences, King's College London, London, UK
| | | | - Jenny Chambers
- School of Life Course Sciences, King's College London, London, UK
- Women's Health Research Centre, Imperial College London, London, UK
| | - Mavis Machirori
- Women's Health Research Centre, Imperial College London, London, UK
| | | | - Kevin Murphy
- Department of Medicine, Imperial College London, London, UK
| | - Marcus Martineau
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Kristina Schoonjans
- Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Peter Jones
- School of Life Course Sciences, King's College London, London, UK
| | - Catherine Williamson
- School of Life Course Sciences, King's College London, London, UK.
- Maternal and Fetal Disease Group, Hodgkin Building, Guy's Campus, King's College London, London, SE1 1UL, UK.
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26
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You S, Cui AM, Hashmi SF, Zhang X, Nadolny C, Chen Y, Chen Q, Bush X, Hurd Z, Ali W, Qin G, Deng R. Dysregulation of bile acids increases the risk for preterm birth in pregnant women. Nat Commun 2020; 11:2111. [PMID: 32355283 PMCID: PMC7193585 DOI: 10.1038/s41467-020-15923-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 04/03/2020] [Indexed: 12/13/2022] Open
Abstract
Preterm birth (PTB) is the leading cause of perinatal mortality and newborn complications. Bile acids are recognized as signaling molecules regulating a myriad of cellular and metabolic activities but have not been etiologically linked to PTB. In this study, a hospital-based cohort study with 36,755 pregnant women is conducted. We find that serum total bile acid levels directly correlate with the PTB rates regardless of the characteristics of the subjects and etiologies of liver disorders. Consistent with the findings from pregnant women, PTB is successfully reproduced in mice with liver injuries and dysregulated bile acids. More importantly, bile acids dose-dependently induce PTB with minimal hepatotoxicity. Furthermore, restoring bile acid homeostasis by farnesoid X receptor activation markedly reduces PTB and dramatically improves newborn survival rates. The findings thus establish an etiologic link between bile acids and PTB, and open an avenue for developing etiology-based therapies to prevent or delay PTB.
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Affiliation(s)
- Sangmin You
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Ai-Min Cui
- Nantong Maternal and Child Health Hospital, Nantong University, Nantong, China
| | - Syed F Hashmi
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Xinmu Zhang
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Christina Nadolny
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Yuan Chen
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Qiwen Chen
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Xin Bush
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Zachary Hurd
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Winifer Ali
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Gang Qin
- Department of Epidemiology and Biostatistics, School of Public Health, Nantong University, 226006, Nantong, Jiangsu Province, China
| | - Ruitang Deng
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA.
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Lee J, Garcia V, Nambiar SM, Jiang H, Dai G. Pregnancy facilitates maternal liver regeneration after partial hepatectomy. Am J Physiol Gastrointest Liver Physiol 2020; 318:G772-G780. [PMID: 32003603 PMCID: PMC7191459 DOI: 10.1152/ajpgi.00125.2019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver resection induces robust liver regrowth or regeneration to compensate for the lost tissue mass. In a clinical setting, pregnant women may need liver resection without terminating pregnancy in some cases. However, how pregnancy affects maternal liver regeneration remains elusive. We performed 70% partial hepatectomy (PH) in nonpregnant mice and gestation day 14 mice, and histologically and molecularly compared their liver regrowth during the next 4 days. We found that compared with the nonpregnant state, pregnancy altered the molecular programs driving hepatocyte replication, indicated by enhanced activities of epidermal growth factor receptor and STAT5A, reduced activities of cMet and p70S6K, decreased production of IL-6, TNFα, and hepatocyte growth factor, suppressed cyclin D1 expression, increased cyclin A1 expression, and early activated cyclin A2 expression. As a result, pregnancy allowed the remnant hepatocytes to enter the cell cycle at least 12 h earlier, increased hepatic fat accumulation, and enhanced hepatocyte mitosis. Consequently, pregnancy ameliorated maternal liver regeneration following PH. In addition, a report showed that maternal liver regrowth after PH is driven mainly by hepatocyte hypertrophy rather than hyperplasia during the second half of gestation in young adult mice. In contrast, we demonstrate that maternal liver relies mainly on hepatocyte hyperplasia instead of hypertrophy to restore the lost mass after PH. Overall, we demonstrate that pregnancy facilitates maternal liver regeneration likely via triggering an early onset of hepatocyte replication, accumulating excessive liver fat, and promoting hepatocyte mitosis. The results from our current studies enable us to gain more insights into how maternal liver regeneration progresses during gestation.NEW & NOTEWORTHY We demonstrate that pregnancy may generate positive effects on maternal liver regeneration following partial hepatectomy, which are manifested by early entry of the cell cycle of remnant hepatocytes, increased hepatic fat accumulation, enhanced hepatocyte mitosis, and overall accelerated liver regrowth.
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Affiliation(s)
- Joonyong Lee
- 1Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Veronica Garcia
- 1Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Shashank Manohar Nambiar
- 1Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Huaizhou Jiang
- 1Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana,2School of Traditional Chinese Medicine, Anhui University of Chinese Medicine, Anhui, China
| | - Guoli Dai
- 1Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
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The Hepatobiliary System: An Overview of Normal Function and Diagnostic Testing in Pregnancy. Clin Obstet Gynecol 2019; 63:122-133. [PMID: 31770121 DOI: 10.1097/grf.0000000000000504] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Pregnancy is associated with physiological adaptions that affect every organ system. Changes in liver function in pregnancy have important effects on nutrient metabolism, protein synthesis, and the biotransformation of substances in preparation for excretion. A clear understanding of the anatomic and functional changes of the hepatobiliary system is necessary for the diagnosis and evaluation of disease, as well as understanding how these changes predispose women to pregnancy-specific hepatic conditions. In this review, the effect of gestational changes in hepatobiliary function on laboratory tests and the role of diagnostic imaging of the liver and gallbladder in pregnancy will be discussed.
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McIlvride S, Nikolova V, Fan HM, McDonald JAK, Wahlström A, Bellafante E, Jansen E, Adorini L, Shapiro D, Jones P, Marchesi JR, Marschall HU, Williamson C. Obeticholic acid ameliorates dyslipidemia but not glucose tolerance in mouse model of gestational diabetes. Am J Physiol Endocrinol Metab 2019; 317:E399-E410. [PMID: 31237448 PMCID: PMC6732461 DOI: 10.1152/ajpendo.00407.2018] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 05/21/2019] [Accepted: 06/18/2019] [Indexed: 12/14/2022]
Abstract
Metabolism alters markedly with advancing gestation, characterized by progressive insulin resistance, dyslipidemia, and raised serum bile acids. The nuclear receptor farnesoid X receptor (FXR) has an integral role in bile acid homeostasis and modulates glucose and lipid metabolism. FXR is known to be functionally suppressed in pregnancy. The FXR agonist, obeticholic acid (OCA), improves insulin sensitivity in patients with type 2 diabetes with nonalcoholic fatty liver disease. We therefore hypothesized that OCA treatment during pregnancy could improve disease severity in a mouse model of gestational diabetes mellitus (GDM). C57BL/6J mice were fed a high-fat diet (HFD; 60% kcal from fat) for 4 wk before and throughout pregnancy to induce GDM. The impact of the diet supplemented with 0.03% OCA throughout pregnancy was studied. Pregnant HFD-fed mice displayed insulin resistance and dyslipidemia. OCA significantly reduced plasma cholesterol concentrations in nonpregnant and pregnant HFD-fed mice (by 22.4%, P < 0.05 and 36.4%, P < 0.001, respectively) and reduced the impact of pregnancy on insulin resistance but did not change glucose tolerance. In nonpregnant HFD-fed mice, OCA ameliorated weight gain, reduced mRNA expression of inflammatory markers in white adipose tissue, and reduced plasma glucagon-like peptide 1 concentrations (by 62.7%, P < 0.01). However, these effects were not evident in pregnant mice. OCA administration can normalize plasma cholesterol levels in a mouse model of GDM. However, the absence of several of the effects of OCA in pregnant mice indicates that the agonistic action of OCA is not sufficient to overcome many metabolic consequences of the pregnancy-associated reduction in FXR activity.
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Affiliation(s)
- Saraid McIlvride
- School of Life Course Sciences, King's College London, London, United Kingdom
| | - Vanya Nikolova
- School of Life Course Sciences, King's College London, London, United Kingdom
| | - Hei Man Fan
- School of Life Course Sciences, King's College London, London, United Kingdom
| | - Julie A K McDonald
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Annika Wahlström
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Elena Bellafante
- School of Life Course Sciences, King's College London, London, United Kingdom
| | - Eugene Jansen
- National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | | | | | - Peter Jones
- School of Life Course Sciences, King's College London, London, United Kingdom
| | - Julian R Marchesi
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
- School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
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Ovadia C, Perdones‐Montero A, Spagou K, Smith A, Sarafian MH, Gomez‐Romero M, Bellafante E, Clarke LC, Sadiq F, Nikolova V, Mitchell A, Dixon PH, Santa‐Pinter N, Wahlström A, Abu‐Hayyeh S, Walters JR, Marschall H, Holmes E, Marchesi JR, Williamson C. Enhanced Microbial Bile Acid Deconjugation and Impaired Ileal Uptake in Pregnancy Repress Intestinal Regulation of Bile Acid Synthesis. Hepatology 2019; 70:276-293. [PMID: 30983011 PMCID: PMC6619257 DOI: 10.1002/hep.30661] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 02/28/2019] [Indexed: 01/05/2023]
Abstract
Pregnancy is associated with progressive hypercholanemia, hypercholesterolemia, and hypertriglyceridemia, which can result in metabolic disease in susceptible women. Gut signals modify hepatic homeostatic pathways, linking intestinal content to metabolic activity. We sought to identify whether enteric endocrine signals contribute to raised serum bile acids observed in human and murine pregnancies, by measuring fibroblast growth factor (FGF) 19/15 protein and mRNA levels, and 7α-hydroxy-4-cholesten-3-one. Terminal ileal farnesoid X receptor (FXR)-mediated gene expression and apical sodium bile acid transporter (ASBT) protein concentration were measured by qPCR and western blotting. Shotgun whole-genome sequencing and ultra-performance liquid chromatography tandem mass spectrometry were used to determine the cecal microbiome and metabonome. Targeted and untargeted pathway analyses were performed to predict the systemic effects of the altered metagenome and metabolite profiles. Dietary CA supplementation was used to determine whether the observed alterations could be overcome by intestinal bile acids functioning as FXR agonists. Human and murine pregnancy were associated with reduced intestinal FXR signaling, with lower FGF19/15 and resultant increased hepatic bile acid synthesis. Terminal ileal ASBT protein was reduced in murine pregnancy. Cecal bile acid conjugation was reduced in pregnancy because of elevated bile salt hydrolase-producing Bacteroidetes. CA supplementation induced intestinal FXR signaling, which was not abrogated by pregnancy, with strikingly similar changes to the microbiota and metabonome as identified in pregnancy. Conclusion: The altered intestinal microbiota of pregnancy enhance bile acid deconjugation, reducing ileal bile acid uptake and lowering FXR induction in enterocytes. This exacerbates the effects mediated by reduced bile acid uptake transporters in pregnancy. Thus, in pregnant women and mice, there is reduced FGF19/15-mediated hepatic repression of hepatic bile acid synthesis, resulting in hypercholanemia.
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Affiliation(s)
- Caroline Ovadia
- Division of Women and Children's HealthKing's College LondonLondonUnited Kingdom
| | - Alvaro Perdones‐Montero
- Section of Biomolecular Medicine, Division of Computational & Systems Medicine, Department of Surgery & Cancer, Faculty of MedicineImperial College LondonLondonUnited Kingdom
| | - Konstantina Spagou
- Section of Biomolecular Medicine, Division of Computational & Systems Medicine, Department of Surgery & Cancer, Faculty of MedicineImperial College LondonLondonUnited Kingdom
| | - Ann Smith
- School of BiosciencesCardiff UniversityCardiffUnited Kingdom
| | - Magali H. Sarafian
- Section of Biomolecular Medicine, Division of Computational & Systems Medicine, Department of Surgery & Cancer, Faculty of MedicineImperial College LondonLondonUnited Kingdom
| | - Maria Gomez‐Romero
- Section of Biomolecular Medicine, Division of Computational & Systems Medicine, Department of Surgery & Cancer, Faculty of MedicineImperial College LondonLondonUnited Kingdom
| | - Elena Bellafante
- Division of Women and Children's HealthKing's College LondonLondonUnited Kingdom
| | - Louise C.D. Clarke
- Division of Women and Children's HealthKing's College LondonLondonUnited Kingdom
| | - Fouzia Sadiq
- Division of Digestive DiseasesHammersmith Hospital, Imperial College LondonLondonUnited Kingdom
| | - Vanya Nikolova
- Division of Women and Children's HealthKing's College LondonLondonUnited Kingdom
| | - Alice Mitchell
- Division of Women and Children's HealthKing's College LondonLondonUnited Kingdom
| | - Peter H. Dixon
- Division of Women and Children's HealthKing's College LondonLondonUnited Kingdom
| | - Natalie Santa‐Pinter
- Division of Women and Children's HealthKing's College LondonLondonUnited Kingdom
| | - Annika Wahlström
- Institute of Medicine, Department of Molecular and Clinical Medicine and Wallenberg LaboratoryUniversity of GothenburgGothenburgSweden
| | - Shadi Abu‐Hayyeh
- Division of Women and Children's HealthKing's College LondonLondonUnited Kingdom
| | - Julian R.F. Walters
- Division of Digestive DiseasesHammersmith Hospital, Imperial College LondonLondonUnited Kingdom
| | - Hanns‐Ulrich Marschall
- Institute of Medicine, Department of Molecular and Clinical Medicine and Wallenberg LaboratoryUniversity of GothenburgGothenburgSweden
| | - Elaine Holmes
- Section of Biomolecular Medicine, Division of Computational & Systems Medicine, Department of Surgery & Cancer, Faculty of MedicineImperial College LondonLondonUnited Kingdom
| | - Julian R. Marchesi
- School of BiosciencesCardiff UniversityCardiffUnited Kingdom,Centre for Digestive and Gut Health, Department of Surgery and CancerImperial College LondonLondonUnited Kingdom
| | - Catherine Williamson
- Division of Women and Children's HealthKing's College LondonLondonUnited Kingdom
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31
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Wu W, Wu Q, Liu X. Chronic activation of FXR-induced liver growth with tissue-specific targeting Cyclin D1. Cell Cycle 2019; 18:1784-1797. [PMID: 31223053 DOI: 10.1080/15384101.2019.1634955] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The nuclear receptor (FXR) plays essential roles in maintaining bile acid and lipid homeostasis by regulating diverse target genes. And its agonists were promising agents for treating various liver diseases. Nevertheless, the potential side effect of chronic FXR activation by specific agonists is not fully understood. In this study, we investigated the mechanism of FXR agonist WAY-362450 induced liver enlargement during treating liver diseases. We demonstrated that chronic ingestion of WAY-362450 induced liver hypertrophy instead of hyperplasia in mouse. Global transcriptional pattern was also examined in mouse livers after treatment with WAY-362450 by RNA-seq assay. Through GO and KEGG enrichment analyses, we demonstrated that the expression of Cyclin D1 (Ccnd1) among the cell cycle-regulating genes was notably increased in WAY-362450-treated mouse liver. Activation of FXR-induced Ccnd1 expression in hepatocyte in a time-dependent manner in vivo and in vitro. Through bioinformatics analysis and ChIP assay, we identified FXR as a direct transcriptional activator of Ccnd1 through binding to a potential enhancer, which was specifically active in livers. We also found active histone acetylation was essential for Ccnd1 induction by FXR. Thus, our study indicated that activation of FXR-induced harmless liver hypertrophy with spatiotemporal modulation of Ccnd1. With a better understanding of the mechanism of tissue-specific gene regulation by FXR, it is beneficial for development and appropriate application of its specific agonist in preventing hepatic diseases.
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Affiliation(s)
- Weibin Wu
- a The International Peace Maternity and Child Health Hospital, School of Medicine , Shanghai Jiao Tong University , Shanghai , China.,b Shanghai Key Laboratory of Embryo Original Diseases , Shanghai , China.,c Shanghai Municipal Key Clinical Specialty , Shanghai , China
| | - Qing Wu
- d Department of Gynecology and Obstetrics , Central Hospital of Minhang District , Shanghai , China
| | - Xinmei Liu
- a The International Peace Maternity and Child Health Hospital, School of Medicine , Shanghai Jiao Tong University , Shanghai , China.,b Shanghai Key Laboratory of Embryo Original Diseases , Shanghai , China.,c Shanghai Municipal Key Clinical Specialty , Shanghai , China
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32
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Tsugawa Y, Hiramoto M, Imai T. Estrogen induces estrogen receptor α expression and hepatocyte proliferation in late pregnancy. Biochem Biophys Res Commun 2019; 511:592-596. [DOI: 10.1016/j.bbrc.2019.02.119] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 02/21/2019] [Indexed: 10/27/2022]
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Quinn MA, McCalla A, He B, Xu X, Cidlowski JA. Silencing of maternal hepatic glucocorticoid receptor is essential for normal fetal development in mice. Commun Biol 2019; 2:104. [PMID: 30911679 PMCID: PMC6420645 DOI: 10.1038/s42003-019-0344-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 01/17/2019] [Indexed: 12/19/2022] Open
Abstract
Excessive or chronic stress can lead to a variety of diseases due to aberrant activation of the glucocorticoid receptor (GR), a ligand activated transcription factor. Pregnancy represents a particular window of sensitivity in which excessive stress can have adverse outcomes, particularly on the developing fetus. Here we show maternal hepatic stress hormone responsiveness is diminished via epigenetic silencing of the glucocorticoid receptor during pregnancy. Provocatively, reinstallation of GR to hepatocytes during pregnancy by adeno-associated viral transduction dysregulates genes involved in proliferation, resulting in impaired pregnancy-induced hepatomegaly. Disruption of the maternal hepatic adaptation to pregnancy results in in utero growth restriction (IUGR). These data demonstrate pregnancy antagonizes the liver-specific effects of stress hormone signaling in the maternal compartment to ultimately support the healthy development of embryos.
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Affiliation(s)
- Matthew A. Quinn
- Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina 27517 USA
| | - Amy McCalla
- Signal Transduction Laboratory, Research Triangle Park, North Carolina USA
| | - Bo He
- Signal Transduction Laboratory, Research Triangle Park, North Carolina USA
| | - Xiaojiang Xu
- Laboratory of Integrative Bioinformatics, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709 USA
| | - John A. Cidlowski
- Signal Transduction Laboratory, Research Triangle Park, North Carolina USA
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Baptissart M, Martinot E, Vega A, Sédes L, Rouaisnel B, de Haze A, Baron S, Schoonjans K, Caira F, Volle DH. Bile acid-FXRα pathways regulate male sexual maturation in mice. Oncotarget 2017; 7:19468-82. [PMID: 26848619 PMCID: PMC4991395 DOI: 10.18632/oncotarget.7153] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 01/22/2016] [Indexed: 12/21/2022] Open
Abstract
The bile acid receptor Farnesol-X-Receptor alpha (FRXα) is a member of the nuclear receptor superfamily. FRXα is expressed in the interstitial compartment of the adult testes, which contain the Leydig cells. In adult, short term treatment (12 hours) with FRXα agonist inhibits the expression of steroidogenic genes via the induction of the Small heterodimer partner (SHP). However the consequences of FRXα activation on testicular pathophysiology have never been evaluated. We demonstrate here that mice fed a diet supplemented with bile acid during pubertal age show increased incidence of infertility. This is associated with altered differentiation and increase apoptosis of germ cells due to lower testosterone levels. At the molecular level, next to the repression of basal steroidogenesis via the induction expression of Shp and Dax-1, two repressors of steroidogenesis, the main action of the BA-FRXα signaling is through lowering the Leydig cell sensitivity to the hypothalamo-pituitary axis, the main regulator of testicular endocrine function. In conclusion, BA-FRXα signaling is a critical actor during sexual maturation.
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Affiliation(s)
- Marine Baptissart
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Emmanuelle Martinot
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Aurélie Vega
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Lauriane Sédes
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Betty Rouaisnel
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Angélique de Haze
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Silvère Baron
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Kristina Schoonjans
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Françoise Caira
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - David H Volle
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
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Martinot E, Sèdes L, Baptissart M, Holota H, Rouaisnel B, Damon-Soubeyrand C, De Haze A, Saru JP, Thibault-Carpentier C, Keime C, Lobaccaro JMA, Baron S, Benoit G, Caira F, Beaudoin C, Volle DH. The Bile Acid Nuclear Receptor FXRα Is a Critical Regulator of Mouse Germ Cell Fate. Stem Cell Reports 2017; 9:315-328. [PMID: 28669602 PMCID: PMC5511114 DOI: 10.1016/j.stemcr.2017.05.036] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 05/31/2017] [Accepted: 05/31/2017] [Indexed: 12/14/2022] Open
Abstract
Spermatogenesis is the process by which spermatozoa are generated from spermatogonia. This cell population is heterogeneous, with self-renewing spermatogonial stem cells (SSCs) and progenitor spermatogonia that will continue on a path of differentiation. Only SSCs have the ability to regenerate and sustain spermatogenesis. This makes the testis a good model to investigate stem cell biology. The Farnesoid X Receptor alpha (FXRα) was recently shown to be expressed in the testis. However, its global impact on germ cell homeostasis has not yet been studied. Here, using a phenotyping approach in Fxrα−/− mice, we describe unexpected roles of FXRα on germ cell physiology independent of its effects on somatic cells. FXRα helps establish and maintain an undifferentiated germ cell pool and in turn influences male fertility. FXRα regulates the expression of several pluripotency factors. Among these, in vitro approaches show that FXRα controls the expression of the pluripotency marker Lin28 in the germ cells.
FXRα regulated germ cell apoptotis independently of androgen homeostasis FXRα controls germ cell differentiation FXRα regulates the establishment and maintenance of undifferentiated germ cells In germ cells, FXRα controls the expression of pluripotency markers such as Lin28
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Affiliation(s)
- Emmanuelle Martinot
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France
| | - Lauriane Sèdes
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France
| | - Marine Baptissart
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France
| | - Hélène Holota
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France
| | - Betty Rouaisnel
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France
| | - Christelle Damon-Soubeyrand
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France; Centre de Recherche en Nutrition Humaine d'Auvergne, 63000 Clermont-Ferrand, France
| | - Angélique De Haze
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France; Centre de Recherche en Nutrition Humaine d'Auvergne, 63000 Clermont-Ferrand, France
| | - Jean-Paul Saru
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France; Centre de Recherche en Nutrition Humaine d'Auvergne, 63000 Clermont-Ferrand, France
| | | | - Céline Keime
- IGBMC - CNRS UMR 7104 - Inserm U 964, 1 BP 10142, 67404 Illkirch Cedex, France
| | - Jean-Marc A Lobaccaro
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France; Centre de Recherche en Nutrition Humaine d'Auvergne, 63000 Clermont-Ferrand, France
| | - Silvère Baron
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France; Centre de Recherche en Nutrition Humaine d'Auvergne, 63000 Clermont-Ferrand, France
| | - Gérard Benoit
- Laboratoire de Biologie Moléculaire de la Cellule, Ecole normale supérieure de Lyon, UMR5239 CNRS/ENS Lyon/UCBL/HCL, 46, allée d'Italie, 69364 Lyon Cedex 07, France
| | - Françoise Caira
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France
| | - Claude Beaudoin
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France
| | - David H Volle
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France.
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Massafra V, Milona A, Vos HR, Ramos RJJ, Gerrits J, Willemsen ECL, Ramos Pittol JM, Ijssennagger N, Houweling M, Prinsen HCMT, Verhoeven-Duif NM, Burgering BMT, van Mil SWC. Farnesoid X Receptor Activation Promotes Hepatic Amino Acid Catabolism and Ammonium Clearance in Mice. Gastroenterology 2017; 152:1462-1476.e10. [PMID: 28130067 DOI: 10.1053/j.gastro.2017.01.014] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 01/09/2017] [Accepted: 01/17/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The nuclear receptor subfamily 1 group H member 4 (NR1H4 or farnesoid X receptor [FXR]) regulates bile acid synthesis, transport, and catabolism. FXR also regulates postprandial lipid and glucose metabolism. We performed quantitative proteomic analyses of liver tissues from mice to evaluate these functions and investigate whether FXR regulates amino acid metabolism. METHODS To study the role of FXR in mouse liver, we used mice with a disruption of Nr1h4 (FXR-knockout mice) and compared them with floxed control mice. Mice were gavaged with the FXR agonist obeticholic acid or vehicle for 11 days. Proteome analyses, as well as targeted metabolomics and chromatin immunoprecipitation, were performed on the livers of these mice. Primary rat hepatocytes were used to validate the role of FXR in amino acid catabolism by gene expression and metabolomics studies. Finally, control mice and mice with liver-specific disruption of Nr1h4 (liver FXR-knockout mice) were re-fed with a high-protein diet after 6 hours fasting and gavaged a 15NH4Cl tracer. Gene expression and the metabolome were studied in the livers and plasma from these mice. RESULTS In livers of control mice and primary rat hepatocytes, activation of FXR with obeticholic acid increased expression of proteins that regulate amino acid degradation, ureagenesis, and glutamine synthesis. We found FXR to bind to regulatory sites of genes encoding these proteins in control livers. Liver tissues from FXR-knockout mice had reduced expression of urea cycle proteins, and accumulated precursors of ureagenesis, compared with control mice. In liver FXR-knockout mice on a high-protein diet, the plasma concentration of newly formed urea was significantly decreased compared with controls. In addition, liver FXR-knockout mice had reduced hepatic expression of enzymes that regulate ammonium detoxification compared with controls. In contrast, obeticholic acid increased expression of genes encoding enzymes involved in ureagenesis compared with vehicle in C57Bl/6 mice. CONCLUSIONS In livers of mice, FXR regulates amino acid catabolism and detoxification of ammonium via ureagenesis and glutamine synthesis. Failure of the urea cycle and hyperammonemia are common in patients with acute and chronic liver diseases; compounds that activate FXR might promote ammonium clearance in these patients.
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Affiliation(s)
- Vittoria Massafra
- Center for Molecular Medicine, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
| | - Alexandra Milona
- Center for Molecular Medicine, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
| | - Harmjan R Vos
- Center for Molecular Medicine, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
| | - Rúben J J Ramos
- Department of Genetics, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
| | - Johan Gerrits
- Center for Molecular Medicine, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands; Department of Genetics, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
| | - Ellen C L Willemsen
- Center for Molecular Medicine, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
| | - José M Ramos Pittol
- Center for Molecular Medicine, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
| | - Noortje Ijssennagger
- Center for Molecular Medicine, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
| | - Martin Houweling
- Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | | | - Nanda M Verhoeven-Duif
- Center for Molecular Medicine, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands; Department of Genetics, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
| | - Boudewijn M T Burgering
- Center for Molecular Medicine, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
| | - Saskia W C van Mil
- Center for Molecular Medicine, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands.
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Della Torre S, Maggi A. Sex Differences: A Resultant of an Evolutionary Pressure? Cell Metab 2017; 25:499-505. [PMID: 28190772 DOI: 10.1016/j.cmet.2017.01.006] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Revised: 11/27/2016] [Accepted: 01/11/2017] [Indexed: 11/19/2022]
Abstract
Spurred by current research policy, we are witnessing a significant growth in the number of studies that observe and describe sexual diversities in human physiology and sex prevalence in a large number of pathologies. Yet we are far from the comprehension of the mechanisms underpinning these differences, which are the result of a long evolutionary history. This Essay is meant to underline female reproductive function as a driver for the positive selection of the specific physiological features that explain male and female differential susceptibility to diseases and metabolic disturbances, in particular. A clear understanding of the causes underlying sexual dimorphisms in the physio-pathology is crucial for precision medicine.
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Affiliation(s)
- Sara Della Torre
- Center of Excellence on Neurodegenerative Diseases, University of Milan, via Balzaretti 9, 20133 Milan, Italy
| | - Adriana Maggi
- Center of Excellence on Neurodegenerative Diseases, University of Milan, via Balzaretti 9, 20133 Milan, Italy.
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Bile acid homeostasis controls CAR signaling pathways in mouse testis through FXRalpha. Sci Rep 2017; 7:42182. [PMID: 28181583 PMCID: PMC5299845 DOI: 10.1038/srep42182] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 01/06/2017] [Indexed: 12/11/2022] Open
Abstract
Bile acids (BAs) are molecules with endocrine activities controlling several physiological functions such as immunity, glucose homeostasis, testicular physiology and male fertility. The role of the nuclear BA receptor FXRα in the control of BA homeostasis has been well characterized. The present study shows that testis synthetize BAs. We demonstrate that mice invalidated for the gene encoding FXRα have altered BA homeostasis in both liver and testis. In the absence of FXRα, BA exposure differently alters hepatic and testicular expression of genes involved in BA synthesis. Interestingly, Fxrα-/- males fed a diet supplemented with BAs show alterations of testicular physiology and sperm production. This phenotype was correlated with the altered testicular BA homeostasis and the production of intermediate metabolites of BAs which led to the modulation of CAR signaling pathways within the testis. The role of the CAR signaling pathways within testis was validated using specific CAR agonist (TCPOBOP) and inverse agonist (androstanol) that respectively inhibited or reproduced the phenotype observed in Fxrα-/- males fed BA-diet. These data open interesting perspectives to better define how BA homeostasis contributes to physiological or pathophysiological conditions via the modulation of CAR activity.
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Goddard ET, Hill RC, Nemkov T, D'Alessandro A, Hansen KC, Maller O, Mongoue-Tchokote S, Mori M, Partridge AH, Borges VF, Schedin P. The Rodent Liver Undergoes Weaning-Induced Involution and Supports Breast Cancer Metastasis. Cancer Discov 2017; 7:177-187. [PMID: 27974414 PMCID: PMC5459606 DOI: 10.1158/2159-8290.cd-16-0822] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 12/08/2016] [Accepted: 12/08/2016] [Indexed: 01/01/2023]
Abstract
Patients with postpartum breast cancer are at increased risk for metastasis compared with age-matched nulliparous or pregnant patients. Here, we address whether circulating tumor cells have a metastatic advantage in the postpartum host and find the postlactation rodent liver preferentially supports metastasis. Upon weaning, we observed liver weight loss, hepatocyte apoptosis, extracellular matrix remodeling including deposition of collagen and tenascin-C, and myeloid cell influx, data consistent with weaning-induced liver involution and establishment of a prometastatic microenvironment. Using intracardiac and intraportal metastasis models, we observed increased liver metastasis in post-weaning BALB/c mice compared with nulliparous controls. Human relevance is suggested by a ∼3-fold increase in liver metastasis in patients with postpartum breast cancer (n = 564) and by liver-specific tropism (n = 117). In sum, our data reveal a previously unknown biology of the rodent liver, weaning-induced liver involution, which may provide insight into the increased liver metastasis and poor prognosis of women diagnosed with postpartum breast cancer. SIGNIFICANCE We find that patients with postpartum breast cancer are at elevated risk for liver metastasis. We identify a previously unrecognized biology, namely weaning-induced liver involution, that establishes a prometastatic microenvironment, and which may account in part for the poor prognosis of patients with postpartum breast cancer. Cancer Discov; 7(2); 177-87. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 115.
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Affiliation(s)
- Erica T Goddard
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon
| | - Ryan C Hill
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, Colorado
| | - Travis Nemkov
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, Colorado
| | - Angelo D'Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, Colorado
| | - Kirk C Hansen
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, Colorado
| | - Ori Maller
- Department of Surgery, Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, California
| | | | - Motomi Mori
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
- School of Public Health, Oregon Health & Science University, Portland, Oregon
| | - Ann H Partridge
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Virginia F Borges
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
- University of Colorado Cancer Center, Aurora, Colorado
- Young Women's Breast Cancer Translational Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Pepper Schedin
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon.
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
- Young Women's Breast Cancer Translational Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado
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Maternal Betaine Supplementation throughout Gestation and Lactation Modifies Hepatic Cholesterol Metabolic Genes in Weaning Piglets via AMPK/LXR-Mediated Pathway and Histone Modification. Nutrients 2016; 8:nu8100646. [PMID: 27763549 PMCID: PMC5084033 DOI: 10.3390/nu8100646] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 09/20/2016] [Accepted: 10/02/2016] [Indexed: 11/16/2022] Open
Abstract
Betaine serves as an animal and human nutrient which has been heavily investigated in glucose and lipid metabolic regulation, yet the underlying mechanisms are still elusive. In this study, feeding sows with betaine-supplemented diets during pregnancy and lactation increased cholesterol content and low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SR-BI) gene expression, but decreasing bile acids content and cholesterol-7a-hydroxylase (CYP7a1) expression in the liver of weaning piglets. This was associated with the significantly elevated serum betaine and methionine levels and hepatic S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) content. Concurrently, the hepatic nuclear transcription factor liver X receptor LXR was downregulated along with activated signal protein AMP-activated protein kinase (AMPK). Moreover, a chromatin immunoprecipitation assay showed lower LXR binding on CYP7a1 gene promoter and more enriched activation histone marker H3K4me3 on LDLR and SR-BI promoters. These results suggest that gestational and lactational betaine supplementation modulates hepatic gene expression involved in cholesterol metabolism via an AMPK/LXR pathway and histone modification in the weaning offspring.
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Bright AS, Herrera-Garcia G, Moscovitz JE, You D, Guo GL, Aleksunes LM. Regulation of Drug Disposition Gene Expression in Pregnant Mice with Car Receptor Activation. NUCLEAR RECEPTOR RESEARCH 2016; 3. [PMID: 27818994 DOI: 10.11131/2016/101193] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
More than half of pregnant women use prescription medications in order to maintain both maternal and fetal health. The constitutive androstane receptor (Car) critically affects the disposition of chemicals by regulating the transcription of genes encoding metabolic enzymes and transporters. However, the effects of Car activation on chemical disposition during pregnancy are unclear. This study aims to determine the degree to which pregnancy alters the expression of drug metabolizing enzymes and transporters in response to the pharmacological activation of Car. To test this, pregnant C57BL/6 mice were administered IP doses of vehicle, or a potent Car agonist, TCPOBOP, on gestation days 14, 15 and 16. Hepatic mRNA and protein expression of Car target genes (phase I, II and transporters) were quantified on gestation day 17. Pregnancy-related changes, such as induction of Cyp2b10, Ugt1a1 and Sult1a1 and repression of Ugt1a6, Gsta1, Gsta2 and Mrp6, were observed. Interestingly, the induction of Cyp2b10, Gsta1, Gsta2 and Mrp2-4 mRNAs by TCPOBOP was attenuated in maternal livers suggesting that Car activation is impeded by the biochemical and/or physiological changes that occur during gestation. Taken together, these findings suggest that pregnancy and pharmacological activation of Car can differentially regulate the expression of drug metabolism and transport genes.
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Affiliation(s)
- Amanda S Bright
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Guadalupe Herrera-Garcia
- Department of Obstetrics and Gynecology, Rutgers-Robert Wood Johnson Medical School, 1 Robert Wood Johnson Place, New Brunswick, NJ 08901, USA
| | - Jamie E Moscovitz
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Dahea You
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Grace L Guo
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA; Environmental and Occupational Health Sciences Institute, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Lauren M Aleksunes
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA; Environmental and Occupational Health Sciences Institute, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA
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van de Laarschot LFM, Jansen PLM, Schaap FG, Olde Damink SWM. The role of bile salts in liver regeneration. Hepatol Int 2016; 10:733-40. [PMID: 27048617 PMCID: PMC5003899 DOI: 10.1007/s12072-016-9723-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 03/08/2016] [Indexed: 12/11/2022]
Abstract
A growing body of evidence has demonstrated that bile salts are important for liver regeneration following partial hepatectomy. The relative bile salt overload after partial liver resection causes activation of bile salt receptors in non-parenchymal (viz. the plasma membrane receptor TGR5) and parenchymal (viz. the intracellular receptor FXR) cells in the liver, thus, providing signals to the regenerative process. Impaired bile salt signaling in mice with genetic deficiency of Tgr5 or Fxr results in delayed liver regeneration after partial hepatectomy, and is accompanied by mortality in case of Fxr knock-out mice. Conversely, compensatory liver re-growth in hepatectomized mice can be stimulated by feeding of bile salts or alisol B 23-acetate, a natural triterpenoid agonist of Fxr. A large number of animal studies underscore the importance of strict maintenance of bile salt homeostasis for proper progression of liver regeneration. Both ileal and hepatic Fxr play a key role in regulation of bile salt homeostasis and, thus, preventing hepatotoxicity caused by excessive levels of bile salts. They further contribute to liver regeneration by induction of mitogenic factors. Agents that target bile salt receptors hold promise as drugs to stimulate liver regeneration in selected patients.
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Affiliation(s)
- Liyanne F M van de Laarschot
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD, Maastricht, The Netherlands
| | - Peter L M Jansen
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD, Maastricht, The Netherlands
| | - Frank G Schaap
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD, Maastricht, The Netherlands.
| | - Steven W M Olde Damink
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD, Maastricht, The Netherlands
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Yuzhik EI, Proskurnyak LP, Nazarova GG. Correlations of reproductive indices of water vole females (Arvicola amphibius) with morphometric and hormonal characteristics. J EVOL BIOCHEM PHYS+ 2015. [DOI: 10.1134/s0022093015020076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Fan M, Wang X, Xu G, Yan Q, Huang W. Bile acid signaling and liver regeneration. BIOCHIMICA ET BIOPHYSICA ACTA 2015; 1849:196-200. [PMID: 24878541 PMCID: PMC4246016 DOI: 10.1016/j.bbagrm.2014.05.021] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Revised: 04/20/2014] [Accepted: 05/20/2014] [Indexed: 12/25/2022]
Abstract
The liver is able to regenerate itself in response to partial hepatectomy or liver injury. This is accomplished by a complex network of different cell types and signals both inside and outside the liver. Bile acids (BAs) are recently identified as liver-specific metabolic signals and promote liver regeneration by activating their receptors: Farnesoid X Receptor (FXR) and G-protein-coupled BA receptor 1 (GPBAR1, or TGR5). FXR is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. FXR promotes liver regeneration after 70% partial hepatectomy (PHx) or liver injury. Moreover, activation of FXR is able to alleviate age-related liver regeneration defects. Both liver- and intestine-FXR are activated by BAs after liver resection or injury and promote liver regeneration through distinct mechanism. TGR5 is a membrane-bound BA receptor and it is also activated during liver regeneration. TGR5 regulates BA hydrophobicity and stimulates BA excretion in urine during liver regeneration. BA signaling thus represents a novel metabolic pathway during liver regeneration. This article is part of a Special Issue entitled: Nuclear receptors in animal development.
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Affiliation(s)
- Mingjie Fan
- Institute of Genetics, College of Life Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China
| | - Xichun Wang
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Ganyu Xu
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Qingfeng Yan
- Institute of Genetics, College of Life Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China
| | - Wendong Huang
- Institute of Genetics, College of Life Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China; Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
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Mi Y, Lin A, Fiete D, Steirer L, Baenziger JU. Modulation of mannose and asialoglycoprotein receptor expression determines glycoprotein hormone half-life at critical points in the reproductive cycle. J Biol Chem 2014; 289:12157-12167. [PMID: 24619407 DOI: 10.1074/jbc.m113.544973] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The rate at which glycoproteins are cleared from the circulation has a critical impact on their biologic activity in vivo. We have shown that clearance rates for glycoproteins such as luteinizing hormone (LH) that undergo regulated release into the circulation determine their potency. Two highly abundant, carbohydrate-specific, endocytic receptors, the asialoglycoprotein receptor (ASGR) and the mannose receptor (ManR) are expressed in the liver by parenchymal and sinusoidal endothelial cells, respectively. We demonstrate that the ManR mediates the clearance of glycoproteins such as LH that bear N-linked glycans terminating with β1,4-linked GalNAc-4-SO4, as well as glycoproteins bearing glycans that terminate with Man. Steady state levels of mRNA encoding the ASGR and the ManR are regulated by progesterone in pregnant mice, reaching maximal levels on day 12.5 of pregnancy. Protein expression and glycan-specific binding activity also increase in the livers of pregnant mice. In contrast, ManR mRNA, but not ASGR mRNA, decreases in male mice at the time of sexual maturation. We show that levels of ManR and ASGR expression control the clearance rate for glycoproteins bearing recognized glycans. Thus, reduced expression of the ManR at the time of sexual maturation will increase the potency of LH in vivo, whereas increased expression during pregnancy will reduce LH potency until progesterone and receptor levels fall prior to parturition.
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Affiliation(s)
- Yiling Mi
- Department of Pathology, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63110
| | - Angela Lin
- Department of Pathology, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63110
| | - Dorothy Fiete
- Department of Pathology, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63110
| | - Lindsay Steirer
- Department of Pathology, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63110
| | - Jacques U Baenziger
- Department of Pathology, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63110.
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Martineau M, Raker C, Powrie R, Williamson C. Intrahepatic cholestasis of pregnancy is associated with an increased risk of gestational diabetes. Eur J Obstet Gynecol Reprod Biol 2014; 176:80-5. [PMID: 24462052 DOI: 10.1016/j.ejogrb.2013.12.037] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2013] [Revised: 12/13/2013] [Accepted: 12/22/2013] [Indexed: 12/27/2022]
Abstract
OBJECTIVE To evaluate the association between intrahepatic cholestasis of pregnancy (ICP) and gestational diabetes mellitus (GDM). STUDY DESIGN A retrospective case-control study of pregnancy outcomes in 57,724 women managed at a university teaching hospital in Rhode Island, USA, in whom universal screening for GDM had been performed and who were assessed for the incidence of ICP. Pregnancies complicated by ICP or GDM between February 2005 and June 2011 were identified from the electronic patient records using appropriate ICD codes. A total of 125 cases were required to detect a difference in the incidence of GDM in ICP at 5% significance with 80% power. Demographic and clinical outcome data (including maternal age, ethnic group, BMI, and infant weight and gender) were also collected. RESULTS Of the 57,724 pregnancies, 143 were complicated by ICP (0.25%) and 4880 by GDM (8.5%). Nineteen ICP cases had GDM. The incidence of GDM in ICP was 13.6% (19/140, OR 1.68 CI 1.04-2.72). Where gestational ages were available (n=105), of those screened for GDM prior to developing ICP, 13.4% (11/82, OR 1.64 CI 0.88-3.06) had a confirmed diagnosis, rising to 30% (7/23, OR 4.69 CI 1.98-11.1) in cases that were screened following the onset of cholestasis. Simple linear regression analysis of adjusted birth weight centiles in ICP revealed a significant linear trend of increasing centiles with gestational age (p=0.005). CONCLUSIONS These data support the hypothesis that the incidence of GDM is higher in women predisposed to developing ICP. It is likely that this susceptibility increases further following the onset of cholestasis.
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Affiliation(s)
- Marcus Martineau
- Division of Obstetric & Consultative Medicine, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI 02905, USA; Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Imperial College, London W12 0NN, United Kingdom.
| | - Christina Raker
- Division of Research, Women and Infants Hospital of Rhode Island, Providence, RI 02903, USA.
| | - Raymond Powrie
- Division of Obstetric & Consultative Medicine, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI 02905, USA; Division of Research, Women and Infants Hospital of Rhode Island, Providence, RI 02903, USA.
| | - Catherine Williamson
- Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Imperial College, London W12 0NN, United Kingdom; Women's Health Academic Centre, Kings College London, 2nd Floor Hodgkin Building, King's College London, Guy's campus, London SE1 1UL, United Kingdom.
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Martineau M, Papacleovoulou G, Abu-Hayyeh S, Dixon P, Ji H, Powrie R, Larson L, Chien E, Williamson C. Cholestatic pregnancy is associated with reduced placental 11βHSD2 expression. Placenta 2014; 35:37-43. [DOI: 10.1016/j.placenta.2013.10.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2013] [Revised: 10/22/2013] [Accepted: 10/23/2013] [Indexed: 12/27/2022]
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Papacleovoulou G, Abu-Hayyeh S, Nikolopoulou E, Briz O, Owen BM, Nikolova V, Ovadia C, Huang X, Vaarasmaki M, Baumann M, Jansen E, Albrecht C, Jarvelin MR, Marin JJ, Knisely A, Williamson C. Maternal cholestasis during pregnancy programs metabolic disease in offspring. J Clin Invest 2013; 123:3172-81. [PMID: 23934127 PMCID: PMC3696570 DOI: 10.1172/jci68927] [Citation(s) in RCA: 103] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 04/04/2013] [Indexed: 12/20/2022] Open
Abstract
The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.
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Affiliation(s)
- Georgia Papacleovoulou
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Shadi Abu-Hayyeh
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Evanthia Nikolopoulou
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Oscar Briz
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Bryn M. Owen
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Vanya Nikolova
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Caroline Ovadia
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Xiao Huang
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Marja Vaarasmaki
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Marc Baumann
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Eugene Jansen
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Christiane Albrecht
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Marjo-Riitta Jarvelin
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Jose J.G. Marin
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - A.S. Knisely
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Catherine Williamson
- Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Division of Women’s Health, Women’s Health Academic Centre, King’s College London, London, United Kingdom.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Institute of Biochemistry and Molecular Medicine,
Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Clinical Medicine/Obstetrics and Gynaecology, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Department of Epidemiology and Biostatistics, MRC Health Protection Agency, Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
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Abu-Hayyeh S, Papacleovoulou G, Williamson C. Nuclear receptors, bile acids and cholesterol homeostasis series - bile acids and pregnancy. Mol Cell Endocrinol 2013; 368:120-8. [PMID: 23159988 DOI: 10.1016/j.mce.2012.10.027] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Revised: 08/28/2012] [Accepted: 10/26/2012] [Indexed: 12/19/2022]
Abstract
Bile acids have been traditionally thought of as having an important role in fat emulsification. It is now emerging that they act as important signalling molecules that not only autoregulate their own synthesis but also influence lipid and glucose metabolism. Although, the mechanisms that underlie the regulation of bile acid homeostasis have been well characterised in normal physiology, the impact of pregnancy on bile acid regulation is still poorly understood. This review summarises the main regulatory mechanisms underlying bile acid homeostasis and discusses how pregnancy, a unique physiological state, can modify them. The fetoplacental adaptations that protect against fetal bile acid toxicity are reviewed. We highlight the importance of bile acid regulation during gestation by discussing the liver disease of pregnancy, intrahepatic cholestasis of pregnancy (ICP) and how genetic, endocrine and environmental factors contribute to the disease aetiology at a cellular and molecular level.
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Affiliation(s)
- Shadi Abu-Hayyeh
- Institute of Reproductive and Developmental Biology, Dept. of Surgery and Cancer, Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom
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