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Guerra-Cantera S, Frago LM, Espinoza-Chavarria Y, Collado-Pérez R, Jiménez-Hernaiz M, Torrecilla-Parra M, Barrios V, Belsham DD, Laursen LS, Oxvig C, Argente J, Chowen JA. Palmitic Acid Modulation of the Insulin-Like Growth Factor System in Hypothalamic Astrocytes and Neurons. Neuroendocrinology 2024; 114:958-974. [PMID: 39043147 DOI: 10.1159/000540442] [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: 11/24/2023] [Accepted: 07/17/2024] [Indexed: 07/25/2024]
Abstract
INTRODUCTION Insulin-like growth factor (IGF)1 and IGF2 have neuroprotective effects, but less is known regarding how other members of the IGF system, including IGF binding proteins (IGFBPs) and the regulatory proteinase pappalysin-1 (PAPP-A) and its endogenous inhibitor stanniocalcin-2 (STC2) participate in this process. Here, we analyzed whether these members of the IGF system are modified in neurons and astrocytes in response to palmitic acid (PA), a fatty acid that induces cell stress when increased centrally. METHODS Primary hypothalamic astrocyte cultures from male and female PND2 rats and the pro-opiomelanocortin (POMC) neuronal cell line, mHypoA-POMC/GFP-2, were treated with PA, IGF1 or both. To analyze the role of STC2 in astrocytes, siRNA assays were employed. RESULTS In astrocytes of both sexes, PA rapidly increased cell stress factors followed by increased Pappa and Stc2 mRNA levels and then a decrease in Igf1, Igf2, and Igfbp2 expression and cell number. Exogenous IGF1 did not revert these effects. In mHypoA-POMC/GFP-2 neurons, PA reduced cell number and Pomc and Igf1 mRNA levels, and increased Igfbp2 and Stc2, again with no effect of exogenous IGF1. PA increased STC2 expression, but no effects of decreasing its levels by interference assays or exogenous STC2 treatment in astrocytes were found. CONCLUSIONS The response of the IGF system to PA was cell and sex specific, but no protective effects of the IGFs were found. However, the modifications in hypothalamic PAPP-A and STC2 indicate that further studies are required to determine their role in the response to fatty acids and possibly in metabolic control.
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Affiliation(s)
- Santiago Guerra-Cantera
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Laura M Frago
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Yesenia Espinoza-Chavarria
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
| | - Roberto Collado-Pérez
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
| | - María Jiménez-Hernaiz
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Marta Torrecilla-Parra
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
| | - Vicente Barrios
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Denise D Belsham
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Lisbeth S Laursen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Claus Oxvig
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Jesús Argente
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain
| | - Julie A Chowen
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain
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Fais G, Casula M, Sidorowicz A, Manca A, Margarita V, Fiori PL, Pantaleo A, Caboni P, Cao G, Concas A. Cultivation of Chroococcidiopsis thermalis Using Available In Situ Resources to Sustain Life on Mars. Life (Basel) 2024; 14:251. [PMID: 38398760 PMCID: PMC10889959 DOI: 10.3390/life14020251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 02/06/2024] [Accepted: 02/10/2024] [Indexed: 02/25/2024] Open
Abstract
The cultivation of cyanobacteria by exploiting available in situ resources represents a possible way to supply food and oxygen to astronauts during long-term crewed missions on Mars. Here, we evaluated the possibility of cultivating the extremophile cyanobacterium Chroococcidiopsis thermalis CCALA 050 under operating conditions that should occur within a dome hosting a recently patented process to produce nutrients and oxygen on Mars. The medium adopted to cultivate this cyanobacterium, named Martian medium, was obtained using a mixture of regolith leachate and astronauts' urine simulants that would be available in situ resources whose exploitation could reduce the mission payload. The results demonstrated that C. thermalis can grow in such a medium. For producing high biomass, the best medium consisted of specific percentages (40%vol) of Martian medium and a standard medium (60%vol). Biomass produced in such a medium exhibits excellent antioxidant properties and contains significant amounts of pigments. Lipidomic analysis demonstrated that biomass contains strategic lipid classes able to help the astronauts facing the oxidative stress and inflammatory phenomena taking place on Mars. These characteristics suggest that this strain could serve as a valuable nutritional resource for astronauts.
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Affiliation(s)
- Giacomo Fais
- Interdepartmental Centre of Environmental Science and Engineering (CINSA), University of Cagliari, Via San Giorgio 12, 09124 Cagliari, Italy; (G.F.); (M.C.); (A.S.); (G.C.)
- Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, Via Marengo 2, 09123 Cagliari, Italy
| | - Mattia Casula
- Interdepartmental Centre of Environmental Science and Engineering (CINSA), University of Cagliari, Via San Giorgio 12, 09124 Cagliari, Italy; (G.F.); (M.C.); (A.S.); (G.C.)
- Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, Via Marengo 2, 09123 Cagliari, Italy
| | - Agnieszka Sidorowicz
- Interdepartmental Centre of Environmental Science and Engineering (CINSA), University of Cagliari, Via San Giorgio 12, 09124 Cagliari, Italy; (G.F.); (M.C.); (A.S.); (G.C.)
- Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, Via Marengo 2, 09123 Cagliari, Italy
| | - Alessia Manca
- Department of Biomedical Science, University of Sassari, Viale San Pietro, 07100 Sassari, Italy; (A.M.); (V.M.); (P.L.F.); (A.P.)
| | - Valentina Margarita
- Department of Biomedical Science, University of Sassari, Viale San Pietro, 07100 Sassari, Italy; (A.M.); (V.M.); (P.L.F.); (A.P.)
| | - Pier Luigi Fiori
- Department of Biomedical Science, University of Sassari, Viale San Pietro, 07100 Sassari, Italy; (A.M.); (V.M.); (P.L.F.); (A.P.)
| | - Antonella Pantaleo
- Department of Biomedical Science, University of Sassari, Viale San Pietro, 07100 Sassari, Italy; (A.M.); (V.M.); (P.L.F.); (A.P.)
| | - Pierluigi Caboni
- Department of Life and Environmental Sciences, University of Cagliari, 09042 Cagliari, Italy;
| | - Giacomo Cao
- Interdepartmental Centre of Environmental Science and Engineering (CINSA), University of Cagliari, Via San Giorgio 12, 09124 Cagliari, Italy; (G.F.); (M.C.); (A.S.); (G.C.)
- Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, Via Marengo 2, 09123 Cagliari, Italy
- Center for Advanced Studies, Research and Development in Sardinia (CRS4), Loc. Piscina Manna, Building 1, 09050 Pula, Italy
| | - Alessandro Concas
- Interdepartmental Centre of Environmental Science and Engineering (CINSA), University of Cagliari, Via San Giorgio 12, 09124 Cagliari, Italy; (G.F.); (M.C.); (A.S.); (G.C.)
- Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, Via Marengo 2, 09123 Cagliari, Italy
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Miles TK, Allensworth-James ML, Odle AK, Silva Moreira AR, Haney AC, LaGasse AN, Gies AJ, Byrum SD, Riojas AM, MacNicol MC, MacNicol AM, Childs GV. Maternal undernutrition results in transcript changes in male offspring that may promote resistance to high fat diet induced weight gain. Front Endocrinol (Lausanne) 2024; 14:1332959. [PMID: 38720938 PMCID: PMC11077627 DOI: 10.3389/fendo.2023.1332959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 12/14/2023] [Indexed: 05/12/2024] Open
Abstract
Maternal nutrition during embryonic development and lactation influences multiple aspects of offspring health. Using mice, this study investigates the effects of maternal caloric restriction (CR) during mid-gestation and lactation on offspring neonatal development and on adult metabolic function when challenged by a high fat diet (HFD). The CR maternal model produced male and female offspring that were significantly smaller, in terms of weight and length, and females had delayed puberty. Adult offspring born to CR dams had a sexually dimorphic response to the high fat diet. Compared to offspring of maternal control dams, adult female, but not male, CR offspring gained more weight in response to high fat diet at 10 weeks. In adipose tissue of male HFD offspring, maternal undernutrition resulted in blunted expression of genes associated with weight gain and increased expression of genes that protect against weight gain. Regardless of maternal nutrition status, HFD male offspring showed increased expression of genes associated with progression toward nonalcoholic fatty liver disease (NAFLD). Furthermore, we observed significant, sexually dimorphic differences in serum TSH. These data reveal tissue- and sex-specific changes in gene and hormone regulation following mild maternal undernutrition, which may offer protection against diet induced weight gain in adult male offspring.
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Affiliation(s)
- Tiffany K. Miles
- Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Melody L. Allensworth-James
- Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Angela K. Odle
- Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Ana Rita Silva Moreira
- Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Anessa C. Haney
- Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Alex N. LaGasse
- Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Allen J. Gies
- Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Stephanie D. Byrum
- Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Angelica M. Riojas
- Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Melanie C. MacNicol
- Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Angus M. MacNicol
- Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Gwen V. Childs
- Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
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Madsen S, Bak SY, Yde CC, Jensen HM, Knudsen TA, Bæch-Laursen C, Holst JJ, Laustsen C, Hedemann MS. Unravelling Effects of Rosemary ( Rosmarinus officinalis L.) Extract on Hepatic Fat Accumulation and Plasma Lipid Profile in Rats Fed a High-Fat Western-Style Diet. Metabolites 2023; 13:974. [PMID: 37755254 PMCID: PMC10534343 DOI: 10.3390/metabo13090974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/11/2023] [Accepted: 08/19/2023] [Indexed: 09/28/2023] Open
Abstract
The objective of the study was to investigate the preventive effect on obesity-related conditions of rosemary (Rosmarinus officinalis L.) extract (RE) in young, healthy rats fed a high-fat Western-style diet to complement the existing knowledge gap concerning the anti-obesity effects of RE in vivo. Sprague Dawley rats (71.3 ± 0.46 g) were fed a high-fat Western-style diet (WD) or WD containing either 1 g/kg feed or 4 g/kg feed RE for six weeks. A group fed standard chow served as a negative control. The treatments did not affect body weight; however, the liver fat percentage was reduced in rats fed RE, and NMR analyses of liver tissue indicated that total cholesterol and triglycerides in the liver were reduced. In plasma, HDL cholesterol was increased while triglycerides were decreased. Rats fed high RE had significantly increased fasting plasma concentrations of Glucagon-like peptide-1 (GLP-1). Proteomics analyses of liver tissue showed that RE increased enzymes involved in fatty acid oxidation, possibly associated with the higher fasting GLP-1 levels, which may explain the improvement of the overall lipid profile and hepatic fat accumulation. Furthermore, high levels of succinic acid in the cecal content of RE-treated animals suggested a modulation of the microbiota composition. In conclusion, our results suggest that RE may alleviate the effects of consuming a high-fat diet through increased GLP-1 secretion and changes in microbiota composition.
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Affiliation(s)
- Sidsel Madsen
- Department of Animal and Veterinary Sciences, Aarhus University, Blichers Allé 20, DK-8830 Tjele, Denmark
| | - Steffen Yde Bak
- IFF—Nutrition Biosciences Aps, Edwin Rahrs Vej 38, DK-8220 Brabrand, Denmark; (S.Y.B.); (C.C.Y.); (H.M.J.); (T.A.K.)
| | - Christian Clement Yde
- IFF—Nutrition Biosciences Aps, Edwin Rahrs Vej 38, DK-8220 Brabrand, Denmark; (S.Y.B.); (C.C.Y.); (H.M.J.); (T.A.K.)
| | - Henrik Max Jensen
- IFF—Nutrition Biosciences Aps, Edwin Rahrs Vej 38, DK-8220 Brabrand, Denmark; (S.Y.B.); (C.C.Y.); (H.M.J.); (T.A.K.)
| | - Tine Ahrendt Knudsen
- IFF—Nutrition Biosciences Aps, Edwin Rahrs Vej 38, DK-8220 Brabrand, Denmark; (S.Y.B.); (C.C.Y.); (H.M.J.); (T.A.K.)
| | - Cecilie Bæch-Laursen
- Department of Biomedical Sciences and Novo Nordisk Foundation, Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark; (C.B.-L.); (J.J.H.)
| | - Jens Juul Holst
- Department of Biomedical Sciences and Novo Nordisk Foundation, Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark; (C.B.-L.); (J.J.H.)
| | - Christoffer Laustsen
- The MR Research Centre, Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark;
| | - Mette Skou Hedemann
- Department of Animal and Veterinary Sciences, Aarhus University, Blichers Allé 20, DK-8830 Tjele, Denmark
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Kantartzis K, Stefan N. Clustering NAFLD: phenotypes of nonalcoholic fatty liver disease and their differing trajectories. Hepatol Commun 2023; 7:02009842-202304010-00012. [PMID: 36972374 PMCID: PMC10043573 DOI: 10.1097/hc9.0000000000000112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 02/08/2023] [Indexed: 03/29/2023] Open
Affiliation(s)
- Konstantinos Kantartzis
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Norbert Stefan
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
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Sun F, Huang Y, Chen H, Huang J, Zhang L, Wei S, Liu F, Chen D, Huang W. BPA and its alternatives BPF and BPAF exaggerate hepatic lipid metabolism disorders in male mice fed a high fat diet. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 867:161521. [PMID: 36632902 DOI: 10.1016/j.scitotenv.2023.161521] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 01/06/2023] [Accepted: 01/06/2023] [Indexed: 06/17/2023]
Abstract
Alternatives to Bisphenol A (BPA), such as BPF and BPAF, have found increasing industrial applications. However, toxicological research on these BPA analogues remains limited. This study aimed to investigate the effects of BPA, BPF, and BPAF exposure on hepatotoxicity in mice fed with high-fat diets (HFD). Male mice were exposed to the bisphenols at a dose of 0.05 mg per kg body weight per day (mg/kg bw/day) for eight consecutive weeks, or 5 mg/kg bw/day for the first week followed by 0.05 mg/kg bw/day for seven weeks under HFD. The low dose (0.05 mg/kg bw/day) was corresponding to the tolerable daily intake (TDI) of BPA and the high dose (5 mg/kg bw/day) was corresponding to its no observed adverse effect level (NOAEL). Biochemical analysis revealed that exposure to these bisphenols resulted in liver damage. Metabolomics analysis showed disturbances of fatty acid and lipid metabolism in bisphenol-exposed mouse livers. BPF and BPAF exposure reduced lipid accumulation in HFD mouse liver by lowering glyceride and cholesterol levels. Transcriptomics analysis demonstrated that expression levels of genes related to fatty acid synthesis and metabolism were changed, which might be related to the activation of the PPAR signaling pathway. Besides, a feedback regulation mechanism might exist to maintain hepatic metabolic homeostasis. For the first time, this study demonstrated the effects of BPF and BPAF exposure in HFD-mouse liver. Considering the reality of the high prevalence of obesity nowadays and the ubiquitous environmental distribution of bisphenols, this study provides insight and highlights the adverse effects of BPA alternatives, further contributing to the consideration of the safe use of such compounds.
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Affiliation(s)
- Fengjiang Sun
- School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Yichao Huang
- Department of Toxicology, School of Public Health, Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China
| | - Hexia Chen
- School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Jialing Huang
- School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Long Zhang
- School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Shuchao Wei
- School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Fangyi Liu
- School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Da Chen
- School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Wei Huang
- School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China.
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Basset-Sagarminaga J, Roumans KHM, Havekes B, Mensink RP, Peters HPF, Zock PL, de Mutsert R, Borén J, Lindeboom L, Schrauwen P, Schrauwen-Hinderling VB. Replacing Foods with a High-Glycemic Index and High in Saturated Fat by Alternatives with a Low Glycemic Index and Low Saturated Fat Reduces Hepatic Fat, Even in Isocaloric and Macronutrient Matched Conditions. Nutrients 2023; 15:nu15030735. [PMID: 36771441 PMCID: PMC9920748 DOI: 10.3390/nu15030735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/27/2023] [Accepted: 01/29/2023] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Current guidelines aim to limit the dietary glycemic index (GI) and intake of saturated fatty acids (SFA). Several studies have shown favorable effects of low-GI or low-SFA diets on intrahepatic lipid content (IHL), but these studies were performed under overfeeding conditions or extreme differences in GI or SFA to maximize the contrast between diets. By combining changes in GI and SFA, we can mimic how people can improve their diet in a realistic setting. OBJECTIVES We investigated the effect on liver fat content and substrate metabolism of both reducing GI and replacing SFA with polyunsaturated fat in practically realistic amounts under isocaloric conditions. DESIGN AND METHODS In a randomized crossover study, thirteen overweight participants consumed two diets, one high in GI and SFA (high GI/SFA) and one low in GI and SFA (low GI/SFA) with identical macronutrient composition, for two weeks each. Diets were equal in caloric content, consisted of habitual food items, and had a macronutrient composition that can be easily achieved in daily life. At the end of each intervention, IHL content/composition and liver glycogen were measured by magnetic resonance spectroscopy. Additionally, fasted and postprandial hepatic de novo lipogenesis and glycemic and metabolic responses were investigated. RESULTS IHL was significantly lower (-28%) after the two-week low-GI/SFA diet (2.4 ± 0.5% 95% CI [1.4, 3.4]) than after the two-week high-GI/SFA diet (3.3 ± 0.6% 95% CI [1.9, 4.7], p < 0.05). Although hepatic glycogen content, hepatic de novo lipogenesis, hepatic lipid composition, and substrate oxidation during the night were similar between the two diets, the glycemic response to the low-GI/SFA diet was reduced (p < 0.05). CONCLUSIONS Changes in macronutrient quality can already have drastic effects on liver fat content and postprandial glycemia after two weeks and even when energy content and the percentage of total fat and carbohydrate remains unchanged.
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Affiliation(s)
- Jeremy Basset-Sagarminaga
- Department of Nutrition and Movement Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
| | - Kay H. M. Roumans
- Department of Nutrition and Movement Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
| | - Bas Havekes
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
| | - Ronald P. Mensink
- Department of Nutrition and Movement Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
| | - Harry P. F. Peters
- Unilever Food Innovation Center, Plantage 14, 6708 WJ Wageningen, The Netherlands
| | - Peter L. Zock
- Unilever Food Innovation Center, Plantage 14, 6708 WJ Wageningen, The Netherlands
| | - Renée de Mutsert
- Department of Clinical Epidemiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands
| | - Jan Borén
- Department of Molecular and Clinical Medicine, University of Gothenburg, P.O. Box 428, 40530 Gothenburg, Sweden
| | - Lucas Lindeboom
- Department of Nutrition and Movement Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
| | - Patrick Schrauwen
- Department of Nutrition and Movement Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
| | - Vera B. Schrauwen-Hinderling
- Department of Nutrition and Movement Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany
- Correspondence:
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Kotlyarov S. Immune and metabolic cross-links in the pathogenesis of comorbid non-alcoholic fatty liver disease. World J Gastroenterol 2023; 29:597-615. [PMID: 36742172 PMCID: PMC9896611 DOI: 10.3748/wjg.v29.i4.597] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/28/2022] [Accepted: 11/07/2022] [Indexed: 01/20/2023] Open
Abstract
In recent years, there has been a steady growth of interest in non-alcoholic fatty liver disease (NAFLD), which is associated with negative epidemiological data on the prevalence of the disease and its clinical significance. NAFLD is closely related to the metabolic syndrome and these relationships are the subject of active research. A growing body of evidence shows cross-linkages between metabolic abnormalities and the innate immune system in the development and progression of NAFLD. These links are bidirectional and largely still unclear, but a better understanding of them will improve the quality of diagnosis and management of patients. In addition, lipid metabolic disorders and the innate immune system link NAFLD with other diseases, such as atherosclerosis, which is of great clinical importance.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, Ryazan 390026, Russia
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9
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Zhang C, Kikushima K, Endo M, Kahyo T, Horikawa M, Matsudaira T, Tanaka T, Takanashi Y, Sato T, Takahashi Y, Xu L, Takayama N, Islam A, Mamun MA, Ozawa T, Setou M. Imaging and Manipulation of Plasma Membrane Fatty Acid Clusters Using TOF-SIMS Combined Optogenetics. Cells 2022; 12:cells12010010. [PMID: 36611804 PMCID: PMC9818728 DOI: 10.3390/cells12010010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/16/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022] Open
Abstract
The plasma membrane (PM) serves multiple functions to support cell activities with its heterogeneous molecular distribution. Fatty acids (FAs) are hydrophobic components of the PM whose saturation and length determine the membrane's physical properties. The FA distribution contributes to the PM's lateral heterogeneity. However, the distribution of PM FAs is poorly understood. Here, we proposed the FA cluster hypothesis, which suggested that FAs on the PM exist as clusters. By the optogenetic tool translocating the endoplasmic reticulum (ER), we were able to manipulate the distribution of PM FAs. We used time-of-flight combined secondary ion mass spectrometry (TOF-SIMS) to image PM FAs and discovered that PM FAs were presented and distributed as clusters and are also manipulated as clusters. We also found the existence of multi-FA clusters formed by the colocalization of more than one FA. Our optogenetic tool also decreased the clustering degree of FA clusters and the formation probability of multi-FA clusters. This research opens up new avenues and perspectives to study PM heterogeneity from an FA perspective. This research also suggests a possible treatment for diseases caused by PM lipid aggregation and furnished a convenient tool for therapeutic development.
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Affiliation(s)
- Chi Zhang
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Kenji Kikushima
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
- International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Mizuki Endo
- Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Tomoaki Kahyo
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
- International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Makoto Horikawa
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
- International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
- Hiroshima Research Center for Healthy Aging, Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8530, Japan
| | - Takaomi Matsudaira
- Foundation for Promotion of Material Science and Technology of Japan, 1-18-6 Kitami, Setagaya-ku, Tokyo 157-0067, Japan
| | - Tatsuya Tanaka
- Foundation for Promotion of Material Science and Technology of Japan, 1-18-6 Kitami, Setagaya-ku, Tokyo 157-0067, Japan
| | - Yusuke Takanashi
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Tomohito Sato
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
- International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Yutaka Takahashi
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
- International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Lili Xu
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Naoki Takayama
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Ariful Islam
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Md. Al Mamun
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Takeaki Ozawa
- Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Mitsutoshi Setou
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
- International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
- Department of Systems Molecular Anatomy, Institute for Medical Photonics Research, Preeminent Medical Photonics Education & Research Center, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
- Correspondence:
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10
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Kotlyarov S, Bulgakov A. Lipid Metabolism Disorders in the Comorbid Course of Nonalcoholic Fatty Liver Disease and Chronic Obstructive Pulmonary Disease. Cells 2021; 10:2978. [PMID: 34831201 PMCID: PMC8616072 DOI: 10.3390/cells10112978] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/25/2021] [Accepted: 10/30/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently among the most common liver diseases. Unfavorable data on the epidemiology of metabolic syndrome and obesity have increased the attention of clinicians and researchers to the problem of NAFLD. The research results allow us to emphasize the systemicity and multifactoriality of the pathogenesis of liver parenchyma lesion. At the same time, many aspects of its classification, etiology, and pathogenesis remain controversial. Local and systemic metabolic disorders are also a part of the pathogenesis of chronic obstructive pulmonary disease and can influence its course. The present article analyzes the metabolic pathways mediating the links of impaired lipid metabolism in NAFLD and chronic obstructive pulmonary disease (COPD). Free fatty acids, cholesterol, and ceramides are involved in key metabolic and inflammatory pathways underlying the pathogenesis of both diseases. Moreover, inflammation and lipid metabolism demonstrate close links in the comorbid course of NAFLD and COPD.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia;
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11
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Fetal programming by androgen excess impairs liver lipid content and PPARg expression in adult rats. J Dev Orig Health Dis 2021; 13:300-309. [PMID: 34275515 DOI: 10.1017/s2040174421000416] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
It is known that prenatal hyperandrogenization induces alterations since early stages of life, contributing to the development of polycystic ovary syndrome affecting the reproductive axis and the metabolic status, thus promoting others associated disorders, such as dyslipidemia, insulin resistance, liver dysfunction, and even steatosis. In this study, we aimed to evaluate the effect of fetal programming by androgen excess on the hepatic lipid content and metabolic mediators at adult life. Pregnant rats were hyperandrogenized with daily subcutaneous injections of 1 mg of free testosterone from days 16 to 19 of pregnancy. The prenatally hyperandrogenized (PH) female offspring displayed two phenotypes: irregular ovulatory phenotype (PHiov) and anovulatory phenotype (PHanov), with different metabolic and endocrine features. We evaluated the liver lipid content and the main aspect of the balance between fatty acid (FA) synthesis and oxidation. We investigated the status of the peroxisomal proliferator-activated receptors (PPARs) alpha and gamma, which act as lipid mediators, and the adipokine chemerin, one marker of liver alterations. We found that prenatal hyperandrogenization altered the liver lipid profile with increased FAs levels in the PHanov phenotype and decreased cholesterol content in the PHiov phenotype. FA metabolism was also disturbed, including decreased mRNA and protein PPARgamma levels and impaired gene expression of the main enzymes involved in lipid metabolism. Moreover, we found low chemerin protein levels in both PH phenotypes. In conclusion, these data suggest that prenatal hyperandrogenization exerts a negative effect on the liver and alters lipid content and metabolic mediators' expression at adult age.
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12
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Cristofano M D, A F, Giacomo M D, C F, F B, D L, Rotondi Aufiero V, F M, E C, G M, V Z, M R, P B. Mechanisms underlying the hormetic effect of conjugated linoleic acid: Focus on Nrf2, mitochondria and NADPH oxidases. Free Radic Biol Med 2021; 167:276-286. [PMID: 33753237 DOI: 10.1016/j.freeradbiomed.2021.03.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/14/2021] [Accepted: 03/15/2021] [Indexed: 12/17/2022]
Abstract
Nuclear factor erythroid 2-related factor2 (Nrf2) is a redox-sensitive transcription factor. Its activation by low dietary intake of ligands leads to antioxidant effects (eustress), while pro-oxidant effects (oxidative distress) may be associated with high doses. NADPH oxidases (NOXs) and the mitochondrial electron transport chain are the main sources of intracellular ROS, but their involvement in the biphasic/hormetic activity elicited by Nrf2 ligands is not fully understood. In this study, we investigated the involvement of NOX expression and mitochondrial function in the hormetic properties of omega-3 typically present in fish oil (FO) and conjugated linoleic acid (CLA) in the mouse liver. Four-week administration of FO, at both low and high doses (L-FO and H-FO) improves Nrf2-activated cyto-protection (by phase 2 enzymes), while a significant increase in respiration efficiency occurs in the liver mitochondria of H-FO BALB/c mice. Eustress conditions elicited by low dose CLA (L-CLA) are associated with increased activity of phase 2 enzymes, and with higher NOX1-2, mitochondrial defences, mitochondrial uncoupling protein 2 (UCP2), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression, compared with controls. Steatogenic effects (lipid accumulation and alteration of lipid metabolism) elicited by high CLA (H-CLA) elicited that are associated with oxidative distress, increased mitochondrial complex I/III activity and reduced levels of phase 2 enzymes, in comparison with L-CLA-treated mice. Our results confirm the steatogenic activity of H-CLA and first demonstrate the role of NOX1 and NOX2 in the eustress conditions elicited by L-CLA. Notably, the negative association of the Nrf2/PGC-1α axis with the different CLA doses provides new insight into the mechanisms underlying the hormetic effect triggered by this Nrf2 ligand.
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Affiliation(s)
- Di Cristofano M
- Institute of Food Sciences, National Research Council (CNR-ISA), 83100, Avellino, Italy
| | - Ferramosca A
- Department of Environmental and Biological Sciences and Technologies, University of Salento, 73100, Lecce, Italy
| | - Di Giacomo M
- Department of Environmental and Biological Sciences and Technologies, University of Salento, 73100, Lecce, Italy
| | - Fusco C
- Institute of Biosciences and Bio-Resources, National Research Council (CNR-IBBR), 80100, Naples, Italy
| | - Boscaino F
- Institute of Food Sciences, National Research Council (CNR-ISA), 83100, Avellino, Italy
| | - Luongo D
- Institute of Food Sciences, National Research Council (CNR-ISA), 83100, Avellino, Italy
| | - Vera Rotondi Aufiero
- Institute of Food Sciences, National Research Council (CNR-ISA), 83100, Avellino, Italy
| | - Maurano F
- Institute of Food Sciences, National Research Council (CNR-ISA), 83100, Avellino, Italy
| | - Cocca E
- Institute of Biosciences and Bio-Resources, National Research Council (CNR-IBBR), 80100, Naples, Italy
| | - Mazzarella G
- Institute of Food Sciences, National Research Council (CNR-ISA), 83100, Avellino, Italy
| | - Zara V
- Department of Environmental and Biological Sciences and Technologies, University of Salento, 73100, Lecce, Italy
| | - Rossi M
- Institute of Food Sciences, National Research Council (CNR-ISA), 83100, Avellino, Italy
| | - Bergamo P
- Institute of Food Sciences, National Research Council (CNR-ISA), 83100, Avellino, Italy.
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13
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Potential of Erythrocyte Membrane Lipid Profile as a Novel Inflammatory Biomarker to Distinguish Metabolically Healthy Obesity in Children. J Pers Med 2021; 11:jpm11050337. [PMID: 33922764 PMCID: PMC8145511 DOI: 10.3390/jpm11050337] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/19/2021] [Accepted: 04/22/2021] [Indexed: 02/07/2023] Open
Abstract
Metabolically healthy obesity (MHO) has been described as BMI ≥ 30 kg/m2, without metabolic disorders traditionally associated with obesity. Beyond this definition, a standardized criterion, for adults and children, has not been established yet to explain the absence of those metabolic disorders. In this context, biomarkers of inflammation have been proposed as suitable candidates to describe MHO. The use of mature red blood cell fatty acid (RBC FA) profile is here proposed since its membrane lipidome includes biomarkers of pro- and anti-inflammatory conditions with a strict relationship with metabolic and nutritional status. An observational study was carried out in 194 children (76 children with obesity and 118 children with normal weight) between 6 and 16 years old. RBC FAs were analyzed by gas chromatography-flame ionization detector (GC-FID). An unsupervised hierarchical clustering method was conducted on children with obesity, based on the RBC FA profile, to isolate the MHO cluster. The MHO cluster showed FA levels similar to children with normal weight, characterized by lower values of arachidonic acid, (total ω-6 FA, ω6/ω3 FA ratios and higher values for EPA, DHA, and total ω-3 FA) (for all of them p ≤ 0.01) compared to the rest of the children with obesity (obese cluster). The MHO cluster also presented lipid indexes for higher desaturase enzymatic activity and lower SFA/MUFA ratio compared to the obese cluster. These differences are relevant for the follow-up of patients, also in view of personalized protocols providing tailored nutritional recommendations for the essential fatty acid intakes.
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14
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Mazzoli A, Gatto C, Crescenzo R, Cigliano L, Iossa S. Prolonged Changes in Hepatic Mitochondrial Activity and Insulin Sensitivity by High Fructose Intake in Adolescent Rats. Nutrients 2021; 13:nu13041370. [PMID: 33921866 PMCID: PMC8073121 DOI: 10.3390/nu13041370] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/15/2021] [Accepted: 04/17/2021] [Indexed: 12/16/2022] Open
Abstract
Persistence of damage induced by unhealthy diets during youth has been little addressed. Therefore, we investigated the impact of a short-term fructose-rich diet on liver metabolic activity in adolescent rats and the putative persistence of alterations after removing fructose from the diet. Adolescent rats were fed a fructose-rich diet for three weeks and then switched to a control diet for further three weeks. Body composition and energy balance were not affected by fructose-rich diet, while increased body lipids and lipid gain were found after the rescue period. Switching to a control diet reversed the upregulation of plasma fructose, uric acid, lipocalin, and haptoglobin, while plasma triglycerides, alanine aminotransferase, lipopolysaccharide, and tumor necrosis factor alpha remained higher. Hepatic steatosis and ceramide were increased by fructose-rich diet, but reversed by returning to a control diet, while altered hepatic response to insulin persisted. Liver fatty acid synthase and stearoyl-CoA desaturase (SCD) activities were upregulated by fructose-rich diet, and SCD activity remained higher after returning to the control diet. Fructose-induced upregulation of complex II-driven mitochondrial respiration, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, and peroxisome proliferator activated receptor α also persisted after switching to control diet. In conclusion, our results show prolonged fructose-induced dysregulation of liver metabolic activity.
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15
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Nonalcoholic Fatty Liver Disease: Focus on New Biomarkers and Lifestyle Interventions. Int J Mol Sci 2021; 22:ijms22083899. [PMID: 33918878 PMCID: PMC8069944 DOI: 10.3390/ijms22083899] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/07/2021] [Accepted: 04/08/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered a hepatic manifestation of metabolic syndrome, characterized from pathological changes in lipid and carbohydrate metabolism. Its main characteristics are excessive lipid accumulation and oxidative stress, which create a lipotoxic environment in hepatocytes leading to liver injury. Recently, many studies have focused on the identification of the genetic and epigenetic modifications that also contribute to NAFLD pathogenesis and their prognostic implications. The present review is aimed to discuss on cellular and metabolic alterations associated with NAFLD, which can be helpful to identify new noninvasive biomarkers. The identification of accumulated lipids in the cell membranes, as well as circulating cytokeratins and exosomes, provides new insights in understanding of NAFLD. This review also suggests that lifestyle modifications remain the main prevention and/or treatment for NAFLD.
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16
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Manca C, Carta G, Murru E, Abolghasemi A, Ansar H, Errigo A, Cani PD, Banni S, Pes GM. Circulating fatty acids and endocannabinoidome-related mediator profiles associated to human longevity. GeroScience 2021; 43:1783-1798. [PMID: 33650014 PMCID: PMC8492808 DOI: 10.1007/s11357-021-00342-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 02/10/2021] [Indexed: 12/12/2022] Open
Abstract
To evaluate whether a peculiar plasma profile of fatty acids and endocannabinoidome (eCBome)-related mediators may be associated to longevity, we assessed them in octogenarians (Old; n=42) living in the east-central mountain area of Sardinia, a High-Longevity Zone (HLZ), compared to sexagenarian (Young; n=21) subjects from the same area, and to Olds (n=22) from the Northern Sardinia indicated as Lower-Longevity Zone (LLZ). We found significant increases in conjugated linoleic acid (CLA) and heptadecanoic acid (17:0) levels in Old-HLZ with respect to younger subjects and Old-LLZ subjects. Young-HLZ subjects exhibited higher circulating levels of pentadecanoic acid (15:0) and retinol. Palmitoleic acid (POA) was elevated in both Young and Old subjects from the HLZ. eCBome profile showed a significantly increased plasma level of the two endocannabinoids, N-arachidonoyl-ethanolamine (AEA) and 2-arachidonoyl-glycerol (2-AG) in Old-HLZ subjects compared to Young-HLZ and Old-LLZ respectively. In addition, we found increased N-oleoyl-ethanolamine (OEA), 2-linoleoyl-glycerol (2-LG) and 2-oleoyl-glycerol (2-OG) levels in Old-HLZ group with respect to Young-HLZ (as for OEA an d 2-LG) and both the Old-LLZ and Young-HLZ for 2-OG. The endogenous metabolite of docosahexaenoic acid (DHA), N-docosahexaenoyl-ethanolamine (DHEA) was significantly increased in Old-HLZ subjects. In conclusion, our results suggest that in the HLZ area, Young and Old subjects exhibited a favourable, albeit distinctive, fatty acids and eCBome profile that may be indicative of a metabolic pattern potentially protective from adverse chronic conditions. These factors could point to a suitable physiological metabolic pattern that may counteract the adverse stimuli leading to age-related disorders such as neurodegenerative and metabolic diseases.
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Affiliation(s)
- Claudia Manca
- Department of Biomedical Sciences, Section of Physiology, University of Cagliari, Monserrato, CA, Italy
| | - Gianfranca Carta
- Department of Biomedical Sciences, Section of Physiology, University of Cagliari, Monserrato, CA, Italy
| | - Elisabetta Murru
- Department of Biomedical Sciences, Section of Physiology, University of Cagliari, Monserrato, CA, Italy
| | - Armita Abolghasemi
- Department of Biomedical Sciences, Section of Physiology, University of Cagliari, Monserrato, CA, Italy
| | - Hastimansooreh Ansar
- Department of Biomedical Sciences, Section of Physiology, University of Cagliari, Monserrato, CA, Italy
| | - Alessandra Errigo
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Patrice D Cani
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.,WELBIO-Walloon Excellence in Life Sciences and BIOtechnology, Brussels, Belgium
| | - Sebastiano Banni
- Department of Biomedical Sciences, Section of Physiology, University of Cagliari, Monserrato, CA, Italy.
| | - Giovanni Mario Pes
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.,Sardinia Longevity Blue Zone Observatory, Ogliastra, Italy
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17
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Roumans KH, Basset Sagarminaga J, Peters HP, Schrauwen P, Schrauwen-Hinderling VB. Liver fat storage pathways: methodologies and dietary effects. Curr Opin Lipidol 2021; 32:9-15. [PMID: 33234776 PMCID: PMC7810416 DOI: 10.1097/mol.0000000000000720] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW Nonalcoholic fatty liver is the result of an imbalance between lipid storage [from meal, de novo lipogenesis (DNL) and fatty acid (FA) uptake] and disposal (oxidation and VLDL output). Knowledge on the contribution of each of these pathways to liver fat content in humans is essential to develop tailored strategies to prevent and treat nonalcoholic fatty liver. Here, we review the techniques available to study the different storage pathways and review dietary modulation of these pathways. RECENT FINDINGS The type of carbohydrate and fat could be of importance in modulating DNL, as complex carbohydrates and omega-3 FAs have been shown to reduce DNL. No effects were found on the other pathways, however studies investigating this are scarce. SUMMARY Techniques used to assess storage pathways are predominantly stable isotope techniques, which require specific expertise and are costly. Validated biomarkers are often lacking. These methodological limitations also translate into a limited number of studies investigating to what extent storage pathways can be modulated by diet. Further research is needed to elucidate in more detail the impact that fat and carbohydrate type can have on liver fat storage pathways and content.
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Affiliation(s)
- Kay H.M. Roumans
- Department of Nutrition and Movement Sciences, Maastricht University, Maastricht
| | | | | | - Patrick Schrauwen
- Department of Nutrition and Movement Sciences, Maastricht University, Maastricht
| | - Vera B. Schrauwen-Hinderling
- Department of Nutrition and Movement Sciences, Maastricht University, Maastricht
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
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18
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Jauregibeitia I, Portune K, Gaztambide S, Rica I, Tueros I, Velasco O, Grau G, Martín A, Castaño L, Larocca AV, Di Nolfo F, Ferreri C, Arranz S. Molecular Differences Based on Erythrocyte Fatty Acid Profile to Personalize Dietary Strategies between Adults and Children with Obesity. Metabolites 2021; 11:43. [PMID: 33435565 PMCID: PMC7827034 DOI: 10.3390/metabo11010043] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/23/2020] [Accepted: 01/05/2021] [Indexed: 12/30/2022] Open
Abstract
As the obesity epidemic continues to grow inexorably worldwide, the need to develop effective strategies to prevent and control obesity seems crucial. The use of molecular tools can be useful to characterize different obesity phenotypes to provide more precise nutritional recommendations. This study aimed to determine the fatty acid (FA) profile of red blood cell (RBC) membranes, together with the evaluation of their dietary intake and biochemical parameters, of children and adults with obesity. An observational study was carried out on 196 children (113 with normal weight and 83 with obesity) and 91 adults (30 with normal weight and 61 with obesity). Mature RBC membrane phospholipids were analyzed for FA composition by gas chromatography-mass spectrometry (GC-MS). Dietary habits were evaluated using validated food frequency questionnaires (FFQ). Children with obesity presented higher levels of ω-6 polyunsaturated FAs (mainly linoleic acid, p = 0.01) and lower values of ω-3 FAs (mainly DHA, p < 0.001) compared with adults. Regarding blood biochemical parameters, children with obesity presented lower levels of glucose, LDL cholesterol, and alanine aminotransferase compared with adults with obesity. These lipidomic differences could be considered to provide specific nutritional recommendations for different age groups, based on an adequate fat intake.
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Affiliation(s)
- Iker Jauregibeitia
- AZTI, Food Research, Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Astondo Bidea, Edificio 609, 48160 Derio–Bizkaia, Spain; (I.J.); (K.P.); (I.T.)
| | - Kevin Portune
- AZTI, Food Research, Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Astondo Bidea, Edificio 609, 48160 Derio–Bizkaia, Spain; (I.J.); (K.P.); (I.T.)
| | - Sonia Gaztambide
- Biocruces Bizkaia Health Research Institute, Cruces University Hospital, CIBERDEM/CIBERER, UPV/EHU, Endo–ERN, 48903 Barakaldo, Spain; (S.G.); (I.R.); (O.V.); (G.G.); (A.M.); (L.C.)
| | - Itxaso Rica
- Biocruces Bizkaia Health Research Institute, Cruces University Hospital, CIBERDEM/CIBERER, UPV/EHU, Endo–ERN, 48903 Barakaldo, Spain; (S.G.); (I.R.); (O.V.); (G.G.); (A.M.); (L.C.)
| | - Itziar Tueros
- AZTI, Food Research, Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Astondo Bidea, Edificio 609, 48160 Derio–Bizkaia, Spain; (I.J.); (K.P.); (I.T.)
| | - Olaia Velasco
- Biocruces Bizkaia Health Research Institute, Cruces University Hospital, CIBERDEM/CIBERER, UPV/EHU, Endo–ERN, 48903 Barakaldo, Spain; (S.G.); (I.R.); (O.V.); (G.G.); (A.M.); (L.C.)
| | - Gema Grau
- Biocruces Bizkaia Health Research Institute, Cruces University Hospital, CIBERDEM/CIBERER, UPV/EHU, Endo–ERN, 48903 Barakaldo, Spain; (S.G.); (I.R.); (O.V.); (G.G.); (A.M.); (L.C.)
| | - Alicia Martín
- Biocruces Bizkaia Health Research Institute, Cruces University Hospital, CIBERDEM/CIBERER, UPV/EHU, Endo–ERN, 48903 Barakaldo, Spain; (S.G.); (I.R.); (O.V.); (G.G.); (A.M.); (L.C.)
| | - Luis Castaño
- Biocruces Bizkaia Health Research Institute, Cruces University Hospital, CIBERDEM/CIBERER, UPV/EHU, Endo–ERN, 48903 Barakaldo, Spain; (S.G.); (I.R.); (O.V.); (G.G.); (A.M.); (L.C.)
| | - Anna Vita Larocca
- Lipidomic Laboratory, Lipinutragen srl, Via di Corticella 181/4, 40128 Bologna, Italy; (A.V.L.); (F.D.N.)
| | - Federica Di Nolfo
- Lipidomic Laboratory, Lipinutragen srl, Via di Corticella 181/4, 40128 Bologna, Italy; (A.V.L.); (F.D.N.)
| | - Carla Ferreri
- Consiglio Nazionale delle Ricerche, ISOF, Via Piero Gobetti 101, 40129 Bologna, Italy
| | - Sara Arranz
- AZTI, Food Research, Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Astondo Bidea, Edificio 609, 48160 Derio–Bizkaia, Spain; (I.J.); (K.P.); (I.T.)
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DeMoranville KJ, Carter WA, Pierce BJ, McWilliams SR. Flight training in a migratory bird drives metabolic gene expression in the flight muscle but not liver, and dietary fat quality influences select genes. Am J Physiol Regul Integr Comp Physiol 2020; 319:R637-R652. [PMID: 32966121 DOI: 10.1152/ajpregu.00163.2020] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Training and diet are hypothesized to directly stimulate key molecular pathways that mediate animal performance, and flight training, dietary fats, and dietary antioxidants are likely important in modulating molecular metabolism in migratory birds. This study experimentally investigated how long-distance flight training, as well as diet composition, affected the expression of key metabolic genes in the pectoralis muscle and the liver of European starlings (Sturnus vulgaris, n = 95). Starlings were fed diets composed of either a high or low polyunsaturated fatty acid (PUFA; 18:2n-6) and supplemented with or without a water-soluble antioxidant, and one-half of these birds were flight trained in a wind-tunnel while the rest were untrained. We measured the expression of 7 (liver) or 10 (pectoralis) key metabolic genes in flight-trained and untrained birds. Fifty percent of genes involved in mitochondrial metabolism and fat utilization were upregulated by flight training in the pectoralis (P < 0.05), whereas flight training increased the expression of only one gene responsible for fatty acid hydrolysis [lipoprotein lipase (LPL)] in the liver (P = 0.04). Dietary PUFA influenced the gene expression of LPL and fat transporter fatty acid translocase (CD36) in the pectoralis and one metabolic transcription factor [peroxisome proliferator-activated receptor (PPAR)-α (PPARα)] in the liver, whereas dietary antioxidants had no effect on the metabolic genes measured in this study. Flight training initiated a simpler causal network between PPARγ coactivators, PPARs, and metabolic genes involved in mitochondrial metabolism and fat storage in the pectoralis. Molecular metabolism is modulated by flight training and dietary fat quality in a migratory songbird, indicating that these environmental factors will affect the migratory performance of birds in the wild.
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Affiliation(s)
- Kristen J DeMoranville
- Department of Natural Resources Science, University of Rhode Island, Kingston, Rhode Island
| | - Wales A Carter
- Department of Natural Resources Science, University of Rhode Island, Kingston, Rhode Island
| | - Barbara J Pierce
- Department of Biology, Sacred Heart University, Fairfield, Connecticut
| | - Scott R McWilliams
- Department of Natural Resources Science, University of Rhode Island, Kingston, Rhode Island
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20
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Short-Term Effects of Early Menopause on Adiposity, Fatty Acids Profile and Insulin Sensitivity of a Swine Model of Female Obesity. BIOLOGY 2020; 9:biology9090284. [PMID: 32932852 PMCID: PMC7565410 DOI: 10.3390/biology9090284] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 08/31/2020] [Accepted: 09/03/2020] [Indexed: 02/07/2023]
Abstract
Menopause strongly increases incidence and consequences of obesity and non-communicable diseases in women, with recent research suggesting a very early onset of changes in lipid accumulation, dyslipidemia, and insulin resistance. However, there is a lack of adequate preclinical models for its study. The present trial evaluated the usefulness of an alternative method to surgical ovariectomy, the administration of two doses of a GnRH analogue-protein conjugate (Vacsincel®), for inducing ovarian inactivity in sows used as preclinical models of obesity and menopause. All the sows treated with the compound developed ovarian stoppage after the second dose and, when exposed to obesogenic diets during the following three months, showed changes in the patterns of fat deposition, in the fatty acids profiles at the different tissues and in the plasma concentrations of fructosamine, urea, β-hydroxibutirate, and haptoglobin when compared to obese fed with the same diet but maintaining ovarian activity. Altogether, these results indicate that menopause early augments the deleterious effects induced by overfeeding and obesity on metabolic traits, paving the way for future research on physiopathology of these conditions and possible therapeutic targets using the swine model.
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21
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Moore MC, Smith MS, Swift LL, Cincotta AH, Ezrokhi M, Cominos N, Zhang Y, Farmer B, Cherrington AD. Bromocriptine mesylate improves glucose tolerance and disposal in a high-fat-fed canine model. Am J Physiol Endocrinol Metab 2020; 319:E133-E145. [PMID: 32459527 PMCID: PMC7468784 DOI: 10.1152/ajpendo.00479.2019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Bromocriptine mesylate treatment was examined in dogs fed a high fat diet (HFD) for 8 wk. After 4 wk on HFD, daily bromocriptine (Bromo; n = 6) or vehicle (CTR; n = 5) injections were administered. Oral glucose tolerance tests were performed before beginning HFD (OGTT1), 4 wk after HFD began (Bromo only), and after 7.5 wk on HFD (OGTT3). After 8 wk on HFD, clamp studies were performed, with infusion of somatostatin and intraportal replacement of insulin (4× basal) and glucagon (basal). From 0 to 90 min (P1), glucose was infused via peripheral vein to double the hepatic glucose load; and from 90 to 180 min (P2), glucose was infused via the hepatic portal vein at 4 mg·kg-1·min-1, with the HGL maintained at 2× basal. Bromo decreased the OGTT glucose ΔAUC0-30 and ΔAUC0-120 by 62 and 27%, respectively, P < 0.05 for both) without significantly altering the insulin response. Bromo dogs exhibited enhanced net hepatic glucose uptake (NHGU) compared with CTR (~33 and 21% greater, P1 and P2, respectively, P < 0.05). Nonhepatic glucose uptake (non-HGU) was increased ~38% in Bromo in P2 (P < 0.05). Bromo vs. CTR had higher (P < 0.05) rates of glucose infusion (36 and 30%) and non-HGU (~40 and 27%) than CTR during P1 and P2, respectively. In Bromo vs. CTR, hepatic 18:0/16:0 and 16:1/16:0 ratios tended to be elevated in triglycerides and were higher (P < 0.05) in phospholipids, consistent with a beneficial effect of bromocriptine on liver fat accumulation. Thus, bromocriptine treatment improved glucose disposal in a glucose-intolerant model, enhancing both NHGU and non-HGU.
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Affiliation(s)
- Mary Courtney Moore
- Department of Metabolic Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Marta S Smith
- Department of Metabolic Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Larry L Swift
- Vanderbilt Diabetes Research and Training Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | | | | | | | - Ben Farmer
- Department of Metabolic Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
- Vanderbilt Diabetes Research and Training Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Alan D Cherrington
- Department of Metabolic Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
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22
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Machate DJ, Figueiredo PS, Marcelino G, Guimarães RDCA, Hiane PA, Bogo D, Pinheiro VAZ, de Oliveira LCS, Pott A. Fatty Acid Diets: Regulation of Gut Microbiota Composition and Obesity and Its Related Metabolic Dysbiosis. Int J Mol Sci 2020; 21:E4093. [PMID: 32521778 PMCID: PMC7312778 DOI: 10.3390/ijms21114093] [Citation(s) in RCA: 138] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 03/27/2020] [Accepted: 03/27/2020] [Indexed: 02/06/2023] Open
Abstract
Long-term high-fat dietary intake plays a crucial role in the composition of gut microbiota in animal models and human subjects, which affect directly short-chain fatty acid (SCFA) production and host health. This review aims to highlight the interplay of fatty acid (FA) intake and gut microbiota composition and its interaction with hosts in health promotion and obesity prevention and its related metabolic dysbiosis. The abundance of the Bacteroidetes/Firmicutes ratio, as Actinobacteria and Proteobacteria species are associated with increased SCFA production, reported high-fat diet rich in medium-chain fatty acids (MCFAs), monounsaturated fatty acids (MUFAs), and n-3 polyunsaturated fatty acids (PUFAs) as well as low-fat diets rich in long-chain fatty acids (LCFAs). SCFAs play a key role in health promotion and prevention and, reduction and reversion of metabolic syndromes in the host. Furthermore, in this review, we discussed the type of fatty acids and their amount, including the administration time and their interplay with gut microbiota and its results about health or several metabolic dysbioses undergone by hosts.
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Affiliation(s)
- David Johane Machate
- Graduate Program in Biotechnology and Biodiversity in the Central-West Region of Brazil, Federal University of Mato Grosso do Sul, Campo Grande 79079-900, Brazil; (D.J.M.); (A.P.)
| | - Priscila Silva Figueiredo
- Graduate Program in Health and Development in the Central-West Region of Brazil, Federal University of Mato Grosso do Sul, Campo Grande 79079-900, Brazil; (P.S.F.); (G.M.); (P.A.H.); (D.B.); (V.A.Z.P.)
| | - Gabriela Marcelino
- Graduate Program in Health and Development in the Central-West Region of Brazil, Federal University of Mato Grosso do Sul, Campo Grande 79079-900, Brazil; (P.S.F.); (G.M.); (P.A.H.); (D.B.); (V.A.Z.P.)
| | - Rita de Cássia Avellaneda Guimarães
- Graduate Program in Health and Development in the Central-West Region of Brazil, Federal University of Mato Grosso do Sul, Campo Grande 79079-900, Brazil; (P.S.F.); (G.M.); (P.A.H.); (D.B.); (V.A.Z.P.)
| | - Priscila Aiko Hiane
- Graduate Program in Health and Development in the Central-West Region of Brazil, Federal University of Mato Grosso do Sul, Campo Grande 79079-900, Brazil; (P.S.F.); (G.M.); (P.A.H.); (D.B.); (V.A.Z.P.)
| | - Danielle Bogo
- Graduate Program in Health and Development in the Central-West Region of Brazil, Federal University of Mato Grosso do Sul, Campo Grande 79079-900, Brazil; (P.S.F.); (G.M.); (P.A.H.); (D.B.); (V.A.Z.P.)
| | - Verônica Assalin Zorgetto Pinheiro
- Graduate Program in Health and Development in the Central-West Region of Brazil, Federal University of Mato Grosso do Sul, Campo Grande 79079-900, Brazil; (P.S.F.); (G.M.); (P.A.H.); (D.B.); (V.A.Z.P.)
| | | | - Arnildo Pott
- Graduate Program in Biotechnology and Biodiversity in the Central-West Region of Brazil, Federal University of Mato Grosso do Sul, Campo Grande 79079-900, Brazil; (D.J.M.); (A.P.)
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23
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Trentzsch M, Nyamugenda E, Miles TK, Griffin H, Russell S, Koss B, Cooney KA, Phelan KD, Tackett AJ, Iyer S, Boysen G, Baldini G. Delivery of phosphatidylethanolamine blunts stress in hepatoma cells exposed to elevated palmitate by targeting the endoplasmic reticulum. Cell Death Discov 2020; 6:8. [PMID: 32123584 PMCID: PMC7028721 DOI: 10.1038/s41420-020-0241-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/18/2020] [Accepted: 01/24/2020] [Indexed: 02/07/2023] Open
Abstract
Genetic obesity increases in liver phosphatidylcholine (PC)/phosphatidylethanolamine (PE) ratio, inducing endoplasmic reticulum (ER) stress without concomitant increase of ER chaperones. Here, it is found that exposing mice to a palm oil-based high fat (HF) diet induced obesity, loss of liver PE, and loss of the ER chaperone Grp78/BiP in pericentral hepatocytes. In Hepa1-6 cells treated with elevated concentration of palmitate to model lipid stress, Grp78/BiP mRNA was increased, indicating onset of stress-induced Unfolded Protein Response (UPR), but Grp78/BiP protein abundance was nevertheless decreased. Exposure to elevated palmitate also induced in hepatoma cells decreased membrane glycosylation, nuclear translocation of pro-apoptotic C/EBP-homologous-protein-10 (CHOP), expansion of ER-derived quality control compartment (ERQC), loss of mitochondrial membrane potential (MMP), and decreased oxidative phosphorylation. When PE was delivered to Hepa1-6 cells exposed to elevated palmitate, effects by elevated palmitate to decrease Grp78/BiP protein abundance and suppress membrane glycosylation were blunted. Delivery of PE to Hepa1-6 cells treated with elevated palmitate also blunted expansion of ERQC, decreased nuclear translocation of CHOP and lowered abundance of reactive oxygen species (ROS). Instead, delivery of the chemical chaperone 4-phenyl-butyrate (PBA) to Hepa1-6 cells treated with elevated palmitate, while increasing abundance of Grp78/BiP protein and restoring membrane glycosylation, also increased ERQC, expression and nuclear translocation of CHOP, non-mitochondrial oxygen consumption, and generation of ROS. Data indicate that delivery of PE to hepatoma cells under lipid stress recovers cell function by targeting the secretory pathway and by blunting pro-apoptotic branches of the UPR.
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Affiliation(s)
- Marcus Trentzsch
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Eugene Nyamugenda
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Tiffany K. Miles
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Haven Griffin
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Susan Russell
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Brian Koss
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Kimberly A. Cooney
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Kevin D. Phelan
- Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Alan J. Tackett
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Srividhya Iyer
- Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Gunnar Boysen
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Giulia Baldini
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
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Perera E, Turkmen S, Simó-Mirabet P, Zamorano MJ, Xu H, Naya-Català F, Izquierdo M, Pérez-Sánchez J. Stearoyl-CoA desaturase ( scd1a) is epigenetically regulated by broodstock nutrition in gilthead sea bream ( Sparus aurata). Epigenetics 2019; 15:536-553. [PMID: 31790638 DOI: 10.1080/15592294.2019.1699982] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The aim of this study was to generate new knowledge on fish epigenetics, assessing the effects of linolenic acid (ALA) conditioning of broodstock in the offspring of the marine fish Sparus aurata. Attention was focused on gene organization, methylation signatures and gene expression patterns of fatty acid desaturase 2 (fads2) and stearoyl-CoA desaturase 1a (scd1a). Blat searches in the genomic IATS-CSIC database (www.nutrigroup-iats.org/seabreamdb) highlighted a conserved exon-intron organization, a conserved PUFA response region, and CG islands at the promoter regions of each gene. The analysed CpG positions in the fads2 promoter were mostly hypomethylated and refractory to broodstock nutrition. The same response was achieved after conditioning of juvenile fish to low water oxygen concentrations, thus methylation susceptibility at individual CpG sites seems to be stringently regulated in fish of different origin and growth trajectories. Conversely, the scd1a promoter was responsive to broodstock nutrition and the offspring of parents fed the ALA-rich diet shared an increased DNA-methylation, mainly in CpG sites neighbouring SP1 and HNF4α binding sites. Cytosine methylation at these sites correlated inversely with the hepatic scd1a expression of the offspring. Co-expression analyses supported that the HNF4α-dependent regulation of scd1a is affected by DNA methylation. The phenotypic output is a regulated liver fat deposition through changes in scd1 expression, which would also allow the preservation of fatty acid unsaturation levels in fish fed reduced levels of n-3 LC-PUFA. Collectively, these findings reveal a reliable mechanism by which parent's nutrition can shape scd1a gene expression in the fish offspring.
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Affiliation(s)
- Erick Perera
- Nutrigenomics and Fish Growth Endocrinology Group, Institute of Aquaculture Torre de la Sal, IATS-CSIC, Castellón, Spain
| | - Serhat Turkmen
- Aquaculture Research Group (GIA), IU-ECOAQUA, Universidad de Las Palmas de Gran Canaria (ULPGC), Telde, Spain
| | - Paula Simó-Mirabet
- Nutrigenomics and Fish Growth Endocrinology Group, Institute of Aquaculture Torre de la Sal, IATS-CSIC, Castellón, Spain
| | - Maria J Zamorano
- Aquaculture Research Group (GIA), IU-ECOAQUA, Universidad de Las Palmas de Gran Canaria (ULPGC), Telde, Spain
| | - Hanlin Xu
- Aquaculture Research Group (GIA), IU-ECOAQUA, Universidad de Las Palmas de Gran Canaria (ULPGC), Telde, Spain
| | - Fernando Naya-Català
- Nutrigenomics and Fish Growth Endocrinology Group, Institute of Aquaculture Torre de la Sal, IATS-CSIC, Castellón, Spain
| | - Marisol Izquierdo
- Aquaculture Research Group (GIA), IU-ECOAQUA, Universidad de Las Palmas de Gran Canaria (ULPGC), Telde, Spain
| | - Jaume Pérez-Sánchez
- Nutrigenomics and Fish Growth Endocrinology Group, Institute of Aquaculture Torre de la Sal, IATS-CSIC, Castellón, Spain
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25
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Svegliati-Baroni G, Pierantonelli I, Torquato P, Marinelli R, Ferreri C, Chatgilialoglu C, Bartolini D, Galli F. Lipidomic biomarkers and mechanisms of lipotoxicity in non-alcoholic fatty liver disease. Free Radic Biol Med 2019; 144:293-309. [PMID: 31152791 DOI: 10.1016/j.freeradbiomed.2019.05.029] [Citation(s) in RCA: 170] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 05/13/2019] [Accepted: 05/27/2019] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease worldwide (about 25% of the general population) and 3-5% of patients develop non-alcoholic steatohepatitis (NASH), characterized by hepatocytes damage, inflammation and fibrosis, which increase the risk of developing liver failure, cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD, particularly the mechanisms whereby a minority of patients develop a more severe phenotype, is still incompletely understood. In this review we examine the available literature on initial mechanisms of hepatocellular damage and inflammation, deriving from toxic effects of excess lipids. Accumulating data indicate that the total amount of triglycerides stored in the liver cells is not the main determinant of lipotoxicity and that specific lipid classes act as damaging agents. These lipotoxic species affect the cell behavior via multiple mechanisms, including activation of death receptors, endoplasmic reticulum stress, modification of mitochondrial function and oxidative stress. The gut microbiota, which provides signals through the intestine to the liver, is also reported to play a key role in lipotoxicity. Finally, we summarize the most recent lipidomic strategies utilized to explore the liver lipidome and its modifications in the course of NALFD. These include measures of lipid profiles in blood plasma and erythrocyte membranes that can surrogate to some extent lipid investigation in the liver.
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Affiliation(s)
- Gianluca Svegliati-Baroni
- Department of Gastroenterology, Università Politecnica Delle Marche, Ancona, Italy; Obesity Center, Università Politecnica Delle Marche, Ancona, Italy.
| | - Irene Pierantonelli
- Department of Gastroenterology, Università Politecnica Delle Marche, Ancona, Italy; Department of Gastroenterology, Senigallia Hospital, Senigallia, Italy
| | | | - Rita Marinelli
- Department of Pharmaceutical Sciences, University of Perugia, Italy
| | - Carla Ferreri
- ISOF, Consiglio Nazionale Delle Ricerche, Via P. Gobetti 101, 40129, Bologna, Italy
| | | | | | - Francesco Galli
- Department of Pharmaceutical Sciences, University of Perugia, Italy
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26
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The Novel Perspectives of Adipokines on Brain Health. Int J Mol Sci 2019; 20:ijms20225638. [PMID: 31718027 PMCID: PMC6887733 DOI: 10.3390/ijms20225638] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 12/13/2022] Open
Abstract
First seen as a fat-storage tissue, the adipose tissue is considered as a critical player in the endocrine system. Precisely, adipose tissue can produce an array of bioactive factors, including cytokines, lipids, and extracellular vesicles, which target various systemic organ systems to regulate metabolism, homeostasis, and immune response. The global effects of adipokines on metabolic events are well defined, but their impacts on brain function and pathology remain poorly defined. Receptors of adipokines are widely expressed in the brain. Mounting evidence has shown that leptin and adiponectin can cross the blood–brain barrier, while evidence for newly identified adipokines is limited. Significantly, adipocyte secretion is liable to nutritional and metabolic states, where defective circuitry, impaired neuroplasticity, and elevated neuroinflammation are symptomatic. Essentially, neurotrophic and anti-inflammatory properties of adipokines underlie their neuroprotective roles in neurodegenerative diseases. Besides, adipocyte-secreted lipids in the bloodstream can act endocrine on the distant organs. In this article, we have reviewed five adipokines (leptin, adiponectin, chemerin, apelin, visfatin) and two lipokines (palmitoleic acid and lysophosphatidic acid) on their roles involving in eating behavior, neurotrophic and neuroprotective factors in the brain. Understanding and regulating these adipokines can lead to novel therapeutic strategies to counteract metabolic associated eating disorders and neurodegenerative diseases, thus promote brain health.
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27
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Cordoba-Chacon J, Sugasini D, Yalagala PCR, Tummala A, White ZC, Nagao T, Kineman RD, Subbaiah PV. Tissue-dependent effects of cis-9,trans-11- and trans-10,cis-12-CLA isomers on glucose and lipid metabolism in adult male mice. J Nutr Biochem 2019; 67:90-100. [PMID: 30856468 DOI: 10.1016/j.jnutbio.2019.01.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 12/22/2018] [Accepted: 01/29/2019] [Indexed: 12/22/2022]
Abstract
Mixtures of the two major conjugated linoleic acid (CLA) isomers trans-10,cis-12-CLA and cis-9,trans-11-CLA are used as over the counter supplements for weight loss. Because of the reported adverse effects of CLA on insulin sensitivity in some mouse studies, we sought to compare the impact of dietary t10c12-CLA and c9t11-CLA on liver, adipose tissue, and systemic metabolism of adult lean mice. We fed 8 week-old C57Bl/6J male mice with low fat diets (10.5% Kcal from fat) containing 0.8% t10c12-CLA or c9t11-CLA for 9 or 38 days. Diets containing c9t11-CLA had minimal impact on the endpoints studied. However, 7 days after starting the t10c12-CLA diet, we observed a dramatic reduction in fat mass measured by NMR spectroscopy, which interestingly rebounded by 38 days. This rebound was apparently due to a massive accumulation of lipids in the liver, because adipose tissue depots were visually undetectable. Hepatic steatosis and the disappearance of adipose tissue after t10c12-CLA feeding was associated with elevated plasma insulin levels and insulin resistance, compared to mice fed a control diet or c9t11-CLA diet. Unexpectedly, despite being insulin resistant, mice fed t10c12-CLA had normal levels of blood glucose, without signs of impaired glucose clearance. Hepatic gene expression and fatty acid composition suggested enhanced hepatic de novo lipogenesis without an increase in expression of gluconeogenic genes. These data indicate that dietary t10c12-CLA may alter hepatic glucose and lipid metabolism indirectly, in response to the loss of adipose tissue in mice fed a low fat diet.
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Affiliation(s)
- Jose Cordoba-Chacon
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL.
| | - Dhavamani Sugasini
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL
| | - Poorna C R Yalagala
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL
| | - Apoorva Tummala
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL
| | - Zachary C White
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL
| | - Toshihiro Nagao
- Osaka Research Institute of Industrial Science and Technology, Osaka, Japan
| | - Rhonda D Kineman
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL; Research and Development Division, Jesse Brown Veterans Affairs Medical Center, Chicago, IL
| | - Papasani V Subbaiah
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL; Research and Development Division, Jesse Brown Veterans Affairs Medical Center, Chicago, IL.
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28
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Rosqvist F, McNeil CA, Pramfalk C, Parry SA, Low WS, Cornfield T, Fielding BA, Hodson L. Fasting hepatic de novo lipogenesis is not reliably assessed using circulating fatty acid markers. Am J Clin Nutr 2019; 109:260-268. [PMID: 30721918 PMCID: PMC6367991 DOI: 10.1093/ajcn/nqy304] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 10/03/2018] [Indexed: 12/18/2022] Open
Abstract
Background Observational studies often infer hepatic de novo lipogenesis (DNL) by measuring circulating fatty acid (FA) markers; however, it remains to be elucidated whether these markers accurately reflect hepatic DNL. Objectives We investigated associations between fasting hepatic DNL and proposed FA markers of DNL in subjects consuming their habitual diet. Methods Fasting hepatic DNL was assessed using 2H2O (deuterated water) in 149 nondiabetic men and women and measuring the synthesis of very low-density lipoprotein triglyceride (VLDL-TG) palmitate. FA markers of blood lipid fractions were determined by gas chromatography. Results Neither the lipogenic index (16:0/18:2n-6) nor the SCD index (16:1n-7/16:0) in VLDL-TG was associated with isotopically assessed DNL (r = 0.13, P = 0.1 and r = -0.08, P = 0.35, respectively). The relative abundances (mol%) of 14:0, 16:0, and 18:0 in VLDL-TG were weakly (r ≤ 0.35) associated with DNL, whereas the abundances of 16:1n-7, 18:1n-7, and 18:1n-9 were not associated. When the cohort was split by median DNL, only the abundances of 14:0 and 18:0 in VLDL-TG could discriminate between subjects having high (11.5%) and low (3.8%) fasting hepatic DNL. Based on a subgroup, FA markers in total plasma TG, plasma cholesteryl esters, plasma phospholipids, and red blood cell phospholipids were generally not associated with DNL. Conclusions The usefulness of circulating FAs as markers of hepatic DNL in healthy individuals consuming their habitual diet is limited due to their inability to discriminate clearly between individuals with low and high fasting hepatic DNL.
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Affiliation(s)
- Fredrik Rosqvist
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom
- Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden
| | - Catriona A McNeil
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom
| | - Camilla Pramfalk
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Sion A Parry
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom
| | - Wee Suan Low
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom
| | - Thomas Cornfield
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom
| | - Barbara A Fielding
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom
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29
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Choo VL, Viguiliouk E, Blanco Mejia S, Cozma AI, Khan TA, Ha V, Wolever TMS, Leiter LA, Vuksan V, Kendall CWC, de Souza RJ, Jenkins DJA, Sievenpiper JL. Food sources of fructose-containing sugars and glycaemic control: systematic review and meta-analysis of controlled intervention studies. BMJ 2018; 363:k4644. [PMID: 30463844 PMCID: PMC6247175 DOI: 10.1136/bmj.k4644] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/28/2018] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To assess the effect of different food sources of fructose-containing sugars on glycaemic control at different levels of energy control. DESIGN Systematic review and meta-analysis of controlled intervention studies. DATA SOURCES Medine, Embase, and the Cochrane Library up to 25 April 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES Controlled intervention studies of at least seven days' duration and assessing the effect of different food sources of fructose-containing sugars on glycaemic control in people with and without diabetes were included. Four study designs were prespecified on the basis of energy control: substitution studies (sugars in energy matched comparisons with other macronutrients), addition studies (excess energy from sugars added to diets), subtraction studies (energy from sugars subtracted from diets), and ad libitum studies (sugars freely replaced by other macronutrients without control for energy). Outcomes were glycated haemoglobin (HbA1c), fasting blood glucose, and fasting blood glucose insulin. DATA EXTRACTION AND SYNTHESIS Four independent reviewers extracted relevant data and assessed risk of bias. Data were pooled by random effects models and overall certainty of the evidence assessed by the GRADE approach (grading of recommendations assessment, development, and evaluation). RESULTS 155 study comparisons (n=5086) were included. Total fructose-containing sugars had no harmful effect on any outcome in substitution or subtraction studies, with a decrease seen in HbA1c in substitution studies (mean difference -0.22% (95% confidence interval to -0.35% to -0.08%), -25.9 mmol/mol (-27.3 to -24.4)), but a harmful effect was seen on fasting insulin in addition studies (4.68 pmol/L (1.40 to 7.96)) and ad libitum studies (7.24 pmol/L (0.47 to 14.00)). There was interaction by food source, with specific food sources showing beneficial effects (fruit and fruit juice) or harmful effects (sweetened milk and mixed sources) in substitution studies and harmful effects (sugars-sweetened beverages and fruit juice) in addition studies on at least one outcome. Most of the evidence was low quality. CONCLUSIONS Energy control and food source appear to mediate the effect of fructose-containing sugars on glycaemic control. Although most food sources of these sugars (especially fruit) do not have a harmful effect in energy matched substitutions with other macronutrients, several food sources of fructose-containing sugars (especially sugars-sweetened beverages) adding excess energy to diets have harmful effects. However, certainty in these estimates is low, and more high quality randomised controlled trials are needed. STUDY REGISTRATION Clinicaltrials.gov (NCT02716870).
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Affiliation(s)
- Vivian L Choo
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Undergraduate Medical Education, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Effie Viguiliouk
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Sonia Blanco Mejia
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Adrian I Cozma
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Tauseef A Khan
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Vanessa Ha
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Undergraduate Medical Education, School of Medicine, Queen's University, Kingston, ON, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
| | - Thomas M S Wolever
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St Michael's Hospital, Toronto, ON, Canada
| | - Lawrence A Leiter
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St Michael's Hospital, Toronto, ON, Canada
| | - Vladimir Vuksan
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St Michael's Hospital, Toronto, ON, Canada
| | - Cyril W C Kendall
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
| | - Russell J de Souza
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
| | - David J A Jenkins
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St Michael's Hospital, Toronto, ON, Canada
| | - John L Sievenpiper
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St Michael's Hospital, Toronto, ON, Canada
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González-Aldaco K, Torres-Reyes LA, Ojeda-Granados C, José-Ábrego A, Fierro NA, Román S. Immunometabolic Effect of Cholesterol in Hepatitis C Infection: Implications in Clinical Management and Antiviral Therapy. Ann Hepatol 2018; 17:908-919. [PMID: 30600305 DOI: 10.5604/01.3001.0012.7191] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Hepatitis C virus (HCV) is a lipid-enveloped virion particle that causes infection to the liver, and as part of its life cycle, it disrupts the host lipid metabolic machinery, particularly the cholesterol synthesis pathway. The innate immune response generated by liver resident immune cells is responsible for successful viral eradication. Unfortunately, most patients fail to eliminate HCV and progress to chronic infection. Chronic infection is associated with hepatic fat accumulation and inflammation that triggers fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Despite that the current direct-acting antiviral agents have increased the cure rate of HCV infection, viral genotype and the host genetic background influence both the immune response and lipid metabolism. In this context, recent evidence has shown that cholesterol and its derivatives such as oxysterols might modulate and potentialize the hepatic innate immune response generated against HCV. The impairment of the HCV life cycle modulated by serum cholesterol could be relevant for the clinical management of HCV-infected patients before and after treatment. Alongside, cholesterol levels are modulated either by genetic variations in IL28B, ApoE, and LDLR or by dietary components. Indeed, some nutrients such as unsaturated fatty acids have demonstrated to be effective against HCV replication. Thus, cholesterol modifications may be considered as a new adjuvant strategy for HCV infection therapy by providing a biochemical tool that guides treatment decisions, an improved treatment response and favoring viral clearance. Herein, the mechanisms by which cholesterol contributes to the immune response against HCV infection and how genetic and environmental factors may affect this role are reviewed.
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Affiliation(s)
- Karina González-Aldaco
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Luis A Torres-Reyes
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Claudia Ojeda-Granados
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Alexis José-Ábrego
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Nora A Fierro
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Sonia Román
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
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31
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Green CJ, Parry SA, Gunn PJ, Ceresa CDL, Rosqvist F, Piché ME, Hodson L. Studying non-alcoholic fatty liver disease: the ins and outs of in vivo, ex vivo and in vitro human models. Horm Mol Biol Clin Investig 2018; 41:/j/hmbci.ahead-of-print/hmbci-2018-0038/hmbci-2018-0038.xml. [PMID: 30098284 DOI: 10.1515/hmbci-2018-0038] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 06/22/2018] [Indexed: 02/07/2023]
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Determining the pathogenesis and pathophysiology of human NAFLD will allow for evidence-based prevention strategies, and more targeted mechanistic investigations. Various in vivo, ex situ and in vitro models may be utilised to study NAFLD; but all come with their own specific caveats. Here, we review the human-based models and discuss their advantages and limitations in regards to studying the development and progression of NAFLD. Overall, in vivo whole-body human studies are advantageous in that they allow for investigation within the physiological setting, however, limited accessibility to the liver makes direct investigations challenging. Non-invasive imaging techniques are able to somewhat overcome this challenge, whilst the use of stable-isotope tracers enables mechanistic insight to be obtained. Recent technological advances (i.e. normothermic machine perfusion) have opened new opportunities to investigate whole-organ metabolism, thus ex situ livers can be investigated directly. Therefore, investigations that cannot be performed in vivo in humans have the potential to be undertaken. In vitro models offer the ability to perform investigations at a cellular level, aiding in elucidating the molecular mechanisms of NAFLD. However, a number of current models do not closely resemble the human condition and work is ongoing to optimise culturing parameters in order to recapitulate this. In summary, no single model currently provides insight into the development, pathophysiology and progression across the NAFLD spectrum, each experimental model has limitations, which need to be taken into consideration to ensure appropriate conclusions and extrapolation of findings are made.
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Affiliation(s)
- Charlotte J Green
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
| | - Siôn A Parry
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
| | - Pippa J Gunn
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
| | - Carlo D L Ceresa
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Fredrik Rosqvist
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
- Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden
| | - Marie-Eve Piché
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
- Quebec Heart and Lung Institute, Laval University, Quebec, Canada
| | - Leanne Hodson
- University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital,Old Road Headington, Oxford OX3 7LE, United Kingdom of Great Britain and Northern Ireland
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Al-Muzafar HM, Amin KA. Thiazolidinedione induces a therapeutic effect on hepatosteatosis by regulating stearoyl-CoA desaturase-1, lipase activity, leptin and resistin. Exp Ther Med 2018; 16:2938-2948. [PMID: 30214514 PMCID: PMC6125847 DOI: 10.3892/etm.2018.6563] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Accepted: 04/06/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatosteatosis is a disease present worldwide, which presents a number of health problems. Recently, thiazolidinedione (TZD) has been used as a therapy for lipid disorders. The present study demonstrates the potential of TZD as a treatment for hepatosteatosis and its mechanism of action, particularly focusing on its role in lipid metabolism. A total of 60 (80-90 g) rats were divided into three groups: A normal group with a standard diet, a high-fat, high-carbohydrate diet (HFCD) group or a HFCD+TZD group (n=20/group). The HFCD induced hepatosteatosis over a period of 12 weeks and the HFCD+TZD group were administered TZD in weeks 13-16. Blood and tissue samples were collected to measure hepatic function, the lipid profile, metabolism and hormone biomarkers, including serum triglyceride (TG), lipoprotein lipase (LPL), stearoyl-CoA desaturase (SCD-1), leptin and resistin. The HFCD-fed rats exhibited a significant increase in serum TG, total cholesterol, low-density lipoproteins, alanine transaminase and bilirubin compared with the normal group as well as a significant decrease in high-density lipoprotein. In addition, serum leptin and resistin were significantly elevated in the HFCD group compared with the normal group. The administration of TZD significantly increased SCD-1 activity and significantly inhibited LPL activity. It also attenuated the changes in the lipid profiles and normalized serum leptin and resistin levels. The results of the present study indicated that HFCD induced lipid abnormalities associated with hypertriglyceridemia, hypercholesterolemia and hepatosteatosis. These changes resulted from disruption to leptin and resistin, which may be due to alterations in LPL and SCD-1 activity. TZD mitigated the effects of HFCD-induced hepatosteatosis, indicating a possible regulatory effect of TZD in the development of hepatosteatosis. The authors suggest that the manipulation of SCD-1 and lipase by TZD may be useful as a treatment for hepatosteatosis.
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Affiliation(s)
- Hessah Mohammed Al-Muzafar
- Department of Chemistry and Biochemistry, College of Science, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Kamal Adel Amin
- Department of Chemistry and Biochemistry, College of Science, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
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Simó-Mirabet P, Perera E, Calduch-Giner JA, Afonso JM, Pérez-Sánchez J. Co-expression Analysis of Sirtuins and Related Metabolic Biomarkers in Juveniles of Gilthead Sea Bream ( Sparus aurata) With Differences in Growth Performance. Front Physiol 2018; 9:608. [PMID: 29922168 PMCID: PMC5996159 DOI: 10.3389/fphys.2018.00608] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 05/04/2018] [Indexed: 12/16/2022] Open
Abstract
Sirtuins (SIRTs) represent a conserved protein family of deacetylases that act as master regulators of metabolism, but little is known about their roles in fish and livestock animals in general. The present study aimed to assess the value of SIRTs for the metabolic phenotyping of fish by assessing their co-expression with a wide-representation of markers of energy and lipid metabolism and intestinal function and health in two genetically different gilthead sea bream strains with differences in growth performance. Fish from the fast-growing strain exhibited higher feed intake, feed efficiency and plasma IGF-I levels, along with higher hepatosomatic index and lower mesenteric fat (lean phenotype). These observations suggest differences in tissue energy partitioning with an increased flux of fatty acids from adipose tissue toward the liver. The resulting increased risk of hepatic steatosis may be counteracted in the liver by reduced lipogenesis and enhanced triglyceride catabolism, in combination with a higher and more efficient oxidative metabolism in white skeletal muscle. These effects were supported by co-regulated changes in the expression profile of SIRTs (liver, sirt1; skeletal muscle, sirt2; adipose tissue, sirt5-6) and markers of oxidative metabolism (pgc1α, cpt1a, cs, nd2, cox1), mitochondrial respiration uncoupling (ucp3) and fatty acid and triglyceride metabolism (pparα, pparγ, elovl5, scd1a, lpl, atgl) that were specific to each strain and tissue. The anterior intestine of the fast-growing strain was better suited to cope with improved growth by increased expression of markers of nutrient absorption (fabp2), epithelial barrier integrity (cdh1, cdh17) and immunity (il1β, cd8b, lgals1, lgals8, sIgT, mIgT), which were correlated with low expression levels of sirt4 and markers of fatty acid oxidation (cpt1a). In the posterior intestine, the fast-growing strain showed a consistent up-regulation of sirt2, sirt3, sirt5 and sirt7 concurrently with increased expression levels of markers of cell proliferation (pcna), oxidative metabolism (nd2) and immunity (sIgT, mIgT). Together, these findings indicate that SIRTs may play different roles in the regulation of metabolism, inflammatory tone and growth in farmed fish, arising as powerful biomarkers for a reliable metabolic phenotyping of fish at the tissue-specific level.
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Affiliation(s)
- Paula Simó-Mirabet
- Nutrigenomics and Fish Growth Endocrinology, Institute of Aquaculture Torre de la Sal-CSIC, Castellón, Spain
| | - Erick Perera
- Nutrigenomics and Fish Growth Endocrinology, Institute of Aquaculture Torre de la Sal-CSIC, Castellón, Spain
| | - Josep A Calduch-Giner
- Nutrigenomics and Fish Growth Endocrinology, Institute of Aquaculture Torre de la Sal-CSIC, Castellón, Spain
| | - Juan M Afonso
- Aquaculture Research Group, Institute of Sustainable Aquaculture and Marine Ecosystems (IU-ECOAQUA), University of Las Palmas de Gran Canaria (GIA), Las Palmas, Spain
| | - Jaume Pérez-Sánchez
- Nutrigenomics and Fish Growth Endocrinology, Institute of Aquaculture Torre de la Sal-CSIC, Castellón, Spain
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Zandkarimi F, Vanegas J, Fern X, Maier CS, Bobe G. Metabotypes with elevated protein and lipid catabolism and inflammation precede clinical mastitis in prepartal transition dairy cows. J Dairy Sci 2018; 101:5531-5548. [PMID: 29573799 DOI: 10.3168/jds.2017-13977] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 01/15/2018] [Indexed: 12/22/2022]
Abstract
Clinical mastitis (CM), the most prevalent and costly disease in dairy cows, is diagnosed most commonly shortly after calving. Current indicators do not satisfactorily predict CM. This study aimed to develop a robust and comprehensive mass spectrometry-based metabolomic and lipidomic workflow using untargeted ultra-performance liquid chromatography high-resolution mass spectrometry for predictive biomarker detection. Using a nested case-control design, we measured weekly during the prepartal transition period differences in serum metabolites, lipids, inflammation markers, and minerals between clinically healthy Holstein dairy cows diagnosed with mastitis postcalving (CMP; n = 8; CM diagnosis d 1 = 3 cows, d 2 = 2 cows, d 4 = 1 cow; d 25 = 1 cow, and d 43 = 1 cow that had subclinical mastitis since d 3) or not (control; n = 9). The largest fold differences between CMP and control cows during the prepartal transition period were observed for 3'-sialyllactose in serum. Seven metabolites (N-methylethanolamine phosphate, choline, phosphorylcholine, free carnitine, trimethyl lysine, tyrosine, and proline) and 3 metabolite groups (carnitines, AA metabolites, and water-soluble phospholipid metabolites) could correctly classify cows for their future CM status at both 21 and 14 d before calving. Biochemical analysis using lipid and metabolite-specific commercial diagnostic kits supported our mass spectrometry-based omics results and additionally showed elevated inflammatory markers (serum amyloid A and visfatin) in CMP cows. In conclusion, metabolic phenotypes (i.e., metabotype) with elevated protein and lipid metabolism and inflammation may precede CM in prepartal transition dairy cows. The discovered serum metabolites and lipids may assist in predictive diagnostics, prevention strategies, and early treatment intervention against CM, and thereby improve cow health and welfare.
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Affiliation(s)
- F Zandkarimi
- Department of Chemistry, Oregon State University, Corvallis 97331
| | - J Vanegas
- Department of Veterinary Clinical Sciences, Oregon State University, Corvallis 97331
| | - X Fern
- Department of Electrical Engineering and Computer Science, Oregon State University, Corvallis 97331
| | - C S Maier
- Department of Chemistry, Oregon State University, Corvallis 97331; Linus Pauling Institute, Oregon State University, Corvallis 97331
| | - G Bobe
- Linus Pauling Institute, Oregon State University, Corvallis 97331; Department of Animal and Rangeland Sciences, Oregon State University, Corvallis 97331.
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Carta G, Murru E, Banni S, Manca C. Palmitic Acid: Physiological Role, Metabolism and Nutritional Implications. Front Physiol 2017; 8:902. [PMID: 29167646 PMCID: PMC5682332 DOI: 10.3389/fphys.2017.00902] [Citation(s) in RCA: 437] [Impact Index Per Article: 54.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2017] [Accepted: 10/24/2017] [Indexed: 12/19/2022] Open
Abstract
Palmitic acid (PA) has been for long time negatively depicted for its putative detrimental health effects, shadowing its multiple crucial physiological activities. PA is the most common saturated fatty acid accounting for 20–30% of total fatty acids in the human body and can be provided in the diet or synthesized endogenously via de novo lipogenesis (DNL). PA tissue content seems to be controlled around a well-defined concentration, and changes in its intake do not influence significantly its tissue concentration because the exogenous source is counterbalanced by PA endogenous biosynthesis. Particular physiopathological conditions and nutritional factors may strongly induce DNL, resulting in increased tissue content of PA and disrupted homeostatic control of its tissue concentration. The tight homeostatic control of PA tissue concentration is likely related to its fundamental physiological role to guarantee membrane physical properties but also to consent protein palmitoylation, palmitoylethanolamide (PEA) biosynthesis, and in the lung an efficient surfactant activity. In order to maintain membrane phospholipids (PL) balance may be crucial an optimal intake of PA in a certain ratio with unsaturated fatty acids, especially PUFAs of both n-6 and n-3 families. However, in presence of other factors such as positive energy balance, excessive intake of carbohydrates (in particular mono and disaccharides), and a sedentary lifestyle, the mechanisms to maintain a steady state of PA concentration may be disrupted leading to an over accumulation of tissue PA resulting in dyslipidemia, hyperglycemia, increased ectopic fat accumulation and increased inflammatory tone via toll-like receptor 4. It is therefore likely that the controversial data on the association of dietary PA with detrimental health effects, may be related to an excessive imbalance of dietary PA/PUFA ratio which, in certain physiopathological conditions, and in presence of an enhanced DNL, may further accelerate these deleterious effects.
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Affiliation(s)
- Gianfranca Carta
- Dipartimento Scienze Biomediche, Università degli studi di Cagliari, Cagliari, Italy
| | - Elisabetta Murru
- Dipartimento Scienze Biomediche, Università degli studi di Cagliari, Cagliari, Italy
| | - Sebastiano Banni
- Dipartimento Scienze Biomediche, Università degli studi di Cagliari, Cagliari, Italy
| | - Claudia Manca
- Dipartimento Scienze Biomediche, Università degli studi di Cagliari, Cagliari, Italy
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Bellanti F, Villani R, Facciorusso A, Vendemiale G, Serviddio G. Lipid oxidation products in the pathogenesis of non-alcoholic steatohepatitis. Free Radic Biol Med 2017; 111:173-185. [PMID: 28109892 DOI: 10.1016/j.freeradbiomed.2017.01.023] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 01/11/2017] [Accepted: 01/15/2017] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the major public health challenge for hepatologists in the twenty-first century. NAFLD comprises a histological spectrum ranging from simple steatosis or fatty liver, to steatohepatitis, fibrosis, and cirrhosis. It can be categorized into two principal phenotypes: (1) non-alcoholic fatty liver (NAFL), and (2) non-alcoholic steatohepatitis (NASH). The mechanisms of NAFLD progression consist of lipid homeostasis alterations, redox unbalance, insulin resistance, and inflammation in the liver. Even though several studies show an association between the levels of lipid oxidation products and disease state, experimental evidence suggests that compounds such as reactive aldehydes and cholesterol oxidation products, in addition to representing hallmarks of hepatic oxidative damage, may behave as active players in liver dysfunction and the development of NAFLD. This review summarizes the processes that contribute to the metabolic alterations occurring in fatty liver that produce fatty acid and cholesterol oxidation products in NAFLD, with a focus on inflammation, the control of insulin signalling, and the transcription factors involved in lipid metabolism.
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Affiliation(s)
- Francesco Bellanti
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Rosanna Villani
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Antonio Facciorusso
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Gianluigi Vendemiale
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Gaetano Serviddio
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy.
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Walle P, Takkunen M, Männistö V, Vaittinen M, Käkelä P, Ågren J, Schwab U, Lindström J, Tuomilehto J, Uusitupa M, Pihlajamäki J. Alterations in fatty acid metabolism in response to obesity surgery combined with dietary counseling. Nutr Diabetes 2017; 7:e285. [PMID: 28869586 PMCID: PMC5637104 DOI: 10.1038/nutd.2017.33] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 06/24/2017] [Accepted: 07/16/2017] [Indexed: 12/14/2022] Open
Abstract
Background: The effects of obesity surgery on serum and adipose tissue fatty acid (FA) profile and FA metabolism may modify the risk of obesity-related diseases. Methods: We measured serum (n=122) and adipose tissue (n=24) FA composition and adipose tissue mRNA expression of genes regulating FA metabolism (n=100) in participants of the Kuopio Obesity Surgery Study (KOBS, age 47.2±8.7 years, BMI 44.6±6.0, 40 men, 82 women) before and one year after obesity surgery. As part of the surgery protocol, all the subjects were instructed to add sources of unsaturated fatty acids, such as rapeseed oil and fatty fish, into their diet. The results were compared with changes in serum FA composition in 122 subjects from the Finnish Diabetes Prevention study (DPS) (age 54.3±7.1 years, BMI 32.2±4.6, 28 men, 94 women). Results: The proportion of saturated FAs decreased and the proportion of n-3 and n-6 FAs increased in serum triglycerides after obesity surgery (all P<0.002). Weight loss predicted changes in quantitative amounts of saturated FAs, monounsaturated FAs, n-3 and n-6 FAs in triglycerides (P<0.002 for all). Moreover, the changes in adipose tissue FAs reflected the changes in serum FAs, and some of the changes were associated with mRNA expression of elongases and desaturases in adipose tissue (all P<0.05). In line with this the estimated activity of elongase (18:1 n-7/16:1 n-7) increased significantly after obesity surgery in all lipid fractions (all P<4 × 10−7) and the increase in the estimated activity of D5D in triglycerides was associated with higher weight loss (r=0.415, P<2 × 10−6). Changes in serum FA profile were similar after obesity surgery and lifestyle intervention, except for the change in the absolute amounts of n-3 FAs between the two studies (P=0.044). Conclusions: Beneficial changes in serum and adipose tissue FAs after obesity surgery could be associated with changes in endogenous metabolism and diet.
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Affiliation(s)
- P Walle
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - M Takkunen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - V Männistö
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - M Vaittinen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - P Käkelä
- Department of Surgery, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - J Ågren
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - U Schwab
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.,Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland
| | - J Lindström
- National Institute for Health and Welfare, THL, Helsinki, Finland
| | - J Tuomilehto
- National Institute for Health and Welfare, THL, Helsinki, Finland.,Center for Vascular Prevention, Danube University Krems, Krems, Austria.,Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.,Dasman Diabetes Institute, Dasman, Kuwait
| | - M Uusitupa
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - J Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.,Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland
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Henriquez-Rodriguez E, Pena RN, Seradj AR, Fraile L, Christou P, Tor M, Estany J. Carotenoid intake and SCD genotype exert complementary effects over fat content and fatty acid composition in Duroc pigs. J Anim Sci 2017; 95:2547-2557. [PMID: 28727051 DOI: 10.2527/jas.2016.1350] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Nutritional and genetic strategies are needed to enhance intramuscular fat (IMF) and MUFA content without altering carcass leanness. Dietary vitamin A restriction has been suggested to specifically promote IMF, whereas a polymorphism of the () gene has shown to specifically increase MUFA. The purpose of this study was to investigate the combined effects of provitamin A (PVA) carotenoid intake and genotype (>) on hepatic retinoid content and on the liver, muscle (LM and gluteus medius [GM]), and subcutaneous fat (SF) content and fatty acid composition. Following a split-plot design, 32 castrated Duroc pigs, half of each of the 2 homozygous genotypes (CC and TT), were subjected from 165 to 195 d of age to 2 finishing diets differing in the PVA carotenoid content (an enriched-carotene diet [C+] and a control diet [C-]). Both diets were identical except for the corn line used in the feed. The C+ was formulated with 20% of a carotenoid-fortified corn (M37W-Ph3) whereas the C- instead used 20% of its near isogenic M37W line, which did not contain PVA carotenoids. No vitamin A was added to the diets. The C- was estimated to provide, at most, 1,300 IU of vitamin A/kg and the C+ to supply an extra amount of at least 800 IU vitamin A/kg. Compared with the pigs fed the C-, pigs fed with C+ had 3-fold more retinoic acid ( < 0.01) and 4-fold more gene expression in the liver ( = 0.06). The diet did not affect performance traits and backfat thickness, but pigs fed the C+ had less fat (4.0 vs. 5.0%; = 0.07) and MUFA (18.3 vs. 22.5%; = 0.01) in the liver, less IMF (5.4 vs. 8.3%; = 0.04) in the GM, and more fat content (90.4 vs. 87.9%; = 0.09) and MUFA (48.0 vs. 46.6%; = 0.04) in SF. The TT genotype at the gene increased MUFA ( < 0.05) in all tissues (21.4 vs. 19.5% in the liver, 55.0 vs. 53.1% in the LM, 53.9 vs. 51.7% in the GM, and 48.0 vs. 46.7% in SF for TT and CC genotypes, respectively). Liver fat and MUFA content nonlinearly declined with liver all- retinoic acid, indicating a saturation point at relatively low all- retinoic acid content. The results obtained provide evidence for a complementary role between dietary PVA and genotype, in the sense that the TT pigs fed with a low-PVA diet are expected to show higher and more monounsaturated IMF without increasing total fat content.
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Huang Y, Ye T, Liu C, Fang F, Chen Y, Dong Y. Maternal high-fat diet during pregnancy and lactation affects hepatic lipid metabolism in early life of offspring rat. J Biosci 2017; 42:311-319. [DOI: 10.1007/s12038-017-9675-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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40
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Moța M. Prevention of Diabetes and 4P Medicine. ROMANIAN JOURNAL OF DIABETES NUTRITION AND METABOLIC DISEASES 2017. [DOI: 10.1515/rjdnmd-2017-0001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Affiliation(s)
- Maria Moța
- University of Medicine and Pharmacy Craiova
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41
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Franko A, Neschen S, Rozman J, Rathkolb B, Aichler M, Feuchtinger A, Brachthäuser L, Neff F, Kovarova M, Wolf E, Fuchs H, Häring HU, Peter A, Hrabě de Angelis M. Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice. Mol Metab 2017; 6:256-266. [PMID: 28271032 PMCID: PMC5323884 DOI: 10.1016/j.molmet.2016.12.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 12/08/2016] [Accepted: 12/15/2016] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE Recently, we have shown that Bezafibrate (BEZ), the pan-PPAR (peroxisome proliferator-activated receptor) activator, ameliorated diabetes in insulin deficient streptozotocin treated diabetic mice. In order to study whether BEZ can also improve glucose metabolism in a mouse model for fatty liver and type 2 diabetes, the drug was applied to TallyHo mice. METHODS TallyHo mice were divided into an early (ED) and late (LD) diabetes progression group and both groups were treated with 0.5% BEZ (BEZ group) or standard diet (SD group) for 8 weeks. We analyzed plasma parameters, pancreatic beta-cell morphology, and mass as well as glucose metabolism of the BEZ-treated and control mice. Furthermore, liver fat content and composition as well as hepatic gluconeogenesis and mitochondrial mass were determined. RESULTS Plasma lipid and glucose levels were markedly reduced upon BEZ treatment, which was accompanied by elevated insulin sensitivity index as well as glucose tolerance, respectively. BEZ increased islet area in the pancreas. Furthermore, BEZ treatment improved energy expenditure and metabolic flexibility. In the liver, BEZ ameliorated steatosis, modified lipid composition and increased mitochondrial mass, which was accompanied by reduced hepatic gluconeogenesis. CONCLUSIONS Our data showed that BEZ ameliorates diabetes probably via reduced steatosis, enhanced hepatic mitochondrial mass, improved metabolic flexibility and elevated hepatic insulin sensitivity in TallyHo mice, suggesting that BEZ treatment could be beneficial for patients with NAFLD and impaired glucose metabolism.
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Key Words
- BEZ, Bezafibrate
- BG, blood glucose
- Bezafibrate
- ED, early onset of diabetes
- EM, electron microscopy
- FA, fatty acid
- Glucose metabolism
- HOMA-IR, homeostatic model assessment of insulin resistance
- Insulin resistance
- LD, late onset of diabetes
- Lipid metabolism
- NAFLD
- NAFLD, non-alcoholic fatty liver disease
- NEFA, non-esterified fatty acid
- PPAR, peroxisome proliferator-activated receptor
- RER, respiratory exchange ratios
- SD, standard diet
- T2D, type 2 diabetes
- TG, triglyceride
- qNMR, quantitative nuclear magnetic resonance
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Affiliation(s)
- Andras Franko
- Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
| | - Susanne Neschen
- Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
| | - Jan Rozman
- Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
| | - Birgit Rathkolb
- Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität-München, Hackerstr. 27, 85764 Oberschleißheim, Germany
| | - Michaela Aichler
- Research Unit Analytical Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
| | - Annette Feuchtinger
- Research Unit Analytical Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
| | - Laura Brachthäuser
- Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
| | - Frauke Neff
- Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
| | - Marketa Kovarova
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
| | - Eckhard Wolf
- Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität-München, Hackerstr. 27, 85764 Oberschleißheim, Germany
| | - Helmut Fuchs
- Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
| | - Andreas Peter
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
| | - Martin Hrabě de Angelis
- Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; Center of Life and Food Sciences Weihenstephan, Technische Universität München, Alte Akademie 8, 85354 Freising, Germany.
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Wolf Greenstein A, Majumdar N, Yang P, Subbaiah PV, Kineman RD, Cordoba-Chacon J. Hepatocyte-specific, PPARγ-regulated mechanisms to promote steatosis in adult mice. J Endocrinol 2017; 232:107-121. [PMID: 27799461 PMCID: PMC5120553 DOI: 10.1530/joe-16-0447] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 10/25/2016] [Indexed: 12/15/2022]
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is the target for thiazolidinones (TZDs), drugs that improve insulin sensitivity and fatty liver in humans and rodent models, related to a reduction in hepatic de novo lipogenesis (DNL). The systemic effects of TZDs are in contrast to reports suggesting hepatocyte-specific activation of PPARγ promotes DNL, triacylglycerol (TAG) uptake and fatty acid (FA) esterification. As these hepatocyte-specific effects of PPARγ could counterbalance the positive therapeutic actions of systemic delivery of TZDs, the current study used a mouse model of adult-onset, liver (hepatocyte)-specific PPARγ knockdown (aLivPPARγkd). This model has advantages over existing congenital knockout models, by avoiding compensatory changes related to embryonic knockdown, thus better modeling the impact of altering PPARγ on adult physiology, where metabolic diseases most frequently develop. The impact of aLivPPARγkd on hepatic gene expression and endpoints in lipid metabolism was examined after 1 or 18 weeks (Chow-fed) or after 14 weeks of low- or high-fat (HF) diet. aLivPPARγkd reduced hepatic TAG content but did not impact endpoints in DNL or TAG uptake. However, aLivPPARγkd reduced the expression of the FA translocase (Cd36), in 18-week Chow- and HF-fed mice, associated with increased NEFA after HF feeding. Also, aLivPPARγkd dramatically reduced Mogat1 expression, that was reflected by an increase in hepatic monoacylglycerol (MAG) levels, indicative of reduced MOGAT activity. These results, coupled with previous reports, suggest that Cd36-mediated FA uptake and MAG pathway-mediated FA esterification are major targets of hepatocyte PPARγ, where loss of this control explains in part the protection against steatosis observed after aLivPPARγkd.
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Affiliation(s)
- Abigail Wolf Greenstein
- Research and Development DivisionJesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
- Section of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- Biologic Resources LaboratoryUniversity of Illinois at Chicago, Chicago, Illinois, USA
| | - Neena Majumdar
- Research and Development DivisionJesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
- Section of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Peng Yang
- Research and Development DivisionJesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
- Section of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Papasani V Subbaiah
- Research and Development DivisionJesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
- Section of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Rhonda D Kineman
- Research and Development DivisionJesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
- Section of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Jose Cordoba-Chacon
- Research and Development DivisionJesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
- Section of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
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Liu Z, Cordoba-Chacon J, Kineman RD, Cronstein BN, Muzumdar R, Gong Z, Werner H, Yakar S. Growth Hormone Control of Hepatic Lipid Metabolism. Diabetes 2016; 65:3598-3609. [PMID: 27679560 PMCID: PMC5127251 DOI: 10.2337/db16-0649] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 09/20/2016] [Indexed: 12/15/2022]
Abstract
In humans, low levels of growth hormone (GH) and its mediator, IGF-1, associate with hepatic lipid accumulation. In mice, congenital liver-specific ablation of the GH receptor (GHR) results in reductions in circulating IGF-1 and hepatic steatosis, associated with systemic insulin resistance. Due to the intricate relationship between GH and IGF-1, the relative contribution of each hormone to the development of hepatic steatosis is unclear. Our goal was to dissect the mechanisms by which hepatic GH resistance leads to steatosis and overall insulin resistance, independent of IGF-1. We have generated a combined mouse model with liver-specific ablation of GHR in which we restored liver IGF-1 expression via the hepatic IGF-1 transgene. We found that liver GHR ablation leads to increases in lipid uptake, de novo lipogenesis, hyperinsulinemia, and hyperglycemia accompanied with severe insulin resistance and increased body adiposity and serum lipids. Restoration of IGF-1 improved overall insulin sensitivity and lipid profile in serum and reduced body adiposity, but was insufficient to protect against steatosis-induced hepatic inflammation or oxidative stress. We conclude that the impaired metabolism in states of GH resistance results from direct actions of GH on lipid uptake and de novo lipogenesis, whereas its actions on extrahepatic tissues are mediated by IGF-1.
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Affiliation(s)
- Zhongbo Liu
- Department of Basic Science & Craniofacial Biology, David B. Kriser Dental Center, NYU College of Dentistry, New York, NY
| | - Jose Cordoba-Chacon
- Research and Development, Jesse Brown VA Medical Center, Chicago, IL
- Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL
| | - Rhonda D Kineman
- Research and Development, Jesse Brown VA Medical Center, Chicago, IL
- Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL
| | | | - Radhika Muzumdar
- Division of Pediatric Endocrinology, Diabetes and Metabolism Consultation, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Zhenwei Gong
- Division of Pediatric Endocrinology, Diabetes and Metabolism Consultation, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Haim Werner
- Department of Human Molecular Genetics and Biochemistry, The Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel
| | - Shoshana Yakar
- Department of Basic Science & Craniofacial Biology, David B. Kriser Dental Center, NYU College of Dentistry, New York, NY
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Abstract
This article describes phenotypes observed in a prediabetic population (i.e. a population with increased risk for type 2 diabetes) from data collected at the University hospital of Tübingen. We discuss the impact of genetic variation on insulin secretion, in particular the effect on compensatory hypersecretion, and the incretin-resistant phenotype of carriers of the gene variant TCF7L2 is described. Imaging studies used to characterise subphenotypes of fat distribution, metabolically healthy obesity and metabolically unhealthy obesity are described. Also discussed are ectopic fat stores in liver and pancreas that determine the phenotype of metabolically healthy and unhealthy fatty liver and the recently recognised phenotype of fatty pancreas. The metabolic impact of perivascular adipose tissue and pancreatic fat is discussed. The role of hepatokines, particularly that of fetuin-A, in the crosstalk between these organs is described. Finally, the role of brain insulin resistance in the development of the different prediabetes phenotypes is discussed.
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Affiliation(s)
- Hans-Ulrich Häring
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.
- Institute of Diabetes Research and Metabolic Diseases (IDM), University of Tübingen, Tübingen, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
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45
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Franko A, Huypens P, Neschen S, Irmler M, Rozman J, Rathkolb B, Neff F, Prehn C, Dubois G, Baumann M, Massinger R, Gradinger D, Przemeck GKH, Repp B, Aichler M, Feuchtinger A, Schommers P, Stöhr O, Sanchez-Lasheras C, Adamski J, Peter A, Prokisch H, Beckers J, Walch AK, Fuchs H, Wolf E, Schubert M, Wiesner RJ, Hrabě de Angelis M. Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice. Diabetes 2016; 65:2540-52. [PMID: 27284107 DOI: 10.2337/db15-1670] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 05/25/2016] [Indexed: 11/13/2022]
Abstract
Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in mice with streptozotocin (STZ)-induced diabetes, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin-positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes.
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Affiliation(s)
- Andras Franko
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Peter Huypens
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Susanne Neschen
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany
| | - Martin Irmler
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Jan Rozman
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany
| | - Birgit Rathkolb
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität-München, Munich, Germany
| | - Frauke Neff
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Cornelia Prehn
- Genome Analysis Center, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Guillaume Dubois
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Martina Baumann
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Rebecca Massinger
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Daniel Gradinger
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Gerhard K H Przemeck
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Birgit Repp
- Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Michaela Aichler
- Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Annette Feuchtinger
- Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Philipp Schommers
- Institute of Vegetative Physiology, University of Köln, Cologne, Germany Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany
| | - Oliver Stöhr
- Center for Endocrinology, Diabetes and Preventive Medicine, University of Köln, Cologne, Germany
| | | | - Jerzy Adamski
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany Genome Analysis Center, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan, Germany
| | - Andreas Peter
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany
| | - Holger Prokisch
- Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Johannes Beckers
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany
| | - Axel K Walch
- Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Helmut Fuchs
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany
| | - Eckhard Wolf
- Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität-München, Munich, Germany
| | - Markus Schubert
- Center for Endocrinology, Diabetes and Preventive Medicine, University of Köln, Cologne, Germany Internal Medicine, SCIVIAS Hospital St. Josef, Rüdesheim am Rhein, Germany
| | - Rudolf J Wiesner
- Institute of Vegetative Physiology, University of Köln, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Köln, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Ageing-associated Diseases (CECAD), University of Köln, Cologne, Germany
| | - Martin Hrabě de Angelis
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany
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Walle P, Takkunen M, Männistö V, Vaittinen M, Lankinen M, Kärjä V, Käkelä P, Ågren J, Tiainen M, Schwab U, Kuusisto J, Laakso M, Pihlajamäki J. Fatty acid metabolism is altered in non-alcoholic steatohepatitis independent of obesity. Metabolism 2016; 65:655-666. [PMID: 27085774 DOI: 10.1016/j.metabol.2016.01.011] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 01/18/2016] [Accepted: 01/20/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH) is associated with changes in fatty acid (FA) metabolism. However, specific changes in metabolism and hepatic mRNA expression related to NASH independent of simple steatosis, obesity and diet are unknown. METHODS Liver histology, serum and liver FA composition and estimated enzyme activities based on the FA ratios in cholesteryl esters and triglycerides were assessed in 92 obese participants of the Kuopio Obesity Surgery Study (KOBS) divided to those with normal liver, steatosis or NASH (30 men and 62 women, age 46.8±9.5years (mean±SD), BMI 44.2±6.2kg/m(2)). Plasma FA composition was also investigated in the Metabolic Syndrome in Men (METSIM) Study (n=769), in which serum alanine aminotransferase (ALT) was used as a marker of liver disease. RESULTS Obese individuals with NASH had higher activity of estimated activities of delta-6 desaturase (D6D, p<0.002) and stearoyl-CoA desaturase 1 (SCD1, p<0.002) and lower activity of delta-5 desaturase (D5D, p<0.002) when compared to individuals with normal liver. Estimated activities of D5D, D6D and SCD1 correlated positively between liver and serum indicating that serum estimates reflected liver metabolism. Accordingly, NASH was associated with higher hepatic mRNA expression of corresponding genes FADS1, FADS2 and SCD. Finally, differences in FA metabolism that associated with NASH in obese individuals were also associated with high ALT in the METSIM Study. CONCLUSIONS We demonstrated alterations in FA metabolism and endogenous desaturase activities that associate with NASH, independent of obesity and diet. This suggests that changes in endogenous FA metabolism are related to NASH and that they may contribute to the progression of the disease.
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Affiliation(s)
- Paula Walle
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland
| | - Markus Takkunen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland
| | - Ville Männistö
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Finland
| | - Maija Vaittinen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland
| | - Maria Lankinen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland
| | - Vesa Kärjä
- Department of Pathology, University of Eastern Finland and Kuopio University Hospital, Finland
| | - Pirjo Käkelä
- Department of Surgery, University of Eastern Finland and Kuopio University Hospital, Finland
| | - Jyrki Ågren
- Institute of Biomedicine, University of Eastern Finland, Finland
| | - Mika Tiainen
- School of Pharmacy, University of Eastern Finland
| | - Ursula Schwab
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland; Clinical Nutrition and Obesity Center, Kuopio University Hospital, Finland
| | - Johanna Kuusisto
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Finland
| | - Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Finland
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland; Clinical Nutrition and Obesity Center, Kuopio University Hospital, Finland.
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Kineman RD, Majumdar N, Subbaiah PV, Cordoba-Chacon J. Hepatic PPARγ Is Not Essential for the Rapid Development of Steatosis After Loss of Hepatic GH Signaling, in Adult Male Mice. Endocrinology 2016; 157:1728-35. [PMID: 26950202 PMCID: PMC4870866 DOI: 10.1210/en.2015-2077] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Our group has previously reported de novo lipogenesis (DNL) and hepatic triglyceride content increases in chow-fed male mice within 7 days of hepatocyte-specific GH receptor knockdown (aLivGHRkd). Here, we report that these changes are associated with an increase in hepatic expression of peroxisome proliferator-activated receptor γ (PPARγ), consistent with previous reports showing steatosis is associated with an increase in PPARγ expression in mice with congenital loss of hepatic GH signaling. PPARγ is thought to be an important driver of steatosis by enhancing DNL, as well as increasing the uptake and esterification of extrahepatic fatty acids (FAs). In order to determine whether hepatic PPARγ is critical for the rapid development of steatosis in the aLivGHRkd mouse model, we have generated aLivGHRkd mice, with or without PPARγ (ie, adult-onset, hepatocyte-specific double knockout of GHR and PPARγ). Hepatic PPARγ was not required for the rapid increase in liver triglyceride content or FA indexes of DNL (16:0/18:2 and 16:1/16:0). However, loss of hepatic PPARγ blunted the rise in fatty acid translocase/CD36 and monoacylglycerol acyltransferase 1 expression induced by aLivGHRkd, and this was associated with a reduction in the hepatic content of 18:2. These results suggest that the major role of PPARγ is to enhance pathways critical in uptake and reesterification of extrahepatic FA. Because FAs have been reported to directly increase PPARγ expression, we speculate that in the aLivGHRkd mouse, the FA produced by DNL enhances the expression of PPARγ, which in turn increases extrahepatic FA uptake, thereby further enhancing PPARγ activity and exacerbating steatosis overtime.
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Affiliation(s)
- Rhonda D Kineman
- Research and Development Division (R.D.K., N.M., P.V.S., J.C.-C.), Jesse Brown Veterans Affairs Medical Center; and Department of Medicine (R.D.K., N.M., P.V.S., J.C.-C.), Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, Illinois 60612
| | - Neena Majumdar
- Research and Development Division (R.D.K., N.M., P.V.S., J.C.-C.), Jesse Brown Veterans Affairs Medical Center; and Department of Medicine (R.D.K., N.M., P.V.S., J.C.-C.), Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, Illinois 60612
| | - Papasani V Subbaiah
- Research and Development Division (R.D.K., N.M., P.V.S., J.C.-C.), Jesse Brown Veterans Affairs Medical Center; and Department of Medicine (R.D.K., N.M., P.V.S., J.C.-C.), Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, Illinois 60612
| | - Jose Cordoba-Chacon
- Research and Development Division (R.D.K., N.M., P.V.S., J.C.-C.), Jesse Brown Veterans Affairs Medical Center; and Department of Medicine (R.D.K., N.M., P.V.S., J.C.-C.), Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, Illinois 60612
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Machicao F, Peter A, Machann J, Königsrainer I, Böhm A, Lutz SZ, Heni M, Fritsche A, Schick F, Königsrainer A, Stefan N, Häring HU, Staiger H. Glucose-Raising Polymorphisms in the Human Clock Gene Cryptochrome 2 (CRY2) Affect Hepatic Lipid Content. PLoS One 2016; 11:e0145563. [PMID: 26726810 PMCID: PMC4699770 DOI: 10.1371/journal.pone.0145563] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 12/04/2015] [Indexed: 01/22/2023] Open
Abstract
Circadian rhythms govern vital functions. Their disruption provokes metabolic imbalance favouring obesity and type-2 diabetes. The aim of the study was to assess the role of clock genes in human prediabetes. To this end, genotype-phenotype associations of 121 common single nucleotide polymorphisms (SNPs) tagging ARNTL, ARNTL2, CLOCK, CRY1, CRY2, PER1, PER2, PER3, and TIMELESS were assessed in a study population of 1,715 non-diabetic individuals metabolically phenotyped by 5-point oral glucose tolerance tests. In subgroups, hyperinsulinaemic-euglycaemic clamps, intravenous glucose tolerance tests, and magnetic resonance imaging/spectroscopy were performed. None of the tested SNPs was associated with body fat content, insulin sensitivity, or insulin secretion. Four CRY2 SNPs were associated with fasting glycaemia, as reported earlier. Importantly, carriers of these SNPs’ minor alleles revealed elevated fasting glycaemia and, concomitantly, reduced liver fat content. In human liver tissue samples, CRY2 mRNA expression was directly associated with hepatic triglyceride content. Our data may point to CRY2 as a novel switch in hepatic fuel metabolism promoting triglyceride storage and, concomitantly, limiting glucose production. The anti-steatotic effects of the glucose-raising CRY2 alleles may explain why these alleles do not increase type-2 diabetes risk.
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Affiliation(s)
- Fausto Machicao
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Andreas Peter
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Jürgen Machann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Diagnostic and Interventional Radiology, Section on Experimental Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Ingmar Königsrainer
- Department of General, Visceral, and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
| | - Anja Böhm
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Stefan Zoltan Lutz
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
- Department of Internal Medicine, Division of Nutritional and Preventive Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Fritz Schick
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Diagnostic and Interventional Radiology, Section on Experimental Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Alfred Königsrainer
- Department of General, Visceral, and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
| | - Norbert Stefan
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Harald Staiger
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
- * E-mail:
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Ferolla SM, Silva LC, Ferrari MDLA, da Cunha AS, Martins FDS, Couto CA, Ferrari TCA. Dietary approach in the treatment of nonalcoholic fatty liver disease. World J Hepatol 2015; 7:2522-2534. [PMID: 26523205 PMCID: PMC4621466 DOI: 10.4254/wjh.v7.i24.2522] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 08/24/2015] [Accepted: 10/08/2015] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has been identified as one of the most prevalent chronic liver disease in adults and children populations. NAFLD is usually associated with the metabolic syndrome (MS), which is chiefly related to insulin resistance and its consequences. Insulin resistance has a crucial role in the pathogenesis of hepatic steatosis and potentially nonalcoholic steatohepatitis (NASH). Because of the contemporary epidemics of MS and obesity, the burden of NAFLD is also expected to rise. Unhealthy diets, such as the so-called western diet, are enriched in fructose, trans-fatty acids and saturated fat and seem to be associated with the development of NAFLD. In human studies, certain dietary sugars, particularly fructose, are used as a substrate for lipogenesis leading to hepatic fatty infiltration, inflammation, and possibly fibrosis. Other investigations have shown that fat consumption especially cholesterol and trans/saturated fatty acids are also steatogenic and seem to increase visceral adiposity. The identification of specific dietary components that favor the development of NASH could be important for the management of this disorder. This review focuses on the effects of different dietary approaches to prevent and treat NAFLD emphasizing the macronutrients and energy composition.
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50
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Venäläinen T, Ågren J, Schwab U, de Mello VD, Eloranta AM, Laaksonen DE, Lindi V, Lakka TA. Cross-sectional associations of plasma fatty acid composition and estimated desaturase and elongase activities with cardiometabolic risk in Finnish children--The PANIC study. J Clin Lipidol 2015; 10:82-91. [PMID: 26892124 DOI: 10.1016/j.jacl.2015.09.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 08/31/2015] [Accepted: 09/14/2015] [Indexed: 01/04/2023]
Abstract
BACKGROUND Knowledge on the association of plasma fatty acid (FA) composition in triacylglycerol (TG) and phospholipid (PL) fractions with cardiometabolic risk in population-based samples of children is lacking. OBJECTIVE We investigated the associations of proportions of FA in plasma TG and PL fractions as well as estimated desaturase and elongase activities with cardiometabolic risk in a population sample of 384 children aged 6-8 years. METHODS Plasma FA composition was analyzed by gas chromatography. Desaturase and elongase activities were estimated as product-to-precursor FA ratios. Cardiometabolic risk was assessed using a continuous cardiometabolic risk score (CRS) variable. RESULTS Higher proportions of myristic and palmitoleic acids in plasma TG and PL were associated with a higher CRS. A lower proportion of linoleic acid in plasma TG was related to a higher CRS. Estimated stearoyl-CoA-desaturase and Δ6-desaturase activities in plasma TG and PL were directly associated with CRS, whereas estimated elongase activity in plasma TG and PL was inversely related to CRS. CONCLUSIONS Greater proportions of myristic and palmitoleic acids and a smaller proportion of linoleic acid in plasma, as well as higher estimated stearoyl-CoA-desaturase and Δ6-desaturase activities and a lower estimated elongase activity, are associated with cardiometabolic risk factors among children. These findings reinforce the evidence that FA metabolism is closely associated with cardiometabolic risk, starting already from childhood.
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Affiliation(s)
- Taisa Venäläinen
- Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio, Finland; Institute of Public Health and Clinical Nutrition, Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
| | - Jyrki Ågren
- Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio, Finland
| | - Ursula Schwab
- Institute of Public Health and Clinical Nutrition, Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Institute of Clinical Medicine, Internal Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Vanessa D de Mello
- Institute of Public Health and Clinical Nutrition, Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Aino-Maija Eloranta
- Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio, Finland
| | - David E Laaksonen
- Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio, Finland; Institute of Clinical Medicine, Internal Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Virpi Lindi
- Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio, Finland
| | - Timo A Lakka
- Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio, Finland; Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland; Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
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