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Ueda H, Honda A, Miyazaki T, Morishita Y, Hirayama T, Iwamoto J, Ikegami T. High-fat/high-sucrose diet results in a high rate of MASH with HCC in a mouse model of human-like bile acid composition. Hepatol Commun 2025; 9:e0606. [PMID: 39670881 PMCID: PMC11637755 DOI: 10.1097/hc9.0000000000000606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 10/21/2024] [Indexed: 12/14/2024] Open
Abstract
BACKGROUND Wild-type (WT) mice fed a conventional high-fat/high-sucrose diet (HFHSD) rarely develop metabolic dysfunction-associated steatohepatitis (MASH) with HCC. Because mouse bile acid (BA) is highly hydrophilic, we hypothesized that making it hydrophobic would lead to MASH with HCC. METHODS Eleven-week-old WT and Cyp2a12/Cyp2c70 double knockout (DKO) mice were divided into two groups, including one which was fed a normal chow diet, and one which was fed an HFHSD. Samples were collected after 15, 30, 47, and 58 weeks for histological, biochemical, and immunological analyses. RESULTS In the HFHSD group, body weight gain did not differ in WT versus DKO mice, although HFHSD-fed DKO mice exhibited markedly accelerated liver inflammation, fibrosis, and carcinogenesis. HFHSD upregulated lipogenesis and downregulated fatty acid oxidation in both WT and DKO mice, which increased liver lipid accumulation and lipotoxicity. However, the increase in reactive oxygen species production and carcinogenesis observed in DKO mice could not be explained by abnormal lipid metabolism alone. Regarding BA metabolism, DKO mice had a higher hydrophobicity index. They exhibited an age-associated increase in chenodeoxycholic acid (CDCA) levels because of CYP8B1 activity inhibition due to the farnesoid X receptor activation. HFHSD further downregulated CYP8B1, presumably by activating the Liver X receptor. Liver CDCA accumulation was associated with increased inflammation, reactive oxygen species production, and hepatocyte FGF15 induction. Moreover, in noncancerous liver tissues, HFHSD appeared to activate STAT3, an oncogenic transcription factor, which was enhanced by a CDCA-rich environment. CONCLUSIONS Here, we developed a new model of MASH with HCC using mice with human-like BA composition and found that HFHSD and elevated hepatic CDCA synergistically increased the risk of MASH with HCC.
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Affiliation(s)
- Hajime Ueda
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
| | - Akira Honda
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
| | - Teruo Miyazaki
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
| | - Yukio Morishita
- Diagnostic Pathology Division, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
| | - Takeshi Hirayama
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
| | - Junichi Iwamoto
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
| | - Tadashi Ikegami
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
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Yang Z, Zarbl H, Kong B, Taylor R, Black K, Kipen H, Basaly V, Fang M, Guo GL. Liver-gut axis signaling regulates circadian energy metabolism in shift workers. FASEB J 2024; 38:e70203. [PMID: 39588921 PMCID: PMC11590413 DOI: 10.1096/fj.202402102r] [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: 09/06/2024] [Revised: 11/03/2024] [Accepted: 11/13/2024] [Indexed: 11/27/2024]
Abstract
Circadian rhythm is critical to maintaining the whole-body metabolic homeostasis of an organism. Chronic disruption of circadian rhythm by shift work is an important risk factor for metabolic diseases. Fibroblast growth factor 15/19 (FGF15/19), a key component in the liver-gut axis, potently suppresses bile acid (BA) synthesis and improves insulin sensitivity. FGF15/19 emerges as a novel pharmaceutical target for prevention and treatment of metabolic diseases. The nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin 1 (SIRT1) deacetylase plays an important role in the maintenance of hepatic homeostasis by linking hepatic metabolism to circadian rhythm. Here, our clinical study identified that circadian rhythmicity and levels of plasma FGF19 and BA profiling, and cellular NAD+-dependent SIRT1 signaling were disturbed in night shift (NS, n = 10) compared to day shift (DS, n = 12) nurses. Our in vitro data showed that recombinant FGF19 protein rescued cellular circadian rhythm disrupted by SIRT1 inhibitors. Furthermore, we determined the effect of FGF15 on circadian rhythm and hepatic metabolism in wild-type (WT), Fgf15 knockout (KO), and Fgf15 transgenic (TG) mice. The expressions of circadian-controlled genes (CCGs) involved in SIRT1 signaling, BA and lipid metabolism, and inflammation were disrupted in Fgf15 KO compared to WT and/or Fgf15 TG mice. Moreover, systemic FGF15 deficiency led to the circadian disturbance of NAD+-dependent SIRT1 signaling and significant reduction during nighttime in mice. These findings suggest that FGF15/19 regulates the circadian energy metabolism, which warrants further studies as a putative prognostic biomarker and pharmaceutical target for preventing against metabolic diseases associated with chronic shift work.
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Affiliation(s)
- Zhenning Yang
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, RutgersThe State University of New JerseyPiscatawayNew JerseyUSA
- Environmental and Occupational Health Sciences Institute, RutgersThe State University of New JerseyPiscatawayNew JerseyUSA
| | - Helmut Zarbl
- Environmental and Occupational Health Sciences Institute, RutgersThe State University of New JerseyPiscatawayNew JerseyUSA
- Department of Environmental and Occupational Health and Justice, School of Public Health, RutgersThe State University of New JerseyPiscatawayNew JerseyUSA
| | - Bo Kong
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, RutgersThe State University of New JerseyPiscatawayNew JerseyUSA
| | - Rulaiha Taylor
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, RutgersThe State University of New JerseyPiscatawayNew JerseyUSA
| | - Kathleen Black
- Environmental and Occupational Health Sciences Institute, RutgersThe State University of New JerseyPiscatawayNew JerseyUSA
| | - Howard Kipen
- Environmental and Occupational Health Sciences Institute, RutgersThe State University of New JerseyPiscatawayNew JerseyUSA
- Department of Environmental and Occupational Health and Justice, School of Public Health, RutgersThe State University of New JerseyPiscatawayNew JerseyUSA
| | - Veronia Basaly
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, RutgersThe State University of New JerseyPiscatawayNew JerseyUSA
| | - Mingzhu Fang
- Environmental and Occupational Health Sciences Institute, RutgersThe State University of New JerseyPiscatawayNew JerseyUSA
- Department of Environmental and Occupational Health and Justice, School of Public Health, RutgersThe State University of New JerseyPiscatawayNew JerseyUSA
| | - Grace L. Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, RutgersThe State University of New JerseyPiscatawayNew JerseyUSA
- Environmental and Occupational Health Sciences Institute, RutgersThe State University of New JerseyPiscatawayNew JerseyUSA
- VA New Jersey Health Care SystemVeterans Administration Medical CenterEast OrangeNew JerseyUSA
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Sun R, Fei F, Jin D, Yang H, Xu Z, Cao B, Li J. The integrated analysis of gut microbiota and metabolome revealed steroid hormone biosynthesis is a critical pathway in liver regeneration after 2/3 partial hepatectomy. Front Pharmacol 2024; 15:1407401. [PMID: 39188944 PMCID: PMC11345278 DOI: 10.3389/fphar.2024.1407401] [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: 03/26/2024] [Accepted: 07/23/2024] [Indexed: 08/28/2024] Open
Abstract
Introduction: The liver is the only organ capable of full regeneration in mammals. However, the exact mechanism of gut microbiota and metabolites derived from them relating to liver regeneration has not been fully elucidated. Methods: To demonstrate how the gut-liver axis contributes to liver regeneration, using an LC-QTOF/MS-based metabolomics technique, we examine the gut microbiota-derived metabolites in the gut content of C57BL/6J mice at various points after 2/3 partial hepatectomy (PHx). Compound identification, multivariate/univariate data analysis and pathway analysis were performed subsequently. The diversity of the bacterial communities in the gastrointestinal content was measured using 16S rRNA gene sequencing. Then, the integration analysis of gut microbiota and metabolome was performed. Results: After 2/3 PHx, the residual liver proliferated quickly in the first 3 days and had about 90% of its initial weight by the seventh day. The results of PLS-DA showed that a significant metabolic shift occurred at 6 h and 36 h after 2/3 PHx that was reversed at the late phase of liver regeneration. The α and β-diversity of the gut microbiota significantly changed at the early stage of liver regeneration. Specifically, Escherichia Shigella, Lactobacillus, Akkermansia, and Muribaculaceae were the bacteria that changed the most considerably during liver regeneration. Further pathway analysis found the most influenced co-metabolized pathways between the host and gut bacteria including glycolysis, the TCA cycle, arginine metabolism, glutathione metabolism, tryptophan metabolism, and purine and pyrimidine metabolism. Specifically, steroid hormone biosynthesis is the most significant pathway of the host during liver regeneration. Discussion: These findings revealed that during liver regeneration, there was a broad modification of gut microbiota and systemic metabolism and they were strongly correlated. Targeting specific gut bacterial strains, especially increasing the abundance of Akkermansia and decreasing the abundance of Enterobacteriaceae, may be a promising beneficial strategy to modulate systemic metabolism such as amino acid and nucleotide metabolism and promote liver regeneration.
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Affiliation(s)
- Runbin Sun
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Fei Fei
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Dandan Jin
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Haoyi Yang
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhi Xu
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Bei Cao
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Juan Li
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
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Ghanem M, Archer G, Crestani B, Mailleux AA. The endocrine FGFs axis: A systemic anti-fibrotic response that could prevent pulmonary fibrogenesis? Pharmacol Ther 2024; 259:108669. [PMID: 38795981 DOI: 10.1016/j.pharmthera.2024.108669] [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: 01/12/2024] [Revised: 04/22/2024] [Accepted: 05/21/2024] [Indexed: 05/28/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease for which therapeutic options are limited, with an unmet need to identify new therapeutic targets. IPF is thought to be the consequence of repeated microlesions of the alveolar epithelium, leading to aberrant epithelial-mesenchymal communication and the accumulation of extracellular matrix proteins. The reactivation of developmental pathways, such as Fibroblast Growth Factors (FGFs), is a well-described mechanism during lung fibrogenesis. Secreted FGFs with local paracrine effects can either exert an anti-fibrotic or a pro-fibrotic action during this pathological process through their FGF receptors (FGFRs) and heparan sulfate residues as co-receptors. Among FGFs, endocrine FGFs (FGF29, FGF21, and FGF23) play a central role in the control of metabolism and tissue homeostasis. They are characterized by a low affinity for heparan sulfate, present in the cell vicinity, allowing them to have endocrine activity. Nevertheless, their interaction with FGFRs requires the presence of mandatory co-receptors, alpha and beta Klotho proteins (KLA and KLB). Endocrine FGFs are of growing interest for their anti-fibrotic action during liver, kidney, or myocardial fibrosis. Innovative therapies based on FGF19 or FGF21 analogs are currently being studied in humans during liver fibrosis. Recent data report a similar anti-fibrotic action of endocrine FGFs in the lung, suggesting a systemic regulation of the pulmonary fibrotic process. In this review, we summarize the current knowledge on the protective effect of endocrine FGFs during the fibrotic processes, with a focus on pulmonary fibrosis.
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Affiliation(s)
- Mada Ghanem
- Université Paris Cité, Inserm, Physiopathologie et Épidémiologie des Maladies Respiratoires, F-75018 Paris, France
| | - Gabrielle Archer
- Université Paris Cité, Inserm, Physiopathologie et Épidémiologie des Maladies Respiratoires, F-75018 Paris, France
| | - Bruno Crestani
- Université Paris Cité, Inserm, Physiopathologie et Épidémiologie des Maladies Respiratoires, F-75018 Paris, France; Assistance Publique des Hôpitaux de Paris, Hôpital Bichat, Service de Pneumologie A, FHU APOLLO, Paris, France
| | - Arnaud A Mailleux
- Université Paris Cité, Inserm, Physiopathologie et Épidémiologie des Maladies Respiratoires, F-75018 Paris, France.
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Chow MD, Otersen K, Wassef A, Kong B, Yamarthy S, Rizzolo D, Yang I, Buckley B, Lu A, Crook N, Lee M, Gao J, Naganand S, Stofan MF, Armstrong L, Schumacher J, Taylor R, Henry Z, Basaly V, Yang Z, Zhang M, Huang M, Kagan L, Brunetti L, Sadek R, Lee YH, Guo GL. Effects of intestine-specific deletion of FGF15 on the development of fatty liver disease with vertical sleeve gastrectomy. Hepatol Commun 2024; 8:e0444. [PMID: 38780301 PMCID: PMC11124683 DOI: 10.1097/hc9.0000000000000444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 02/27/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND Vertical sleeve gastrectomy (SGx) is a type of bariatric surgery to treat morbid obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms of SGx to improve MASLD are unclear, but increased bile acids (BAs) and FGF19 (mouse FGF15) were observed. FGF15/19 is expressed in the ileum in response to BAs and is critical in not only suppressing BA synthesis in the liver but also promoting energy expenditure. We hypothesized the reduction of obesity and resolution of MASLD by SGx may be mediated by FGF15/19. METHODS First, we conducted hepatic gene expression analysis in obese patients undergoing SGx, with the results showing increased expression of FGF19 in obese patients' livers. Next, we used wild-type and intestine-specific Fgf15 knockout mice (Fgf15ile-/-) to determine the effects of FGF15 deficiency on improving the metabolic effects. RESULTS SGx improved metabolic endpoints in both genotypes, evidenced by decreased obesity, improved glucose tolerance, and reduced MASLD progression. However, Fgf15ile-/- mice showed better improvement compared to wild-type mice after SGx, suggesting that other mediators than FGF15 are also responsible for the beneficial effects of FGF15 deficiency. Further gene expression analysis in brown adipose tissue suggests increased thermogenesis. CONCLUSIONS FGF15 deficiency, the larger BA pool and higher levels of secondary BAs may increase energy expenditure in extrahepatic tissues, which may be responsible for improved metabolic functions following SGx.
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Affiliation(s)
- Monica D. Chow
- Department of Surgery, Division of Pediatric Surgery, Rutgers Robert Wood Johnson Medical Center School, New Brunswick, New Jersey, USA
| | - Katherine Otersen
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Andrew Wassef
- Department of Pharmaceutics, Ernest Mario School of Pharmacy-Rutgers University, Piscataway, New Jersey, USA
- Center of Excellence for Pharmaceutical Translational Research and Education, Rutgers University, Piscataway, New Jersey, USA
- Center of Excellence for Metabolic and Bariatric Surgery, Robert Wood Johnson Barnabas University Hospital, New Brunswick, New Jersey, USA
- Advanced Surgical & Bariatrics of NJ, Somerset, New Jersey, USA
| | - Bo Kong
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Sowmya Yamarthy
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Daniel Rizzolo
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Ill Yang
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey, USA
| | - Brian Buckley
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey, USA
| | - Alexander Lu
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Naomi Crook
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Matthew Lee
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Judy Gao
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Sareena Naganand
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Mary F. Stofan
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Laura Armstrong
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Justin Schumacher
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Rulaiha Taylor
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Zakiyah Henry
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Veronia Basaly
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Zhenning Yang
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Min Zhang
- Children’s Liver Disease Center, 302 Military Hospital, Beijing, China
| | - Mingxing Huang
- Department of Infectious Diseases, the Fifth Affiliated Hospital of Sun Yat-Sen University (SYSU), Zhuhai, Guangdong, China
| | - Leonid Kagan
- Department of Pharmaceutics, Ernest Mario School of Pharmacy-Rutgers University, Piscataway, New Jersey, USA
- Center of Excellence for Pharmaceutical Translational Research and Education, Rutgers University, Piscataway, New Jersey, USA
| | - Luigi Brunetti
- Department of Pharmaceutics, Ernest Mario School of Pharmacy-Rutgers University, Piscataway, New Jersey, USA
- Center of Excellence for Pharmaceutical Translational Research and Education, Rutgers University, Piscataway, New Jersey, USA
| | - Ragui Sadek
- Center of Excellence for Metabolic and Bariatric Surgery, Robert Wood Johnson Barnabas University Hospital, New Brunswick, New Jersey, USA
- Advanced Surgical & Bariatrics of NJ, Somerset, New Jersey, USA
| | - Yi-Horng Lee
- Department of Surgery, Division of Pediatric Surgery, Rutgers Robert Wood Johnson Medical Center School, New Brunswick, New Jersey, USA
| | - Grace L. Guo
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey, USA
- Department of Veterans Affairs New Jersey Health Care System, East Orange, New Jersey, USA
- Rutgers Center for Lipid Research, New Brunswick, New Jersey, USA
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Uriarte I, Santamaria E, López-Pascual A, Monte MJ, Argemí J, Latasa MU, Adán-Villaescusa E, Irigaray A, Herranz JM, Arechederra M, Basualdo J, Lucena F, Corrales FJ, Rotellar F, Pardo F, Merlen G, Rainteau D, Sangro B, Tordjmann T, Berasain C, Marín JJG, Fernández-Barrena MG, Herrero I, Avila MA. New insights into the regulation of bile acids synthesis during the early stages of liver regeneration: A human and experimental study. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167166. [PMID: 38642480 DOI: 10.1016/j.bbadis.2024.167166] [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: 11/16/2023] [Revised: 04/04/2024] [Accepted: 04/08/2024] [Indexed: 04/22/2024]
Abstract
BACKGROUND AND AIMS Liver regeneration is essential for the preservation of homeostasis and survival. Bile acids (BAs)-mediated signaling is necessary for liver regeneration, but BAs levels need to be carefully controlled to avoid hepatotoxicity. We studied the early response of the BAs-fibroblast growth factor 19 (FGF19) axis in healthy individuals undergoing hepatectomy for living donor liver transplant. We also evaluated BAs synthesis in mice upon partial hepatectomy (PH) and acute inflammation, focusing on the regulation of cytochrome-7A1 (CYP7A1), a key enzyme in BAs synthesis from cholesterol. METHODS Serum was obtained from twelve human liver donors. Mice underwent 2/3-PH or sham-operation. Acute inflammation was induced with bacterial lipopolysaccharide (LPS) in mice fed control or antoxidant-supplemented diets. BAs and 7α-hydroxy-4-cholesten-3-one (C4) levels were measured by HPLC-MS/MS; serum FGF19 by ELISA. Gene expression and protein levels were analyzed by RT-qPCR and western-blot. RESULTS Serum BAs levels increased after PH. In patients with more pronounced hypercholanemia, FGF19 concentrations transiently rose, while C4 levels (a readout of CYP7A1 activity) dropped 2 h post-resection in all cases. Serum BAs and C4 followed the same pattern in mice 1 h after PH, but C4 levels also dropped in sham-operated and LPS-treated animals, without marked changes in CYP7A1 protein levels. LPS-induced serum C4 decline was attenuated in mice fed an antioxidant-supplemented diet. CONCLUSIONS In human liver regeneration FGF19 upregulation may constitute a protective response from BAs excess during liver regeneration. Our findings suggest the existence of post-translational mechanisms regulating CYP7A1 activity, and therefore BAs synthesis, independent from CYP7A1/Cyp7a1 gene transcription.
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Affiliation(s)
- Iker Uriarte
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Eva Santamaria
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Amaya López-Pascual
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - María J Monte
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Université Paris-Saclay, Inserm U1193, Orsay, France
| | - Josepmaria Argemí
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain; Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain
| | - M Ujue Latasa
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Elena Adán-Villaescusa
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Ainara Irigaray
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Jose M Herranz
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - María Arechederra
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Jorge Basualdo
- Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain; Internal Medicine Department, ICOT Hospital Ciudad de Telde, Las Palmas, Spain
| | - Felipe Lucena
- Internal Medicine Department, Navarra University Clinic, Pamplona, Spain
| | - Fernando J Corrales
- Functional Proteomics Laboratory, Centro Nacional de Biotecnología (CSIC), Madrid, Spain
| | - Fernando Rotellar
- General Surgery Department, Navarra University Clinic, Pamplona, Spain
| | - Fernando Pardo
- General Surgery Department, Navarra University Clinic, Pamplona, Spain
| | | | - Dominique Rainteau
- Sorbonne Université, Inserm U938, Centre de Recherche Saint-Antoine, Paris, France
| | - Bruno Sangro
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain; Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain
| | | | - Carmen Berasain
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Jose J G Marín
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Maite G Fernández-Barrena
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Ignacio Herrero
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain; Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain.
| | - Matias A Avila
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain.
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7
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Koelfat KV, Schaap FG, van Mierlo KM, Leníček M, Sauer I, van der Kroft G, Röth AA, Bednarsch J, Amygdalos I, Lurje G, Dewulf MJ, Lang SA, Neumann UP, Olde Damink SW. Partial liver resection alters the bile salt-FGF19 axis in patients with perihilar cholangiocarcinoma: Implications for liver regeneration. Hepatol Commun 2024; 8:e0445. [PMID: 38836805 PMCID: PMC11155560 DOI: 10.1097/hc9.0000000000000445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 02/22/2024] [Indexed: 06/06/2024] Open
Abstract
BACKGROUND Extended liver resection is the only treatment option for perihilar cholangiocarcinoma (pCCA). Bile salts and the gut hormone FGF19, both promoters of liver regeneration (LR), have not been investigated in patients undergoing resection for pCCA. We aimed to evaluate the bile salt-FGF19 axis perioperatively in pCCA and study its effects on LR. METHODS Plasma bile salts, FGF19, and C4 (bile salt synthesis marker) were assessed in patients with pCCA and controls (colorectal liver metastases), before and after resection on postoperative days (PODs) 1, 3, and 7. Hepatic bile salts were determined in intraoperative liver biopsies. RESULTS Partial liver resection in pCCA elicited a sharp decline in bile salt and FGF19 plasma levels on POD 1 and remained low thereafter, unlike in controls, where bile salts rose gradually. Preoperatively, suppressed C4 in pCCA normalized postoperatively to levels similar to those in the controls. The remnant liver volume and postoperative bilirubin levels were negatively associated with postoperative C4 levels. Furthermore, patients who developed postoperative liver failure had nearly undetectable C4 levels on POD 7. Hepatic bile salts strongly predicted hyperbilirubinemia on POD 7 in both groups. Finally, postoperative bile salt levels on day 7 were an independent predictor of LR. CONCLUSIONS Partial liver resection alters the bile salt-FGF19 axis, but its derailment is unrelated to LR in pCCA. Postoperative monitoring of circulating bile salts and their production may be useful for monitoring LR.
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Affiliation(s)
- Kiran V.K. Koelfat
- Department of General, Visceral and Transplant Surgery, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Frank G. Schaap
- Department of General, Visceral and Transplant Surgery, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Kim M.C. van Mierlo
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Martin Leníček
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, General University Hospital in Prague, Charles University, Prague, Czech Republic
| | - Ilka Sauer
- Department of General, Visceral and Transplant Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Gregory van der Kroft
- Department of General, Visceral and Transplant Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Anjali A.J. Röth
- Department of General, Visceral and Transplant Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Jan Bednarsch
- Department of General, Visceral and Transplant Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Iakovos Amygdalos
- Department of General, Visceral and Transplant Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Georg Lurje
- Department of General, Visceral and Transplant Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Maxime J.L. Dewulf
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Sven A. Lang
- Department of General, Visceral and Transplant Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Ulf P. Neumann
- Department of General, Visceral and Transplant Surgery, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Steven W.M. Olde Damink
- Department of General, Visceral and Transplant Surgery, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
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de Haan LR, van Golen RF, Heger M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol Rev 2024; 76:500-558. [PMID: 38697856 DOI: 10.1124/pharmrev.123.000955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/24/2024] [Accepted: 02/08/2024] [Indexed: 05/05/2024] Open
Abstract
The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.
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Affiliation(s)
- Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Rowan F van Golen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
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Qin X, Tan Y, Ren W, Zhou W, Niu R, Liang L, Li J, Cao K, Wei G, Zhu X, Huang M. Elevated expression of LCN13 through FXR activation ameliorates hepatocellular lipid accumulation and inflammation. Int Immunopharmacol 2024; 131:111812. [PMID: 38493698 DOI: 10.1016/j.intimp.2024.111812] [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: 12/16/2023] [Revised: 02/01/2024] [Accepted: 03/04/2024] [Indexed: 03/19/2024]
Abstract
BACKGROUND Lipocalin 13 (LCN13) is a member of the lipocalin family that consists of numerous secretory proteins. LCN13 high-expression has been reported to possess anti-obesity and anti-diabetic effects. Although metabolic dysfunction-associated steatotic liver diseases (MASLD) including metabolic dysfunction-associated steatohepatitis (MASH) are frequently associated with obesity and insulin resistance, the functional role of endogenous LCN13 and the therapeutic effect of LCN13 in MASH and related metabolic deterioration have not been evaluated. METHODS We employed a methionine-choline deficient diet model and MASH cell models to investigate the role of LCN13 in MASH development. We sought to explore the effects of LCN13 on lipid metabolism and inflammation in hepatocytes under PA/OA exposure using Western blotting, real-time RT-PCR, enzyme-linked immunosorbent assay, hematoxylin and eosin staining, oil red O staining. Using RNA sequencing, chromatin immunoprecipitation assay, and luciferase reporter assays to elucidate whether farnesoid X receptor (FXR) regulates human LCN13 transcription as a transcription factor. RESULTS Our study found that LCN13 was down-regulated in MASH patients, MASH mouse and cell models. LCN13 overexpression in hepatocyte cells significantly inhibited lipid accumulation and inflammation in vitro. Conversely, LCN13 downregulation significantly exacerbated lipid accumulation and inflammatory responses in vivo and in vitro. Mechanistically, we provided the first evidence that LCN13 was transcriptionally activated by FXR, representing a novel direct target gene of FXR. And the key promoter region of LCN13 binds to FXR was also elucidated. We further revealed that LCN13 overexpression via FXR activation ameliorates hepatocellular lipid accumulation and inflammation in vivo and in vitro. Furthermore, LCN13-down-regulated mice exhibited aggravated MASH phenotypes, including increased hepatic lipid accumulation and inflammation. CONCLUSION Our findings provide new insight regarding the protective role of LCN13 in MASH development and suggest an innovative therapeutic strategy for treating MASH or related metabolic disorders.
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Affiliation(s)
- Xingliang Qin
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), MinisCtry of Education, Guangzhou 510080, China; Research Center for Clinical Laboratory Standard, Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Yongyao Tan
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), MinisCtry of Education, Guangzhou 510080, China; Research Center for Clinical Laboratory Standard, Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Weishu Ren
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), MinisCtry of Education, Guangzhou 510080, China; Research Center for Clinical Laboratory Standard, Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Weiwei Zhou
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), MinisCtry of Education, Guangzhou 510080, China; Research Center for Clinical Laboratory Standard, Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Rouxi Niu
- School of Biomedical Sciences, the Chinese University of Hong Kong, 999077, Hong Kong, China
| | - Linyue Liang
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), MinisCtry of Education, Guangzhou 510080, China; Research Center for Clinical Laboratory Standard, Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Jinling Li
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), MinisCtry of Education, Guangzhou 510080, China; Research Center for Clinical Laboratory Standard, Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Kaiyuan Cao
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), MinisCtry of Education, Guangzhou 510080, China; Research Center for Clinical Laboratory Standard, Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Guohong Wei
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
| | - Xun Zhu
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), MinisCtry of Education, Guangzhou 510080, China; Research Center for Clinical Laboratory Standard, Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; The Third People's Hospital of Zhuhai, Zhuhai 519060, China.
| | - Mingxing Huang
- The Third People's Hospital of Zhuhai, Zhuhai 519060, China.
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Gao Y, Lin J, Ye C, Guo S, Jiang C. Microbial transformations of bile acids and their receptors in the regulation of metabolic dysfunction-associated steatotic liver disease. LIVER RESEARCH 2023; 7:165-176. [PMID: 39958385 PMCID: PMC11792070 DOI: 10.1016/j.livres.2023.09.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/02/2023] [Accepted: 09/08/2023] [Indexed: 01/03/2025]
Abstract
Bile acids (BAs) play important roles in the digestion of dietary fats and molecular signal transduction, and modulation of the BA composition usually affects the progression of metabolic diseases. While the liver produces primary BAs, the gut microbiota modifies these products into various forms that greatly increase their diversity and biological functions. Mechanistically, BAs can regulate their own metabolism and transport as well as other key aspects of metabolic processes via dedicated BA receptors. Disruption of BA transport and homeostasis leads to the progression of liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). Here, we summarize the microbial transformations of BAs and their downstream signaling in the development of metabolic diseases and present new insights into novel therapeutic strategies targeting BA pathways that may contribute to these diseases.
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Affiliation(s)
- Yuhua Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Jun Lin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Chuan Ye
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Siqi Guo
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
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Ma JT, Xia S, Zhang BK, Luo F, Guo L, Yang Y, Gong H, Yan M. The pharmacology and mechanisms of traditional Chinese medicine in promoting liver regeneration: A new therapeutic option. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 116:154893. [PMID: 37236047 DOI: 10.1016/j.phymed.2023.154893] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/04/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023]
Abstract
BACKGROUND The liver is renowned for its remarkable regenerative capacity to restore its structure, size and function after various types of liver injury. However, in patients with end-stage liver disease, the regenerative capacity is inhibited and liver transplantation is the only option. Considering the limitations of liver transplantation, promoting liver regeneration is suggested as a new therapeutic strategy for liver disease. Traditional Chinese medicine (TCM) has a long history of preventing and treating various liver diseases, and some of them have been proven to be effective in promoting liver regeneration, suggesting the therapeutic potential in liver diseases. PURPOSE This review aims to summarize the molecular mechanisms of liver regeneration and the pro-regenerative activity and mechanism of TCM formulas, extracts and active ingredients. METHODS We conducted a systematic search in PubMed, Web of Science and the Cochrane Library databases using "TCM", "liver regeneration" or their synonyms as keywords, and classified and summarized the retrieved literature. The PRISMA guidelines were followed. RESULTS Forty-one research articles met the themes of this review and previous critical studies were also reviewed to provide essential background information. Current evidences indicate that various TCM formulas, extracts and active ingredients have the effect on stimulating liver regeneration through modulating JAK/STAT, Hippo, PI3K/Akt and other signaling pathways. Besides, the mechanisms of liver regeneration, the limitation of existing studies and the application prospect of TCM to promote liver regeneration are also outlined and discussed in this review. CONCLUSION This review supports TCM as new potential therapeutic options for promoting liver regeneration and repair of the failing liver, although extensive pharmacokinetic and toxicological studies, as well as elaborate clinical trials, are still needed to demonstrate safety and efficacy.
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Affiliation(s)
- Jia-Ting Ma
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Shuang Xia
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Bi-Kui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Fen Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Lin Guo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Yan Yang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Hui Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China.
| | - Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China.
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Hasan MN, Chen J, Matye D, Wang H, Luo W, Gu L, Clayton YD, Du Y, Li T. Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice. J Lipid Res 2023; 64:100340. [PMID: 36737039 PMCID: PMC9986646 DOI: 10.1016/j.jlr.2023.100340] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 02/05/2023] Open
Abstract
Therapeutic reduction of hydrophobic bile acids exposure is considered beneficial in cholestasis. The Cyp2c70 KO mice lack hydrophilic muricholic acids and have a human-like hydrophobic bile acid pool resulting in hepatobiliary injury. This study investigates if combining an apical sodium-dependent bile acid transporter inhibitor GSK2330672 (GSK) and fibroblast growth factor-15 (FGF15) overexpression, via simultaneous inhibition of bile acid synthesis and gut bile acid uptake, achieves enhanced therapeutic efficacy in alleviating hepatobiliary injury in Cyp2c70 KO mice. The effects of GSK, adeno-associated virus (AAV)-FGF15, and the combined treatment on bile acid metabolism and cholangiopathy were compared in Cyp2c70 KO mice. In female Cyp2c70 KO mice with more severe cholangiopathy than male Cyp2c70 KO mice, the combined treatment was more effective in reversing portal inflammation, ductular reaction, and fibrosis than AAV-FGF15, while GSK was largely ineffective. The combined treatment reduced bile acid pool by ∼80% compared to ∼50% reduction by GSK or AAV-FGF15, and enriched tauro-conjugated ursodeoxycholic acid in the bile. Interestingly, the male Cyp2c70 KO mice treated with AAV-FGF15 or GSK showed attenuated cholangiopathy and portal fibrosis but the combined treatment was ineffective despite reducing bile acid pool. Both male and female Cyp2c70 KO mice showed impaired gut barrier integrity. AAV-FGF15 and the combined treatment, but not GSK, reduced gut exposure to lithocholic acid and improved gut barrier function. In conclusion, the combined treatment improved therapeutic efficacy against cholangiopathy than either single treatment in the female but not male Cyp2c70 KO mice by reducing bile acid pool size and hydrophobicity.
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Affiliation(s)
- Mohammad Nazmul Hasan
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Jianglei Chen
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - David Matye
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Huaiwen Wang
- Laboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Wenyi Luo
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Lijie Gu
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Yung Dai Clayton
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Yanhong Du
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Tiangang Li
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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Chen B, Zhang L, Cheng J, Wu T, Lei J, Yang X, Zhang R, Safadi R, Li Y, Si T, Lu Y. Risk Factors for Hepatic Encephalopathy in Hepatocellular Carcinoma After Sorafenib or Lenvatinib Treatment: A Real-World Study. Drug Des Devel Ther 2022; 16:4429-4437. [PMID: 36597443 PMCID: PMC9805705 DOI: 10.2147/dddt.s386829] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 11/16/2022] [Indexed: 12/29/2022] Open
Abstract
Purpose This study aimed to investigate the incidence rate and risk factors for hepatic encephalopathy (HE) among unresectable hepatocellular carcinoma (uHCC) patients with liver cirrhosis who received sorafenib or lenvatinib treatment. Patients and Methods uHCC patients with cirrhosis who received first-line sorafenib or lenvatinib treatment between September 2014 and February 2021 were continually reviewed in our single-center retrospective study. The Hepatic Encephalopathy Scoring Algorithm was used to evaluate the occurrence and grade of HE during treatment, and logistic regression models were used to further explore the risk factors for HE. Results A total of 454 eligible patients were enrolled in our study, with 214 and 240 patients in the sorafenib and lenvatinib groups, respectively. At time of data cut-off (2021-12), the incidence of HE in sorafenib group (4.2%, 95% CI:2-7%) was significantly lower than that in lenvatinib group (11.3%,95% CI:7-15%) (p = 0.006), with alcoholic cirrhosis [OR: 5.857 (95% CI: 1.519-22.591)], Child-Pugh >7 [OR: 3.023 (95% CI: 1.135-8.053)], blood ammonia ≥38.65 μmol/L [OR: 4.693 (95% CI: 1.782-12.358)], total bile acid ≥29.5 μmol/L [OR: 11.047 (95% CI: 4.414-27.650)] and duration of treatment ≥5.6 months [OR: 4.350 (95% CI: 1.701-11.126)] to be risk factors for the occurrence of HE during first-line systemic therapy. Conclusion In our study, for off-label uHCC patients (Child-Pugh >7) with alcoholic cirrhosis, hyperammonemia, hypercholesterolemia, and estimated longer duration of treatment, the application of lenvatinib has to be cautious, which needs to be confirmed in future clinical trials.
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Affiliation(s)
- Bowen Chen
- Peking University 302 Clinical Medical School, Beijing, People’s Republic of China,Senior Department of Hepatology, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China
| | - Linzhi Zhang
- Senior Department of Hepatology, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China,Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of China
| | - Jiamin Cheng
- Senior Department of Hepatology, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China
| | - Tong Wu
- Senior Department of Hepatology, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China
| | - Jin Lei
- Senior Department of Hepatology, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China,Guizhou Medical University, Guiyang, People’s Republic of China
| | - Xu Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Rongling Zhang
- Department of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Rifaat Safadi
- Liver Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel
| | - Yinyin Li
- Senior Department of Hepatology, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China
| | - Tongguo Si
- Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of China,Tongguo Si, Tianjin Medical University Cancer Institute and Hospital, Tiyuan North Huanhu West Road, Hexi District, Tianjin, 300060, People’s Republic of China, Email
| | - Yinying Lu
- Peking University 302 Clinical Medical School, Beijing, People’s Republic of China,Senior Department of Hepatology, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China,Center for Synthetic & System Biology, Tsinghua University, Beijing, People’s Republic of China,Guangdong Key Laboratory of Epigenetics, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, People’s Republic of China,Correspondence: Yinying Lu, Peking University 302 Clinical Medical School, No. 100, Middle Road of the West 4th Ring, Beijing, 100039, People’s Republic of China, Email
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Di Ciaula A, Bonfrate L, Baj J, Khalil M, Garruti G, Stellaard F, Wang HH, Wang DQH, Portincasa P. Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling. Nutrients 2022; 14:4950. [PMID: 36500979 PMCID: PMC9738051 DOI: 10.3390/nu14234950] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/18/2022] [Accepted: 11/20/2022] [Indexed: 11/23/2022] Open
Abstract
Bile acids (BA) are amphiphilic molecules synthesized in the liver (primary BA) starting from cholesterol. In the small intestine, BA act as strong detergents for emulsification, solubilization and absorption of dietary fat, cholesterol, and lipid-soluble vitamins. Primary BA escaping the active ileal re-absorption undergo the microbiota-dependent biotransformation to secondary BA in the colon, and passive diffusion into the portal vein towards the liver. BA also act as signaling molecules able to play a systemic role in a variety of metabolic functions, mainly through the activation of nuclear and membrane-associated receptors in the intestine, gallbladder, and liver. BA homeostasis is tightly controlled by a complex interplay with the nuclear receptor farnesoid X receptor (FXR), the enterokine hormone fibroblast growth factor 15 (FGF15) or the human ortholog FGF19 (FGF19). Circulating FGF19 to the FGFR4/β-Klotho receptor causes smooth muscle relaxation and refilling of the gallbladder. In the liver the binding activates the FXR-small heterodimer partner (SHP) pathway. This step suppresses the unnecessary BA synthesis and promotes the continuous enterohepatic circulation of BAs. Besides BA homeostasis, the BA-FXR-FGF19 axis governs several metabolic processes, hepatic protein, and glycogen synthesis, without inducing lipogenesis. These pathways can be disrupted in cholestasis, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Thus, targeting FXR activity can represent a novel therapeutic approach for the prevention and the treatment of liver and metabolic diseases.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
| | - Jacek Baj
- Department of Anatomy, Medical University of Lublin, 20-059 Lublin, Poland
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
| | - Frans Stellaard
- Institute of Clinical Chemistry and Clinical Pharmacology, Venusberg-Campus 1, University Hospital Bonn, 53127 Bonn, Germany
| | - Helen H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
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Wei D, Li Y, Che M, Li C, Wu Q, Sun C. Melatonin relieves hepatic lipid dysmetabolism caused by aging via modifying the secondary bile acid pattern of gut microbes. Cell Mol Life Sci 2022; 79:527. [PMID: 36151409 PMCID: PMC11803049 DOI: 10.1007/s00018-022-04412-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/17/2022] [Accepted: 06/02/2022] [Indexed: 11/25/2022]
Abstract
It has been reported that aging-generated gut microecosystem may promote host hepatic lipid dysmetabolism through shaping the pattern of secondary bile acids (BAs). Then as an oral drug, melatonin (Mel)-mediated beneficial efforts on the communication between gut microbiota and aging host are still not clearly. Here, we show that aging significantly shapes the pattern of gut microbiota and BAs, whereas Mel treatment reverses these phenotypes (P < 0.05), which is identified to depend on the existence of gut microbiota. Mechanistically, aging-triggered high-level expression of ileac farnesoid X receptor (FXR) is significantly decreased through Mel-mediated inhibition on Campylobacter jejuni (C. jejuni)-induced deconjugation of tauroursodeoxycholic acid (TUDCA) and glycoursodeoxycholic acid (GUDCA) (P < 0.05). The aging-induced high-level of serum taurine chenodeoxycholic acid (TCDCA) activate trimethylamine-N-oxide (TMAO)-triggered activating transcriptional factor 4 (ATF4) signaling via hepatic FXR, which further regulates hepatic BAs metabolism, whereas TUDCA inhibits aging-triggered high-level of hepatic ATF4. Overall, Mel reduces C. jejuni-mediated deconjugation of TUDCA to inhibit aging-triggered high-level expression of hepatic FXR, which further decreases hepatic TMAO production, to relieve hepatic lipid dysmetabolism.
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Affiliation(s)
- Dongqin Wei
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Yizhou Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Meng Che
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Chaowei Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Qiong Wu
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Chao Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, Shaanxi, China.
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16
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Kong B, Huang M, Taylor RE, Rizzolo D, Otersen KD, Guo GL. Effects of intestine-specific deletion of fibroblast growth factor 15 on alcoholic liver disease development in mice. LIVER RESEARCH 2022; 6:84-92. [PMID: 39958627 PMCID: PMC11791802 DOI: 10.1016/j.livres.2022.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/25/2022] [Accepted: 05/05/2022] [Indexed: 11/19/2022]
Abstract
Background and aims Alcoholic liver disease (ALD) is an important and growing cause for the development of chronic liver diseases in the world. Bile acid (BA) levels are increased in patients with ALD and dysregulation of BA homeostasis worsens ALD. BA synthesis is critically regulated by fibroblast growth factor (FGF)15 in mice and FGF19 in humans. FGF15/19 are mainly produced in the ileum and their main function is to suppress BA synthesis in the liver through the activation of fibroblast growth factor receptor 4 (FGFR4) on hepatocytes. The effects of intestine-specific Fgf15 deficiency on the development of ALD were determined in the current study. Methods Enterocyte-specific Fgf15 knockout mice (Fgf15 int-/- ) and the established mouse model by chronic and binge ethanol feeding (NIAAA model) were adapted in this study. Results The Fgf15 int-/- mice had increased BA pool size, consistent with negative effects of FGF15-FGFR4 signaling on BA synthesis. There were not obviously physical and hepatic histological abnormalities presented in Fgf15 int-/- mice compared to wild-type mice. Following alcohol treatment, the Fgf15 int-/- mice exhibited a higher degree of liver injury, increased hepatic expression of Cd14, a receptor for lipopolysaccharide expressed in the liver, and increased hepatic lipid levels. We did not observe alterations in the levels of fibrosis in the liver or expression of genes involved in hepatic fibrosis, regardless of genotypes or following the alcohol treatment. Conclusions FGF15 may prevent hepatic steatosis in the development of ALD in mice, and maintaining FGF19/FGFR4 signaling may be critical in the prevention and/or treatment of ALD in humans in the future.
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Affiliation(s)
- Bo Kong
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Mingxing Huang
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Rulaiha E. Taylor
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Daniel Rizzolo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Katherine D. Otersen
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Grace L. Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
- Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
- Rutgers Center for Lipid Research, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
- VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, NJ, USA
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17
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Updates on novel pharmacotherapeutics for the treatment of nonalcoholic steatohepatitis. Acta Pharmacol Sin 2022; 43:1180-1190. [PMID: 35190696 PMCID: PMC9061746 DOI: 10.1038/s41401-022-00860-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 01/03/2022] [Indexed: 12/14/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD), characterized with hepatocellular steatosis, ballooning, lobular inflammation, fibrotic progression, and insulin resistance. NASH may progress to cirrhosis and hepatocellular carcinoma (HCC), which are the major indications for liver transplantation and the causes for mortality. Thus far, there are no approved pharmacotherapeutics for the treatment of NASH. Given the complexity of NASH pathogenesis at multifaceted aspects, such as lipotoxicity, inflammation, insulin resistance, mitochondrial dysfunction and fibrotic progression, pharmacotherapeutics under investigation target different key pathogenic pathways to gain either the resolution of steatohepatitis or regression of fibrosis, ideally both. Varieties of pharmacologic candidates have been tested in clinical trials and have generated some positive results. On the other hand, recent failure or termination of a few phase II and III trials is disappointing in this field. In face to growing challenges in pharmaceutical development, this review intends to summarize the latest data of new medications which have completed phase II or III trials, and discuss the rationale and preliminary results of several combinatory options. It is anticipated that with improved understanding of NASH pathogenesis and critical endpoints, efficient pharmacotherapeutics will be available for the treatment of NASH with an acceptable safety profile.
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Rizzolo D, Kong B, Piekos S, Chen L, Zhong X, Lu J, Shi J, Zhu HJ, Yang Q, Li A, Li L, Wang H, Siemiątkowska A, Park C, Kagan L, Guo GL. Effects of Overexpression of Fibroblast Growth Factor 15/19 on Hepatic Drug Metabolizing Enzymes. Drug Metab Dispos 2022; 50:468-477. [PMID: 34965924 PMCID: PMC11022908 DOI: 10.1124/dmd.121.000416] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 12/20/2021] [Indexed: 11/22/2022] Open
Abstract
Fibroblast growth factors 15 (FGF15) and 19 (FGF19) are endocrine growth factors that play an important role in maintaining bile acid homeostasis. FGF15/19-based therapies are currently being tested in clinical trials for the treatment of nonalcoholic steatohepatitis and cholestatic liver diseases. To determine the physiologic impact of long-term elevations of FGF15/19, a transgenic mouse model with overexpression of Fgf15 (Fgf15 Tg) was used in the current study. The RNA sequencing (RNA-seq) analysis revealed elevations of the expression of several genes encoding phase I drug metabolizing enzymes (DMEs), including Cyp2b10 and Cyp3a11, in Fgf15 Tg mice. We found that the induction of several Cyp2b isoforms resulted in increased function of CYP2B in microsomal metabolism and pharmacokinetics studies. Because the CYP2B family is known to be induced by constitutive androstane receptor (CAR), to determine the role of CAR in the observed inductions, we crossed Fgf15 Tg mice with CAR knockout mice and found that CAR played a minor role in the observed alterations in DME expression. Interestingly, we found that the overexpression of Fgf15 in male mice resulted in a phenotypical switch from the male hepatic expression pattern of DMEs to that of female mice. Differences in secretion of growth hormone (GH) between male and female mice are known to drive sexually dimorphic, STAT5b-dependent expression patterns of hepatic genes. We found that male Fgf15 Tg mice presented with many features similar to GH deficiency, including lowered body length and weight, Igf-1 and Igfals expression, and STAT5 signaling. SIGNIFICANCE STATEMENT: The overexpression of Fgf15 in mice causes an alteration in DMEs at the mRNA, protein, and functional levels, which is not entirely due to CAR activation but associated with lower GH signaling.
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Affiliation(s)
- Daniel Rizzolo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Bo Kong
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Stephanie Piekos
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Liming Chen
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Xiaobo Zhong
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Jie Lu
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Jian Shi
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Hao-Jie Zhu
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Qian Yang
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Albert Li
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Linhao Li
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Hongbing Wang
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Anna Siemiątkowska
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Celine Park
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Leonid Kagan
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
| | - Grace L Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.R., B.K., G.L.G.), Department of Pharmaceutical Sciences, Ernest Mario School of Pharmacy (A.S., C.P., L.K.), Center of Excellence for Pharmaceutical Translational Research and Education (A.S., C.P., L.K.), and Environmental and Occupational Health Sciences Institute (EOHSI) (D.R., G.L.G.), Rutgers University, Piscataway, New Jersey; Rutgers Center for Lipid Research, Rutgers University-New Brunswick, New Brunswick, New Jersey (D.R., G.L.G.); VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (S.P., L.C., X.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L.); Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.S., H.-J.Z.); In Vitro ADMET Laboratories, LLC, Columbia, Maryland (Q.Y., A.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (L.L., H.W.); and Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland (A.S.)
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Kong B, Rizzolo D, Taylor RE, Guo GL. Bile Acid Profiling in Mouse Biofluids and Tissues. Methods Mol Biol 2022; 2455:305-318. [PMID: 35213003 PMCID: PMC8922367 DOI: 10.1007/978-1-0716-2128-8_23] [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: 06/14/2023]
Abstract
Bile acids (BAs) serve as important signaling molecules and are endogenous ligands of nuclear and cell membrane receptors to regulate physiological and pathological processes. BA synthesis and metabolism have been impaired in NASH patients because of liver injury, inflammation or obstruction of bile ducts. On the other hand, the changes in BA composition might alter the activation status of various cell signaling pathways and contribute to NASH pathogenesis. Due to the rapidly increasing interests in the roles of individual BA in disease development, this chapter will focus on the method for analyzing individual BA profile in mouse biofluids and tissues by high-performance liquid chromatography coupled with ion trap mass spectrometry (HPLC-MS).
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Affiliation(s)
- Bo Kong
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Daniel Rizzolo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Rulaiha E Taylor
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Grace L Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
- Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
- Rutgers Center for Lipid Research, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
- VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, NJ, USA.
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20
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Sun R, Zhao H, Huang S, Zhang R, Lu Z, Li S, Wang G, Aa J, Xie Y. Prediction of Liver Weight Recovery by an Integrated Metabolomics and Machine Learning Approach After 2/3 Partial Hepatectomy. Front Pharmacol 2021; 12:760474. [PMID: 34916939 PMCID: PMC8669962 DOI: 10.3389/fphar.2021.760474] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 11/01/2021] [Indexed: 12/15/2022] Open
Abstract
Liver has an ability to regenerate itself in mammals, whereas the mechanism has not been fully explained. Here we used a GC/MS-based metabolomic method to profile the dynamic endogenous metabolic change in the serum of C57BL/6J mice at different times after 2/3 partial hepatectomy (PHx), and nine machine learning methods including Least Absolute Shrinkage and Selection Operator Regression (LASSO), Partial Least Squares Regression (PLS), Principal Components Regression (PCR), k-Nearest Neighbors (KNN), Support Vector Machines (SVM), Random Forest (RF), eXtreme Gradient Boosting (xgbDART), Neural Network (NNET) and Bayesian Regularized Neural Network (BRNN) were used for regression between the liver index and metabolomic data at different stages of liver regeneration. We found a tree-based random forest method that had the minimum average Mean Absolute Error (MAE), Root Mean Squared Error (RMSE) and the maximum R square (R2) and is time-saving. Furthermore, variable of importance in the project (VIP) analysis of RF method was performed and metabolites with VIP ranked top 20 were selected as the most critical metabolites contributing to the model. Ornithine, phenylalanine, 2-hydroxybutyric acid, lysine, etc. were chosen as the most important metabolites which had strong correlations with the liver index. Further pathway analysis found Arginine biosynthesis, Pantothenate and CoA biosynthesis, Galactose metabolism, Valine, leucine and isoleucine degradation were the most influenced pathways. In summary, several amino acid metabolic pathways and glucose metabolism pathway were dynamically changed during liver regeneration. The RF method showed advantages for predicting the liver index after PHx over other machine learning methods used and a metabolic clock containing four metabolites is established to predict the liver index during liver regeneration.
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Affiliation(s)
- Runbin Sun
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.,Phase I Clinical Trials Unit, Nanjing University Medical School Affiliated Drum Tower Hospital, Nanjing, China
| | - Haokai Zhao
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Shuzhen Huang
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Ran Zhang
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Zhenyao Lu
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Sijia Li
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Guangji Wang
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Jiye Aa
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Yuan Xie
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
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21
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Koelfat KVK, van Mierlo KMC, Lodewick TM, Bloemen JG, van der Kroft G, Amygdalos I, Neumann UP, Dejong CHC, Jansen PLM, Olde Damink SWM, Schaap FG. Bile Salt and FGF19 Signaling in the Early Phase of Human Liver Regeneration. Hepatol Commun 2021; 5:1400-1411. [PMID: 34430784 PMCID: PMC8369949 DOI: 10.1002/hep4.1728] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/07/2021] [Accepted: 02/19/2021] [Indexed: 02/04/2023] Open
Abstract
The involvement of bile salt-fibroblast growth factor 19 (FGF19) signaling in human liver regeneration (LR) is not well studied. Therefore, we studied aspects of bile salt-FGF19 signaling shortly after liver resection in patients. We compared plasma bile salt and FGF19 levels in arterial, portal and hepatic venous blood, calculated venous-arterial differences (ΔVA), and determined hepatic transcript levels on two intra-operative time points: before (< 1 hour) and immediately after (> 2-3 hours) liver resection (i.e., following surgery). Postoperative bile salt and FGF19 levels were assessed on days 1, 2, and 3. LR was studied by computed tomography (CT)-liver volumetry. Following surgery, the liver, arterial, and portal bile salt levels were elevated (P < 0.05). Furthermore, an increased amount of bile salts was released in portal blood and extracted by the remnant liver (P < 0.05). Postoperatively, bile salt levels were elevated from day 1 onward (P < 0.001). For FGF19, intra-operative or postoperative changes of ΔVA or plasma levels were not observed. The bile salt-homeostatic regulator farnesoid X receptor (FXR) was markedly up-regulated following surgery (P < 0.001). Cell-cycle re-entry priming factors (interleukin 6 [IL-6], signal transducer and activator of transcription 3 [STAT3], and cJUN) were up-regulated following surgery and were positively correlated with FXR expression (P < 0.05). Postoperative hyperbilirubinemia was preceded by postsurgery low FXR and high Na+/Taurocholate cotransporting polypeptide (NTCP) expression in the remnant liver coupled with higher liver bile salt content (P < 0.05). Finally, bile salt levels on postoperative day 1 were an independent predictor of LR (P < 0.05). Conclusion: Systemic, portal, and liver bile salt levels are rapidly elevated after liver resection. Postoperative bile salts were positively associated with liver volume gain. In the studied time frame, FGF19 levels remained unaltered, suggesting that FGF19 plays a minor role in human LR. These findings indicate a more relevant role of bile salts in human LR.
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Affiliation(s)
- Kiran V K Koelfat
- Department of SurgeryNUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtThe Netherlands
| | - Kim M C van Mierlo
- Department of SurgeryNUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtThe Netherlands
| | - Toine M Lodewick
- Department of RadiologyMaastricht University Medical Center+MaastrichtThe Netherlands
| | - Johanne G Bloemen
- Department of SurgeryNUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtThe Netherlands
| | - Gregory van der Kroft
- Department of General, Visceral and Transplantation SurgeryRWTH University Hospital AachenAachenGermany
| | - Iakovos Amygdalos
- Department of General, Visceral and Transplantation SurgeryRWTH University Hospital AachenAachenGermany
| | - Ulf P Neumann
- Department of SurgeryNUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtThe Netherlands.,Department of General, Visceral and Transplantation SurgeryRWTH University Hospital AachenAachenGermany
| | - Cornelis H C Dejong
- Department of SurgeryNUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtThe Netherlands.,Department of General, Visceral and Transplantation SurgeryRWTH University Hospital AachenAachenGermany
| | - Peter L M Jansen
- Department of SurgeryNUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtThe Netherlands
| | - Steven W M Olde Damink
- Department of SurgeryNUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtThe Netherlands.,Department of General, Visceral and Transplantation SurgeryRWTH University Hospital AachenAachenGermany
| | - Frank G Schaap
- Department of SurgeryNUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtThe Netherlands.,Department of General, Visceral and Transplantation SurgeryRWTH University Hospital AachenAachenGermany
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22
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Caballeria-Casals A, Micó-Carnero M, Rojano-Alfonso C, Maroto-Serrat C, Casillas-Ramírez A, Álvarez-Mercado AI, Gracia-Sancho J, Peralta C. Role of FGF15 in Hepatic Surgery in the Presence of Tumorigenesis: Dr. Jekyll or Mr. Hyde? Cells 2021; 10:1421. [PMID: 34200439 PMCID: PMC8228386 DOI: 10.3390/cells10061421] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/26/2021] [Accepted: 06/04/2021] [Indexed: 12/11/2022] Open
Abstract
The pro-tumorigenic activity of fibroblast growth factor (FGF) 19 (FGF15 in its rodent orthologue) in hepatocellular carcinoma (HCC), as well as the unsolved problem that ischemia-reperfusion (IR) injury supposes in liver surgeries, are well known. However, it has been shown that FGF15 administration protects against liver damage and regenerative failure in liver transplantation (LT) from brain-dead donors without tumor signals, providing a benefit in avoiding IR injury. The protection provided by FGF15/19 is due to its anti-apoptotic and pro-regenerative properties, which make this molecule a potentially beneficial or harmful factor, depending on the disease. In the present review, we describe the preclinical models currently available to understand the signaling pathways responsible for the apparent controversial effects of FGF15/19 in the liver (to repair a damaged liver or to promote tumorigenesis). As well, we study the potential pharmacological use that has the activation or inhibition of FGF15/19 pathways depending on the disease to be treated. We also discuss whether FGF15/19 non-pro-tumorigenic variants, which have been developed for the treatment of liver diseases, might be promising approaches in the surgery of hepatic resections and LT using healthy livers and livers from extended-criteria donors.
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Affiliation(s)
- Albert Caballeria-Casals
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (M.M.-C.); (C.R.-A.)
| | - Marc Micó-Carnero
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (M.M.-C.); (C.R.-A.)
| | - Carlos Rojano-Alfonso
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (M.M.-C.); (C.R.-A.)
| | | | - Araní Casillas-Ramírez
- Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria 87087, Mexico;
- Facultad de Medicina e Ingeniería en Sistemas Computacionales de Matamoros, Universidad Autónoma de Tamaulipas, Matamoros 87300, Mexico
| | - Ana I. Álvarez-Mercado
- Departamento de Bioquímica y Biología Molecular II, Escuela de Farmacia, Universidad de Granada, 18071 Granada, Spain;
- Institute of Nutrition and Food Technology “José Mataix”, Center of Biomedical Research, University of Granada, 18016 Armilla, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory IDIBAPS, 03036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain
| | - Carmen Peralta
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (M.M.-C.); (C.R.-A.)
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23
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Matye DJ, Wang H, Luo W, Sharp RR, Chen C, Gu L, Jones KL, Ding WX, Friedman JE, Li T. Combined ASBT Inhibitor and FGF15 Treatment Improves Therapeutic Efficacy in Experimental Nonalcoholic Steatohepatitis. Cell Mol Gastroenterol Hepatol 2021; 12:1001-1019. [PMID: 33965587 PMCID: PMC8346663 DOI: 10.1016/j.jcmgh.2021.04.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/24/2021] [Accepted: 04/26/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Pharmacologic agents targeting bile acid signaling show promise for treating nonalcoholic steatohepatitis (NASH). However, clinical findings suggest that new treatment strategies with enhanced therapeutic efficacy and minimized undesired effects are needed. This preclinical study investigates whether combining an apical sodium-bile acid transporter (ASBT) inhibitor GSK233072 (GSK672) and fibroblast growth factor-15 (FGF15) signaling activation improves anti-NASH efficacy. METHODS Mice with high fat, cholesterol, and fructose (HFCFr) diet-induced NASH and stage 2 fibrosis are used as a NASH model. GSK672 or AAV8-TBG-FGF15 interventions are administered alone or in combination to HFCFr diet-fed mice. RESULTS The combined treatment significantly enhances therapeutic efficacy against steatosis, inflammation, ballooning, and fibrosis than either single treatment. Mechanistically, the synergistic actions of GSK672 and FGF15 on inhibiting gut bile acid reuptake and hepatic bile acid synthesis achieve greater magnitude of bile acid pool reduction that not only decreases bile acid burden in NASH livers but also limits intestinal lipid absorption, which, together with FGF15 signaling activation, produces weight loss, reduction of adipose inflammation, and attenuated hepatocellular organelle stress. Furthermore, the combined treatment attenuates increased fecal bile acid excretion and repressed bile acid synthesis, which underlie diarrhea and hypercholesterolemia associated with ASBT inhibition and FGF19 analogue, respectively, in clinical settings. CONCLUSIONS Concomitant ASBT inhibition and FGF15 signaling activation produce metabolic changes that partially mimic the bariatric surgery condition whereby lipid malabsorption and increased FGF15/19 signaling synergistically mediate weight loss and metabolic improvement. Further clinical studies may be warranted to investigate whether combining ASBT inhibitor and FGF19 analogue enhances anti-NASH efficacy and reduced treatment-associated adverse events in humans.
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Affiliation(s)
- David J Matye
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Pharmacology, Toxicology, Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Huaiwen Wang
- Laboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Wenyi Luo
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Rachel R Sharp
- Laboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Harold Hamm Diabetes Center, Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Cheng Chen
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Lijie Gu
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Kenneth L Jones
- Laboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Harold Hamm Diabetes Center, Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology, Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Jacob E Friedman
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Tiangang Li
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
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24
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The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol 2021; 18:335-347. [PMID: 33568795 DOI: 10.1038/s41575-020-00404-2] [Citation(s) in RCA: 234] [Impact Index Per Article: 58.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/14/2020] [Indexed: 01/31/2023]
Abstract
Farnesoid X receptor (FXR) is a ligand-activated transcription factor involved in the control of bile acid (BA) synthesis and enterohepatic circulation. FXR can influence glucose and lipid homeostasis. Hepatic FXR activation by obeticholic acid is currently used to treat primary biliary cholangitis. Late-stage clinical trials investigating the use of obeticholic acid in the treatment of nonalcoholic steatohepatitis are underway. Mouse models of metabolic disease have demonstrated that inhibition of intestinal FXR signalling reduces obesity, insulin resistance and fatty liver disease by modulation of hepatic and gut bacteria-mediated BA metabolism, and intestinal ceramide synthesis. FXR also has a role in the pathogenesis of gastrointestinal and liver cancers. Studies using tissue-specific and global Fxr-null mice have revealed that FXR acts as a suppressor of hepatocellular carcinoma, mainly through regulating BA homeostasis. Loss of whole-body FXR potentiates progression of spontaneous colorectal cancer, and obesity-induced BA imbalance promotes intestinal stem cell proliferation by suppressing intestinal FXR in Apcmin/+ mice. Owing to altered gut microbiota and FXR signalling, changes in overall BA levels and specific BA metabolites probably contribute to enterohepatic tumorigenesis. Modulating intestinal FXR signalling and altering BA metabolites are potential strategies for gastrointestinal and liver cancer prevention and treatment. In this Review, studies on the role of FXR in metabolic diseases and gastrointestinal and liver cancer are discussed, and the potential for development of targeted drugs are summarized.
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25
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Kiseleva YV, Antonyan SZ, Zharikova TS, Tupikin KA, Kalinin DV, Zharikov YO. Molecular pathways of liver regeneration: A comprehensive review. World J Hepatol 2021; 13:270-290. [PMID: 33815672 PMCID: PMC8006075 DOI: 10.4254/wjh.v13.i3.270] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 01/20/2021] [Accepted: 03/12/2021] [Indexed: 02/06/2023] Open
Abstract
The liver is a unique parenchymal organ with a regenerative capacity allowing it to restore up to 70% of its volume. Although knowledge of this phenomenon dates back to Greek mythology (the story of Prometheus), many aspects of liver regeneration are still not understood. A variety of different factors, including inflammatory cytokines, growth factors, and bile acids, promote liver regeneration and control the final size of the organ during typical regeneration, which is performed by mature hepatocytes, and during alternative regeneration, which is performed by recently identified resident stem cells called "hepatic progenitor cells". Hepatic progenitor cells drive liver regeneration when hepatocytes are unable to restore the liver mass, such as in cases of chronic injury or excessive acute injury. In liver maintenance, the body mass ratio is essential for homeostasis because the liver has numerous functions; therefore, a greater understanding of this process will lead to better control of liver injuries, improved transplantation of small grafts and the discovery of new methods for the treatment of liver diseases. The current review sheds light on the key molecular pathways and cells involved in typical and progenitor-dependent liver mass regeneration after various acute or chronic injuries. Subsequent studies and a better understanding of liver regeneration will lead to the development of new therapeutic methods for liver diseases.
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Affiliation(s)
- Yana V Kiseleva
- International School "Medicine of the Future", I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119435, Russia
| | - Sevak Z Antonyan
- Department of Emergency Surgical Gastroenterology, N. V. Sklifosovsky Research Institute for Emergency Medicine, Moscow 129010, Russia
| | - Tatyana S Zharikova
- Department of Human Anatomy, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119048, Russia
| | - Kirill A Tupikin
- Laboratory of Minimally Invasive Surgery, A.I. Evdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia
| | - Dmitry V Kalinin
- Pathology Department, A.V. Vishnevsky National Medical Research Center of Surgery of the Russian Ministry of Healthcare, Moscow 117997, Russia
| | - Yuri O Zharikov
- Department of Human Anatomy, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119048, Russia.
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26
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Leng L, Ma J, Lv L, Gao D, Li M, Wang Y, Zhu Y. Serum proteome profiling provides a deep understanding of the 'gut-liver axis' in relation to liver injury and regeneration. Acta Biochim Biophys Sin (Shanghai) 2021; 53:372-380. [PMID: 33511977 DOI: 10.1093/abbs/gmab001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Indexed: 12/25/2022] Open
Abstract
The gut-liver axis is one of the major contributors to the transport of products from the intestine or intestinal microbes with the progression of liver regeneration. However, the influence of proteins from the hepatic portal vein (HPV), the bridge of enterohepatic circulation, on liver regeneration is unclear. For first time, we applied a quantitative proteomics approach to characterize the molecular pathology of the HPV sera of mice with antibiotic-induced intestinal flora disorder during acute liver injury. The biological processes of lipid metabolism and wound healing were enriched in the HPV of mice with intestinal flora disorder, whereas energy metabolism, liver regeneration, and cytoskeletal processes were downregulated. Moreover, 95 and 35 proteins potentially promoting or inhibiting liver regeneration, respectively, were identified in HPV serum. Our findings will be beneficial to liver donors during liver transplantation.
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Affiliation(s)
- Ling Leng
- Stem cell and Regenerative Medicine Lab, Department of Medical Science Research Center, Translational Medicine Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Jie Ma
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Life Omics, Beijing 102206, China
| | - Luye Lv
- Department of Biological Defense, Institute of NBC Defense, Beijing 102205, China
| | - Dunqin Gao
- Stem cell and Regenerative Medicine Lab, Department of Medical Science Research Center, Translational Medicine Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Mansheng Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Life Omics, Beijing 102206, China
| | - Yujie Wang
- Stem cell and Regenerative Medicine Lab, Department of Medical Science Research Center, Translational Medicine Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yunping Zhu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Life Omics, Beijing 102206, China
- Basic Medical School, Anhui Medical University, Hefei 230032, China
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27
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Ying Y, Xiang G, Chen M, Ye J, Wu Q, Dou H, Sheng S, Zhu S. Gelatine nanostructured lipid carrier encapsulated FGF15 inhibits autophagy and improves recovery in spinal cord injury. Cell Death Discov 2020; 6:137. [PMID: 33298870 PMCID: PMC7710748 DOI: 10.1038/s41420-020-00367-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 10/12/2020] [Accepted: 10/27/2020] [Indexed: 12/13/2022] Open
Abstract
Gelatine nanostructured lipid carriers (GNLs) have attracted increasing attention due to their biodegradable status and capacity to capture various biologically active compounds. Many studies demonstrated that fibroblast growth factor therapies after spinal cord injury (SCI) can be used in the future for the recovery of neurons. In this study, the therapeutic effects of GNL-encapsulated fibroblast growth factor 15 (FGF15) and FGF15 were compared in SCI. The FGF15-GNLs had 88.17 ± 1.22% encapsulation efficiency and 4.82 ± 0.12% loading capacity. The effects of FGF15-GNLs and FGF15 were assessed based on the Basso–Beattie–Bresnahan (BBB) locomotion scale, inclined plane test and footprint analysis. Immunofluorescent staining was used to identify the expression of autophagy-associated proteins, GFAP (glial fibrillary acidic protein) and neurofilament 200 (NF200). FGF15-GNLs use enhanced the repair after SCI compared to the effect of FGF15. The suppression of autophagy-associated proteins LC3-II and beclin-1, and p62 enhancement by FGF15-GNLs treatment were more pronounced. Thus, the effects of FGF15-GNLs on the recovery after SCI are related to the inhibition of autophagy and glial scar, and promotion of nerve regeneration in SCI.
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Affiliation(s)
- Yibo Ying
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325027, China
| | - Guangheng Xiang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325027, China
| | - Min Chen
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325027, China
| | - Jiahui Ye
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325027, China
| | - Qiuji Wu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325027, China
| | - Haicheng Dou
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. .,The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325027, China.
| | - Sunren Sheng
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. .,The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325027, China.
| | - Sipin Zhu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. .,The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325027, China.
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28
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Portincasa P, Di Ciaula A, Garruti G, Vacca M, De Angelis M, Wang DQH. Bile Acids and GPBAR-1: Dynamic Interaction Involving Genes, Environment and Gut Microbiome. Nutrients 2020; 12:3709. [PMID: 33266235 PMCID: PMC7760347 DOI: 10.3390/nu12123709] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 11/25/2020] [Accepted: 11/26/2020] [Indexed: 02/06/2023] Open
Abstract
Bile acids (BA) are amphiphilic molecules synthesized in the liver from cholesterol. BA undergo continuous enterohepatic recycling through intestinal biotransformation by gut microbiome and reabsorption into the portal tract for uptake by hepatocytes. BA are detergent molecules aiding the digestion and absorption of dietary fat and fat-soluble vitamins, but also act as important signaling molecules via the nuclear receptor, farnesoid X receptor (FXR), and the membrane-associated G protein-coupled bile acid receptor 1 (GPBAR-1) in the distal intestine, liver and extra hepatic tissues. The hydrophilic-hydrophobic balance of the BA pool is finely regulated to prevent BA overload and liver injury. By contrast, hydrophilic BA can be hepatoprotective. The ultimate effects of BA-mediated activation of GPBAR-1 is poorly understood, but this receptor may play a role in protecting the remnant liver and in maintaining biliary homeostasis. In addition, GPBAR-1 acts on pathways involved in inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity, and sinusoidal blood flow. Recent evidence suggests that environmental factors influence GPBAR-1 gene expression. Thus, targeting GPBAR-1 might improve liver protection, facilitating beneficial metabolic effects through primary prevention measures. Here, we discuss the complex pathways linked to BA effects, signaling properties of the GPBAR-1, mechanisms of liver damage, gene-environment interactions, and therapeutic aspects.
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Affiliation(s)
- Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy;
| | - Mirco Vacca
- Dipartimento di Scienze del Suolo, Della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (M.V.); (M.D.A.)
| | - Maria De Angelis
- Dipartimento di Scienze del Suolo, Della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (M.V.); (M.D.A.)
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
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29
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Gulfo J, Rotondo F, Ávalos de León CG, Cornide-Petronio ME, Fuster C, Gracia-Sancho J, Jiménez-Castro MB, Peralta C. FGF15 improves outcomes after brain dead donor liver transplantation with steatotic and non-steatotic grafts in rats. J Hepatol 2020; 73:1131-1143. [PMID: 32422221 DOI: 10.1016/j.jhep.2020.05.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 04/29/2020] [Accepted: 05/06/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Donation after brain death (DBD) grafts are associated with reduced graft quality and function post liver transplantation (LT). We aimed to elucidate i) the impact of FGF15 levels on DBD grafts; ii) whether this impact resulted from altered intestinal FXR-FGF15; iii) whether administration of FGF15 to donors after brain death could confer a benefit on graft function post LT; and iv) whether FGF15 affects bile acid (BA) accumulation. METHODS Steatotic and non-steatotic grafts from DBD donors and donors without brain death were transplanted in rats. FGF15 was administered alone or combined with either a BA (cholic acid) or a YAP inhibitor. RESULTS Brain death induced intestinal damage and downregulation of FXR. The resulting reduced intestinal FGF15 was associated with low hepatic FGF15 levels, liver damage and regenerative failure. Hepatic FGFR4-Klb - the receptor for FGF15 - was downregulated whereas CYP7A1 was overexpressed, resulting in BA accumulation. FGF15 administration to DBD donors increased hepatic FGFR4-Klb, reduced CYP7A1 and normalized BA levels. The benefit of FGF15 on liver damage was reversed by cholic acid, whereas its positive effect on regeneration was maintained. YAP signaling in DBD donors was activated after FGF15 treatment. When a YAP inhibitor was administered, the benefits of FGF15 on regeneration were abolished, whereas its positive effect on hepatic damage remained. Neither the Hippo-YAP-BA nor the BA-IQGAP1-YAP axis was involved in the benefits of FGF15. CONCLUSION Alterations in the gut-liver axis contribute to the reduced quality of DBD grafts and the associated pathophysiology of LT. FGF15 pre-treatment in DBD donors protected against damage and promoted cell proliferation. LAY SUMMARY After brain death, potential liver donors have reduced intestinal FXR, which is associated with reduced intestinal, circulatory and hepatic levels of FGF15. A similar reduction in the cell-surface receptor complex Fgfr4/Klb is observed, whereas CYP7A1 is overexpressed; together, these molecular events result in the dangerous accumulation of bile acids, leading to damage and regenerative failure in brain dead donor grafts. Herein, we demonstrate that when such donors receive appropriate doses of FGF15, CYP7A1 levels and hepatic bile acid toxicity are reduced, and liver regeneration is promoted.
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Affiliation(s)
- José Gulfo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Floriana Rotondo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | | | | | - Carla Fuster
- Pathology Department, Hospital Clinic, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas (CIBEREHD), Barcelona, Spain; Liver Vascular Biology Research Group, IDIBAPS, Barcelona, Spain
| | | | - Carmen Peralta
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas (CIBEREHD), Barcelona, Spain.
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30
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Yan S, Khambu B, Chen X, Dong Z, Guo G, Yin XM. Hepatic Autophagy Deficiency Remodels Gut Microbiota for Adaptive Protection via FGF15-FGFR4 Signaling. Cell Mol Gastroenterol Hepatol 2020; 11:973-997. [PMID: 33127558 PMCID: PMC7898036 DOI: 10.1016/j.jcmgh.2020.10.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/28/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The functions of the liver and the intestine are closely tied in both physiological and pathologic conditions. The gut microbiota (GM) often cause deleterious effects during hepatic pathogenesis. Autophagy is essential for liver homeostasis, but the impact of hepatic autophagy function on liver-gut interaction remains unknown. Here we investigated the effect of hepatic autophagy deficiency (Atg5Δhep) on GM and in turn the effect of GM on the liver pathology. METHODS Fecal microbiota were analyzed by 16S sequencing. Antibiotics were used to modulate GM. Cholestyramine was used to reduce the enterohepatic bile acid (BA) level. The functional role of fibroblast growth factor 15 (FGF15) and ileal farnesoid X receptor (FXR) was examined in mice overexpressing FGF15 gene or in mice given a fibroblast growth factor receptor-4 (FGFR4) inhibitor. RESULTS Atg5Δhep causes liver injury and alterations of intestinal BA composition, with a lower proportion of tauro-conjugated BAs and a higher proportion of unconjugated BAs. The composition of GM is significantly changed with an increase in BA-metabolizing bacteria, leading to an increased expression of ileal FGF15 driven by FXR that has a higher affinity to unconjugated BAs. Notably, antibiotics or cholestyramine treatment decreased FGF15 expression and exacerbated liver injury. Consistently, inhibition of FGF15 signaling in the liver enhances liver injury. CONCLUSIONS Deficiency of autophagy function in the liver can affect intestinal environment, leading to gut dysbiosis. Surprisingly, such changes provide an adaptive protection against the liver injury through the FGF15-FGFR4 signaling. Antibiotics use in the condition of liver injury may thus have unexpected adverse consequences via the gut-liver axis.
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Affiliation(s)
- Shengmin Yan
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Bilon Khambu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Xiaoyun Chen
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Zheng Dong
- Department of Cell Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia; Charlie Norwood VA Medical Center, Augusta, Georgia
| | - Grace Guo
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
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31
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Enhanced alcoholic liver disease in mice with intestine-specific farnesoid X receptor deficiency. J Transl Med 2020; 100:1158-1168. [PMID: 32404932 PMCID: PMC8487140 DOI: 10.1038/s41374-020-0439-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 04/27/2020] [Accepted: 04/27/2020] [Indexed: 12/13/2022] Open
Abstract
Alcoholic fatty liver disease (AFLD) is one of the major causes of liver morbidity and mortality worldwide. We have previously shown that whole-body, but not hepatocyte-specific, deficiency of farnesoid X receptor (FXR) in mice worsens AFLD, suggesting that extrahepatic FXR deficiency is critical for AFLD development. Intestinal FXR is critical in suppressing hepatic bile acid (BA) synthesis by inducing fibroblast growth factor 15 (FGF15) in mice and FGF19 in humans. We hypothesized that intestinal FXR is critical for reducing AFLD development in mice. To test this hypothesis, we compared the AFLD severity in wild type (WT) and intestine-specific Fxr knockout (FXRInt-/-) mice following treatment with control or ethanol-containing diet. We found that FXRInt-/- mice were more susceptible to ethanol-induced liver steatosis and inflammation, compared with WT mice. Ethanol treatment altered the expression of hepatic genes involved in lipid and BA homeostasis, and ethanol detoxification. Gut FXR deficiency increased intestinal permeability, likely due to reduced mucosal integrity, as revealed by decreased secretion of Mucin 2 protein and lower levels of E-cadherin protein. In summary, intestinal FXR may protect AFLD development by maintaining gut integrity.
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32
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Tang N, Zhang J, Fu X, Xie W, Qiu Y. PP2Acα inhibits PFKFB2-induced glycolysis to promote termination of liver regeneration. Biochem Biophys Res Commun 2020; 526:1-7. [PMID: 32192773 DOI: 10.1016/j.bbrc.2020.03.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 03/03/2020] [Indexed: 01/17/2023]
Abstract
The mechanisms underlying the initiation and proliferation of liver regeneration (LR) has been extensively studied using the partial hepatectomy (PHx) model, while little is known about the termination of LR. PP2Acα (protein phosphatase 2 A catalytic subunit α isoform) is the catalytic subunit of protein phosphatase 2 A (PP2A), accounting for most of intracellular serine/threonine phosphatase activity. We have previously observed that termination of LR delayed in PP2Acα liver-specific knockout (LKO) mice after PHx. In our study, we used phospho explorer antibody array analysis to screen the potential phosphorylation targets of PP2Acα, and PP2Acα had a great influence on the hepatic phosphoproteomic signaling in the termination of LR after PHx. We then tested the phosphorylation changes and metabolic function of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-2 (PFKFB2), an isoform of the key glycolytic enzyme PFKFB, which was significantly regulated by PP2Acα knockout. PP2Acα knockout enhanced glycolysis in vivo and in vitro, while adenoviral-mediated RNAi of PFKFB2 reversed the extension of postoperative liver regeneration in KO mice along with the downregulation of glycolysis. Therefore, we demonstrated that PP2Acα liver-specific knockout regulated the hepatocytes glycolysis via activating PFKFB2, thus enhancing liver regeneration during the termination stage.
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Affiliation(s)
- Neng Tang
- The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Jingzi Zhang
- Medical School and Model Animal Research Center of Nanjing University, Nanjing, China
| | - Xiao Fu
- The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Weiqi Xie
- The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yudong Qiu
- The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
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33
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Ronis MJ, Mercer KE, Shankar K, Pulliam C, Pedersen K, Ingelman-Sundberg M, Friso S, Samuelson D, Del Valle L, Taylor C, Welsh DA. Potential role of gut microbiota, the proto-oncogene PIKE (Agap2) and cytochrome P450 CYP2W1 in promotion of liver cancer by alcoholic and nonalcoholic fatty liver disease and protection by dietary soy protein. Chem Biol Interact 2020; 325:109131. [PMID: 32417163 DOI: 10.1016/j.cbi.2020.109131] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 05/06/2020] [Indexed: 12/12/2022]
Abstract
We have previously demonstrated promotion of diethylnitrosamine (DEN) initiated liver tumorigenesis after feeding diets high in fat or ethanol (EtOH) to male mice. This was accompanied by hepatic induction of the proto-oncogene PIKE (Agap2). Switch of dietary protein from casein to soy protein isolate (SPI) significantly reduced tumor formation in these models. We have linked EtOH consumption in mice to microbial dysbiosis. Adoptive transfer studies demonstrate that microbiota from mice fed ethanol can induce hepatic steatosis in the absence of ethanol suggesting that microbiota or the microbial metabolome play key roles in development of fatty liver disease. Feeding SPI significantly changed gut bacteria in mice increasing alpha diversity (P < 0.05) and levels of Clostidiales spp. Feeding soy formula to piglets also resulted in significant changes in microbiota, the pattern of bile acid metabolites and in inhibition of the intestinal-hepatic FXR/FGF19-SHP pathway which has been linked to both steatosis and hepatocyte proliferation. Moreover, feeding SPI also resulted in induction of hepatic PPARα signaling and inhibition of PIKE mRNA expression coincident with inhibition of steatosis and cancer prevention. Feeding studies in the DEN model with differing dietary fats demonstrated tumor promotion specific to the saturated fat, cocoa butter relative to diets containing olive oil or corn oil associated with microbial dysbiosis including dramatic increases in Lachnospiraceae particularly from the genus Coprococcus. Immunohistochemical analysis demonstrated that tumors from EtOH-fed mice and patients with alcohol-associated HCC also expressed high levels of a novel cytochrome P450 enzyme CYP2W1. Additional adoptive transfer experiments and studies in knockout mice are required to determine the exact relationship between soy effects on the microbiota, expression of PIKE, CYP2W1, PPARα activation and prevention of tumorigenesis.
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Affiliation(s)
- Martin J Ronis
- Louisiana State University Health Sciences Center, New Orleans, USA.
| | | | | | - Casey Pulliam
- Louisiana State University Health Sciences Center, New Orleans, USA
| | - Kim Pedersen
- Louisiana State University Health Sciences Center, New Orleans, USA
| | | | | | | | - Luis Del Valle
- Louisiana State University Health Sciences Center, New Orleans, USA
| | - Chris Taylor
- Louisiana State University Health Sciences Center, New Orleans, USA
| | - David A Welsh
- Louisiana State University Health Sciences Center, New Orleans, USA
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Merlen G, Bidault-Jourdainne V, Kahale N, Glenisson M, Ursic-Bedoya J, Doignon I, Garcin I, Humbert L, Rainteau D, Tordjmann T. Hepatoprotective impact of the bile acid receptor TGR5. Liver Int 2020; 40:1005-1015. [PMID: 32145703 DOI: 10.1111/liv.14427] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/17/2020] [Accepted: 02/24/2020] [Indexed: 02/13/2023]
Abstract
During liver repair after injury, bile secretion has to be tightly modulated in order to preserve liver parenchyma from bile acid (BA)-induced injury. The mechanisms allowing the liver to maintain biliary homeostasis during repair after injury are not completely understood. Besides their historical role in lipid digestion, bile acids (BA) and their receptors constitute a signalling network with multiple impacts on liver repair, both stimulating regeneration and protecting the liver from BA overload. BA signal through nuclear (mainly Farnesoid X Receptor, FXR) and membrane (mainly G Protein-coupled BA Receptor 1, GPBAR-1 or TGR5) receptors to elicit a wide array of biological responses. While a great number of studies have been dedicated to the hepato-protective impact of FXR signalling, TGR5 is by far less explored in this context. Because the liver has to face massive and potentially harmful BA overload after partial ablation or destruction, BA-induced protective responses crucially contribute to spare liver repair capacities. Based on the available literature, the TGR5 BA receptor protects the remnant liver and maintains biliary homeostasis, mainly through the control of inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity and sinusoidal blood flow. Mouse experimental models of liver injury reveal that in the lack of TGR5, excessive inflammation, leaky biliary epithelium and hydrophobic BA overload result in parenchymal insult and compromise optimal restoration of a functional liver mass. Translational perspectives are thus opened to target TGR5 with the aim of protecting the liver in the context of injury and BA overload.
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Affiliation(s)
- Grégory Merlen
- INSERM U1193, Faculté des Sciences d'Orsay, Université Paris Saclay, Orsay, France
| | | | - Nicolas Kahale
- INSERM U1193, Faculté des Sciences d'Orsay, Université Paris Saclay, Orsay, France
| | - Mathilde Glenisson
- INSERM U1193, Faculté des Sciences d'Orsay, Université Paris Saclay, Orsay, France
| | - José Ursic-Bedoya
- INSERM U1193, Faculté des Sciences d'Orsay, Université Paris Saclay, Orsay, France
| | - Isabelle Doignon
- INSERM U1193, Faculté des Sciences d'Orsay, Université Paris Saclay, Orsay, France
| | - Isabelle Garcin
- INSERM U1193, Faculté des Sciences d'Orsay, Université Paris Saclay, Orsay, France
| | - Lydie Humbert
- Centre de Recherche Saint Antoine, CRSA, Sorbonne Université, Paris, France
| | - Dominique Rainteau
- Centre de Recherche Saint Antoine, CRSA, Sorbonne Université, Paris, France
| | - Thierry Tordjmann
- INSERM U1193, Faculté des Sciences d'Orsay, Université Paris Saclay, Orsay, France
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35
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Xu M, Wang H, Wang J, Burhan D, Shang R, Wang P, Zhou Y, Li R, Liang B, Evert K, Utpatel K, Xu Z, Song X, Che L, Calvisi DF, Wang B, Chen X, Zeng Y, Chen X. mTORC2 Signaling Is Necessary for Timely Liver Regeneration after Partial Hepatectomy. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:817-829. [PMID: 32035060 PMCID: PMC7180798 DOI: 10.1016/j.ajpath.2019.12.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 12/02/2019] [Accepted: 12/05/2019] [Indexed: 02/07/2023]
Abstract
Liver regeneration is a fundamental biological process required for sustaining body homeostasis and restoring liver function after injury. Emerging evidence demonstrates that cytokines, growth factors, and multiple signaling pathways contribute to liver regeneration. Mammalian target of rapamycin complex 2 (mTORC2) regulates cell metabolism, proliferation and survival. The major substrates for mTORC2 are the AGC family members of kinases, including AKT, SGK, and PKC-α. We investigated the functional roles of mTORC2 during liver regeneration. Partial hepatectomy (PHx) was performed in liver-specific Rictor (the pivotal unit of mTORC2 complex) knockout (RictorLKO) and wild-type (Rictorfl/fl) mice. Rictor-deficient mice were found to be more intolerant to PHx and displayed higher mortality after PHx. Mechanistically, loss of Rictor resulted in decreased Akt phosphorylation, leading to a delay in hepatocyte proliferation and lipid droplets formation along liver regeneration. Overall, these results indicate an essential role of the mTORC2 signaling pathway during liver regeneration.
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Affiliation(s)
- Meng Xu
- Department of General Surgery, The Second Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China; Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California
| | - Haichuan Wang
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, PR China; Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, PR China; Department of General Surgery, The Second Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China
| | - Jingxiao Wang
- Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California; School of Life Sciences, Beijing University of Chinese Medicine, Beijing, PR China
| | - Deviana Burhan
- Department of Medicine, Liver Center, University of California, San Francisco, California
| | - Runze Shang
- Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California; Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, PR China
| | - Pan Wang
- Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California; Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, Beijing, PR China
| | - Yi Zhou
- Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California; Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China
| | - Rong Li
- Department of Anesthesiology, The Second Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China
| | - Bingyong Liang
- Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California; Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Katja Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Kirsten Utpatel
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Zhong Xu
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Medical College of Guizhou University, Guiyang, PR China
| | - Xinhua Song
- Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California
| | - Li Che
- Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California
| | - Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Bruce Wang
- Department of Medicine, Liver Center, University of California, San Francisco, California
| | - Xi Chen
- Department of General Surgery, The Second Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China
| | - Yong Zeng
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, PR China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, PR China.
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California.
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36
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Liu L, Liu Z, Li H, Cao Z, Li W, Song Z, Li X, Lu A, Lu C, Liu Y. Naturally Occurring TPE-CA Maintains Gut Microbiota and Bile Acids Homeostasis via FXR Signaling Modulation of the Liver-Gut Axis. Front Pharmacol 2020; 11:12. [PMID: 32116693 PMCID: PMC7015895 DOI: 10.3389/fphar.2020.00012] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 01/07/2020] [Indexed: 12/11/2022] Open
Abstract
Antibiotics-induced changes in intestinal flora (dysbiosis) may have various effects on the host. Dysbiosis is associated with numerous metabolites including bile acids, which are produced in the liver from cholesterol and metabolized in the gut by intestinal microbiota. Total phenolic extracts of Citrus aurantium L. (TPE-CA) are rich in dietary flavanones and their glycosyl derivatives, including flavones, flavonols, polymethoxyflavones and coumarins, which exert positive health effects on the microbiota. The aim of this study is to elucidate the interplays between the intestinal microbiota and bile acids metabolism attributed to antibiotics. Mice were exposed to broad-spectrum antibiotics, such as ampicillin, streptomycin and clindamycin, for 14 days. This exposure resulted in reduced bacterial diversity and richness, and destroyed intestinal permeability. The homeostasis of bile acids was also affected. Subsequent TPE-CA administration, counteracted most of the dysbiosis, and reshaped intestinal permeability, these effects occurred via upregulation of zonula occludens 1 and occludin associated proteins and downregulation of serum endotoxin compared to the antibiotics group. TPE-CA maintained the homeostasis of bile acids via modulation of the liver-gut axis related farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF15) pathway and FXR-targeted protein. Our findings indicated that TPE-CA exerted a protective effect on the restoration of intestinal microbiota composition, reshaped barrier integrity and maintained bile acid homeostasis via the liver-gut axis with antibiotics-induced dysbiosis.
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Affiliation(s)
- Linlin Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhenli Liu
- Institution of Basic Theory, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hui Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhiwen Cao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Wen Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhiqian Song
- Institution of Basic Theory, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiang Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Aiping Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuanyan Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Schumacher JD, Kong B, Wu J, Rizzolo D, Armstrong LE, Chow MD, Goedken M, Lee YH, Guo GL. Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development. Hepatology 2020; 71:670-685. [PMID: 31206730 PMCID: PMC6918008 DOI: 10.1002/hep.30810] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 05/28/2019] [Indexed: 12/18/2022]
Abstract
Farnesoid X receptor (FXR) induces fibroblast growth factor 15 (FGF15; human ortholog FGF19) in the gut to potently inhibit bile acid (BA) synthesis in the liver. FXR activation in hepatic stellate cells (HSCs) reduces liver fibrosis (LF). Fgf15-/- mice develop attenuated LF, but the underlying mechanisms for this protection are unclear. We hypothesized that FGF15/19 functions as a profibrotic mediator or mitogen to HSCs and increased BAs in Fgf15-/- mice leads to enhanced FXR activation in HSCs, subsequently reducing fibrogenesis. In this study, complimentary in vivo and in vitro approaches were used: (1) CCl4 -induced LF model in wild type (WT), Fgf15-/- , and Fgf15 transgenic (TG) mice with BA levels modulated by feeding cholestyramine- or cholic acid-containing diets; (2) analysis of primary HSCs isolated from WT and Fgf15-/- mice; and (3) treatment of a human HSC line, LX-2, with FXR activators and/or recombinant FGF19 protein. The results showed that Fgf15-/- mice had lower basal collagen expression, which was increased by BA sequestration. CCl4 induced fibrosis with similar severity in all genotypes; however, cholestyramine increased fibrosis severity only in Fgf15-/- mice. HSCs from Fgf15-/- mice showed increased FXR activity and reduced expression of profibrotic mediators. In LX-2 cells, FXR activation increased peroxisome proliferator-activated receptor gamma activity and reduced proliferation. FGF19 activated both signal transducer and activator of transcription 3 and c-Jun N-terminal kinase pathways and reduced nuclear factor kappa-light-chain-enhancer of activated B cells signaling without increasing fibrogenic gene expression or cell proliferation. Conclusion: FGF15/19 does not act as a direct profibrotic mediator or mitogen to HSCs in our models, and the protection against fibrosis by FGF15 deficiency may be mediated through increased BA activation of FXR in HSCs.
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Affiliation(s)
- JD Schumacher
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ
| | - B Kong
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ
| | - J Wu
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ
| | - D Rizzolo
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ
| | - LE Armstrong
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ
| | - MD Chow
- Department of Surgery, Robert Wood Johnson University Hospital, New Brunswick, NJ
| | - M Goedken
- Research pathology services, Rutgers University, Piscataway, NJ
| | - YH Lee
- Department of Surgery, Robert Wood Johnson University Hospital, New Brunswick, NJ
| | - GL Guo
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ.,Environmental and Occupational Health Institute, Rutgers University, Piscataway, NJ.,VA New Jersey Health Care System, East Orange, NJ,Corresponding author: Grace L. Guo, MBBS, PhD, 170 Frelinghuysen Road, Piscataway, NJ, 08854; ; phone - 848-445-8186
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Henriksson E, Andersen B. FGF19 and FGF21 for the Treatment of NASH-Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 From Mice to Human. Front Endocrinol (Lausanne) 2020; 11:601349. [PMID: 33414764 PMCID: PMC7783467 DOI: 10.3389/fendo.2020.601349] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 11/10/2020] [Indexed: 12/17/2022] Open
Abstract
FGF19 and FGF21 analogues are currently in clinical development for the potential treatment of NASH. In Phase 2 clinical trials analogues of FGF19 and FGF21 decrease hepatic steatosis with up to 70% (MRI-PDFF) after 12 weeks and as early as 12-16 weeks of treatment an improvement in NASH resolution and fibrosis has been observed. Therefore, this class of compounds is currently of great interest in the field of NASH. FGF19 and FGF21 belong to the endocrine FGF19 subfamily and both require the co-receptor beta-klotho for binding and signalling through the FGF receptors. FGF19 is expressed in the ileal enterocytes and is released into the enterohepatic circulation in response to bile acids stimuli and in the liver FGF19 inhibits hepatic bile acids synthesis by transcriptional regulation of Cyp7A1, which is the rate limiting enzyme. FGF21 is, on the other hand, highly expressed in the liver and is released in response to high glucose, high free-fatty acids and low amino-acid supply and regulates energy, glucose and lipid homeostasis by actions in the CNS and in the adipose tissue. FGF19 and FGF21 are differentially expressed, have distinct target tissues and separate physiological functions. It is therefore of peculiar interest to understand why treatment with both FGF19 and FGF21 analogues have strong beneficial effects on NASH parameters in mice and human and whether the mode of action is overlapping This review will highlight the physiological and pharmacological effects of FGF19 and FGF21. The potential mode of action behind the anti-steatotic, anti-inflammatory and anti-fibrotic effects of FGF19 and FGF21 will be discussed. Finally, development of drugs is always a risk benefit analysis and the human relevance of adverse effects observed in pre-clinical species as well as findings in humans will be discussed. The aim is to provide a comprehensive overview of the current understanding of this drug class for the potential treatment of NASH.
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Rizzolo D, Buckley K, Kong B, Zhan L, Shen J, Stofan M, Brinker A, Goedken M, Buckley B, Guo GL. Bile Acid Homeostasis in a Cholesterol 7α-Hydroxylase and Sterol 27-Hydroxylase Double Knockout Mouse Model. Hepatology 2019; 70:389-402. [PMID: 30864232 PMCID: PMC7893641 DOI: 10.1002/hep.30612] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 03/01/2019] [Indexed: 12/31/2022]
Abstract
Bile acids (BAs) are diverse molecules that are synthesized from cholesterol in the liver. The synthesis of BAs has traditionally been shown to occur through two pathways. Cholesterol 7α-hydroxylase (CYP7A1) performs the initial and rate-limiting step in the classical pathway, and sterol 27-hydroxylase (CYP27A1) initiates the hydroxylation of cholesterol in the alternative pathway. While the role of individual BA species as physiological detergents is relatively ubiquitous, their endocrine functions as signaling molecules and roles in disease pathogenesis have been emerging to be BA species-specific. In order to better understand the pharmacologic and toxicologic roles of individual BA species in an in vivo model, we created cholesterol 7α-hydroxylase (Cyp7a1) and sterol 27-hydroxylase (Cyp27a1) double knockout (DKO) mice by cross-breeding single knockout mice (Cyp7a1-/- and Cyp27a1-/- ). BA profiling and quantification by liquid chromatography-mass spectrometry of serum, gallbladder, liver, small intestine, and colon of wild-type, Cyp7a1-/- , Cyp27a1-/- , and DKO mice showed that DKO mice exhibited a reduction of BAs in the plasma (45.9%), liver (60.2%), gallbladder (76.3%), small intestine (88.7%), and colon (93.6%), while maintaining a similar BA pool composition compared to wild-type mice. The function of the farnesoid X receptor (FXR) in DKO mice was lower, revealed by decreased mRNA expression of well-known FXR target genes, hepatic small heterodimer partner, and ileal fibroblast growth factor 15. However, response to FXR synthetic ligands was maintained in DKO mice as treatment with GW4064 resulted in similar changes in gene expression in all strains of mice. Conclusion: We provide a useful tool for studying the role of individual BAs in vivo; DKO mice have a significantly reduced BA pool, have a similar BA profile, and maintained response to FXR activation.
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Affiliation(s)
- Daniel Rizzolo
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States
| | - Kyle Buckley
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States
| | - Bo Kong
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States
| | - Le Zhan
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, United States
| | - Julia Shen
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States
| | - Mary Stofan
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States
| | - Anita Brinker
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States
| | - Michael Goedken
- Office of Research and Economic Development, Research Pathology Services, Rutgers University, Piscataway, NJ 08854, United States
| | - Brian Buckley
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States,Environmental and Occupational Health Institute, Rutgers University, Piscataway NJ 08854, United States
| | - Grace L. Guo
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States,Environmental and Occupational Health Institute, Rutgers University, Piscataway NJ 08854, United States.,VA NJ Health Care Systems, East Orange NJ 07018, United States.,Corresponding Author Information: Grace L. Guo; EOHSI Room 322, 170 Frelinghuysen Rd, Piscataway, NJ 08854; ; Phone: 848-445-8186; Fax: 732-445-4161
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Somm E, Jornayvaz FR. Fibroblast Growth Factor 15/19: From Basic Functions to Therapeutic Perspectives. Endocr Rev 2018; 39:960-989. [PMID: 30124818 DOI: 10.1210/er.2018-00134] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 07/10/2018] [Indexed: 12/11/2022]
Abstract
Discovered 20 years ago, fibroblast growth factor (FGF)19, and its mouse ortholog FGF15, were the first members of a new subfamily of FGFs able to act as hormones. During fetal life, FGF15/19 is involved in organogenesis, affecting the development of the ear, eye, heart, and brain. At adulthood, FGF15/19 is mainly produced by the ileum, acting on the liver to repress hepatic bile acid synthesis and promote postprandial nutrient partitioning. In rodents, pharmacologic doses of FGF19 induce the same antiobesity and antidiabetic actions as FGF21, with these metabolic effects being partly mediated by the brain. However, activation of hepatocyte proliferation by FGF19 has long been a challenge to its therapeutic use. Recently, genetic reengineering of the molecule has resolved this issue. Despite a global overlap in expression pattern and function, murine FGF15 and human FGF19 exhibit several differences in terms of regulation, molecular structure, signaling, and biological properties. As most of the knowledge originates from the use of FGF19 in murine models, differences between mice and humans in the biology of FGF15/19 have to be considered for a successful translation from bench to bedside. This review summarizes the basic knowledge concerning FGF15/19 in mice and humans, with a special focus on regulation of production, morphogenic properties, hepatocyte growth, bile acid homeostasis, as well as actions on glucose, lipid, and energy homeostasis. Moreover, implications and therapeutic perspectives concerning FGF19 in human diseases (including obesity, type 2 diabetes, hepatic steatosis, biliary disorders, and cancer) are also discussed.
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Affiliation(s)
- Emmanuel Somm
- Service of Endocrinology, Diabetes, Hypertension, and Nutrition, Geneva University Hospitals, University of Geneva Medical School, Geneva, Switzerland
| | - François R Jornayvaz
- Service of Endocrinology, Diabetes, Hypertension, and Nutrition, Geneva University Hospitals, University of Geneva Medical School, Geneva, Switzerland
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