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Cited by 157Sirtuins and Resveratrol in MedicineLiver Disease Diagnosis and TreatmentDiabetes Treatment and Management

Exendin-4 Improves Steatohepatitis by Increasing Sirt1 Expression in High-Fat Diet-Induced Obese C57BL/6J Mice

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Lee, Jinmi, Hong, Seok-Woo, Chae, Seoung Wan, Kim, Dong Hoon, Choi, Ji Hun, Bae, Ji Cheol, Park, Se Eun, Rhee, Eun-Jung +5 more·2012·PLoS ONE
DOI 10.1371/journal.pone.0031394PMC PMC3281956
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Abstract

The effects of exendin-4 on Sirt1 expression as a mechanism of reducing fatty liver have not been previously reported. Therefore, we investigated whether the beneficial effects of exendin-4 treatment on fatty liver are mediated via Sirt1 in high-fat (HF) diet-induced obese C57BL/6J mice and related cell culture models. Exendin-4 treatment decreased body weight, serum free fatty acid (FA), and triglyceride levels in HF-induced obese C57BL/6J mice. Histological analysis showed that exendin-4 reversed HF-induced hepatic accumulation of lipids and inflammation. Exendin-4 treatment increased mRNA and protein expression of Sirt1 and its downstream factor, AMPK, in vivo and also induced genes associated with FA oxidation and glucose metabolism. In addition, a significant increase in the hepatic expression of Lkb1 and Nampt mRNA was observed in exendin-4-treated groups. We also observed increased expression of phospho-Foxo1 and GLUT2, which are involved in hepatic glucose metabolism. In HepG2 and Huh7 cells, mRNA and protein expressions of GLP-1R were increased by exendin-4 treatment in a dose-dependent manner. Exendin-4 enhanced protein expression of Sirt1 and phospho-AMPKα in HepG2 cells treated with 0.4 mM palmitic acid. We also found that Sirt1 was an upstream regulator of AMPK in hepatocytes. A novel finding of this study was the observation that expression of GLP-1R is proportional to exendin-4 concentration and exendin-4 could attenuate fatty liver through activation of Sirt1.

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  • Liraglutide or exendin-4 (1 nmol/kg/day) treatment dose-dependently reduced steatosis and lobular inflammation in HFD-fed rats or mice compared with the saline-injected group.

    “Liraglutide or exendin-4 (1 nmol/kg/day) treatment dose-dependently reduced steatosis and lobular inflammation in HFD-fed rats or mice compared with the saline-injected group [28, 95], probably due to an increase of SIRT1 [96].”

    From Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control (2016) · cites this paper as [95]

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  1. [1]Bellentani S Saccoccio G Masutti F Crocè LS Brandi G 2000 Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 132 112 117 10644271
  2. [2]Tiikkainen M Bergholm R Vehkavaara S Rissanen A Häkkinen AM 2003 Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content. Diabetes 52 701 707 12606511
  3. [3]Donahey JC van Dijk G Woods SC Seeley RJ 1998 Intraventricular GLP-1 reduces short- but not long-term food intake or body weight in lean and obese rats. Brain Res 779 75 83 9473596
  4. [4]Gutzwiller JP Drewe J Göke B Schmidt H Rohrer B 1999 Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol 276 R1541 1544 10233049
  5. [5]Ahrén B Schmitz O 2004 GLP-1 receptor agonists and DPP-4 inhibitors in the treatment of type 2 diabetes. Horm Metab Res 36 867 876 15655721
  6. [7]Thorens B Porret A Bühler L Deng SP Morel P 1993 Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9–39) an antagonist of the receptor. Diabetes 42 1678 1682 8405712
  7. [8]Gupta NA Mells J Dunham RM Grakoui A Handy J 2010 Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 51 1584 1592 20225248 PMC2862093
  8. [10]Tushuizen ME Bunck MC Pouwels PJ van Waesberghe JH Diamant M 2006 Incretin mimetics as a novel therapeutic option for hepatic steatosis. Liver Int 26 1015 1017 16953843
  9. [11]Ajmo JM Liang X Rogers CQ Pennock B You M 2008 Resveratrol alleviates alcoholic fatty liver in mice. Am J Physiol Gastrointest Liver Physiol 295 G833 842 18755807 PMC2575919
  10. [12]Wang GL Fu YC Xu WC Feng YQ Fang SR 2009 Resveratrol inhibits the expression of SREBP1 in cell model of steatosis via Sirt1-FOXO1 signaling pathway. Biochem Biophys Res Commun 380 644 649 19285015
  11. [13]Song Z Song M Lee DY Liu Y Deaciuc IV 2007 Silymarin prevents palmitate-induced lipotoxicity in HepG2 cells: involvement of maintenance of Akt kinase activation. Basic Clin Pharmacol Toxicol 101 262 268 17845508 PMC4219607
  12. [14]Kleiner DE Brunt EM Van Natta M Behling C Contos MJ 2005 Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41 1313 1321 15915461
  13. [16]Szayna M Doyle ME Betkey JA Holloway HW Spencer RG 2000 Exendin-4 decelerates food intake, weight gain, and fat deposition in Zucker rats. Endocrinology 141 1936 1941 10830274
  14. [17]Svegliati-Baroni G Saccomanno S Rychlicki C Agostinelli L De Minicis S 2011 Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int 31 1285 1297 21745271
  15. [18]Adams LA Angulo P 2006 Treatment of non-alcoholic fatty liver disease. Postgrad Med J 82 315 322 16679470 PMC2563793
  16. [19]Cantó C Auwerx J 2009 PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 20 98 105 19276888 PMC3627054
  17. [20]Chaudhary N Pfluger PT 2009 Metabolic benefits from Sirt1 and Sirt1 activators. Curr Opin Clin Nutr Metab Care 12 431 437 19474719
  18. [21]Hou X Xu S Maitland-Toolan KA Sato K Jiang B 2008 SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem 283 20015 20026 18482975 PMC2459285
  19. [22]Lan F Cacicedo JM Ruderman N Ido Y 2008 SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem 283 27628 27635 18687677 PMC2562073
  20. [23]Fulco M Sartorelli V 2008 Comparing and contrasting the roles of AMPK and SIRT1 in metabolic tissues. Cell Cycle 7 3669 3679 19029811 PMC2607479
  21. [24]Cantó C Gerhart-Hines Z Feige JN Lagouge M Noriega L 2009 AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458 1056 1060 19262508 PMC3616311
  22. [25]Yamauchi T Kamon J Minokoshi Y Ito Y Waki H 2002 Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8 1288 1295 12368907
  23. [26]Awazawa M Ueki K Inabe K Yamauchi T Kaneko K 2009 Adiponectin suppresses hepatic SREBP1c expression in an AdipoR1/LKB1/AMPK dependent pathway. Biochem Biophys Res Commun 382 51 56 19254698
  24. [27]Zhou G Myers R Li Y Chen Y Shen X 2001 Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108 1167 1174 11602624 PMC209533
  25. [28]Kadowaki T Yamauchi T Kubota N Hara K Ueki K 2006 Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116 1784 1792 16823476 PMC1483172
  26. [29]Yamada T Fukatsu M Suzuki S Wada T Yoshida T 2010 Fatty liver predicts impaired fasting glucose and type 2 diabetes mellitus in Japanese undergoing a health checkup. J Gastroenterol Hepatol 25 352 356 19817963
  27. [30]Purushotham A Schug TT Li X 2009 SIRT1 performs a balancing act on the tight-rope toward longevity. Aging 1 669 673 20157548 PMC2806045
  28. [31]Banks AS Kon N Knight C Matsumoto M Gutiérrez-Juárez R 2008 SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 8 333 341 18840364 PMC3222897
  29. [32]Arnés L Moreno P Nuche-Berenguer B Valverde I Villanueva-Peñacarrillo ML 2009 Effect of exendin-4 treatment upon glucose uptake parameters in rat liver and muscle, in normal and type 2 diabetic state. Regul Pept 153 88 92 18804493
  30. [33]Park S Hong SM Ahn IS 2010 Exendin-4 and exercise improve hepatic glucose homeostasis by promoting insulin signaling in diabetic rats. Metabolism 59 123 133 19766272
  31. [34]Klonoff DC Buse JB Nielsen LL Guan X Bowlus CL 2008 Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin 24 275 286 18053320

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Authors
Lee, J., Hong, S.-W., Chae, S. W., Kim, D. H., Choi, J. H., Bae, J. C., Park, S. E., Rhee, E.-J., Park, C.-Y., Oh, K.-W., Park, S.-W., Kim, S.-W., & Lee, W.-Y.
Affiliations
Kangbuk Samsung Hospital (KR)
Corresponding author
Lee, Won-Young
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-02-17
Volume
7
Issue
2
Pages
e31394
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0031394
PMC
PMC3281956
OpenAlex
W2056990561
Cited by
157
References
2
Citations by year
2026: 1 · 2025: 8 · 2024: 8 · 2023: 6 · 2022: 11 · 2021: 9 · 2020: 8 · 2019: 9 · 2018: 10 · 2017: 17 · 2016: 13 · 2015: 19 · 2014: 18 · 2013: 15 · 2012: 5
FWCI
8.97
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Korea Science and Engineering Foundation
  • Ministry of Education, Science and Technology
  • Samsung
Topics
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
exendin-4, SIRT1, steatohepatitis, hepatic steatosis, high-fat diet-induced obesity, GLP-1 receptor, AMPK, LKB1, visfatin, FOXO1, GLUT2, hepatic glucose metabolism, fatty acid oxidation, hepatic lipid accumulation, liver inflammation, GLP-1 receptor agonists
MeSH terms
Glucagon-Like Peptide-1 Receptor, Exenatide, Animals, Body Weight, Fatty Liver, Feeding Behavior, Gene Expression Regulation, Glucose, Homeostasis, Humans, Liver, Mice, Inbred C57BL, Mice, Obese, Oxidation-Reduction, Peptides, Triglycerides, Venoms, Cytokines, Protein Serine-Threonine Kinases, Receptors, Glucagon, Palmitic Acid, Cell Line, Tumor, Lipogenesis, Mice, Nicotinamide Phosphoribosyltransferase, AMP-Activated Protein Kinases, Sirtuin 1, Diet, High-Fat

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