Browse > Article
http://dx.doi.org/10.4196/kjpp.2014.18.4.333

Exendin-4 Improves Nonalcoholic Fatty Liver Disease by Regulating Glucose Transporter 4 Expression in ob/ob Mice  

Kim, Seok (Department of Anatomy and Convergence Medical Science, Institutes of Health Science, Gyeongsnag National University School of Medicine)
Jung, Jaehoon (Department of Internal Medicine, Institutes of Health Science, Gyeongsnag National University School of Medicine)
Kim, Hwajin (Department of Anatomy and Convergence Medical Science, Institutes of Health Science, Gyeongsnag National University School of Medicine)
Heo, Rok Won (Department of Anatomy and Convergence Medical Science, Institutes of Health Science, Gyeongsnag National University School of Medicine)
Yi, Chin-Ok (Department of Anatomy and Convergence Medical Science, Institutes of Health Science, Gyeongsnag National University School of Medicine)
Lee, Jung Eun (Department of Thoracic and Cardiovascular Surgery, Institutes of Health Science, Gyeongsnag National University School of Medicine)
Jeon, Byeong Tak (Department of Neurologic Surgery, Biochemistry and Molecular Biology, Mayo Clinic College of Medicine)
Kim, Won-Ho (Division of Metabolic Diseases, Center for Biomedical Sciences, National Institutes of Health)
Hahm, Jong Ryeal (Department of Internal Medicine, Institutes of Health Science, Gyeongsnag National University School of Medicine)
Roh, Gu Seob (Department of Anatomy and Convergence Medical Science, Institutes of Health Science, Gyeongsnag National University School of Medicine)
Publication Information
The Korean Journal of Physiology and Pharmacology / v.18, no.4, 2014 , pp. 333-339 More about this Journal
Abstract
Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been known to reverse hepatic steatosis in ob/ob mice. Although many studies have evaluated molecular targets of Ex-4, its mechanism of action on hepatic steatosis and fibrosis has not fully been determined. In the liver, glucose transporter 4 (GLUT4) is mainly expressed in hepatocytes, endothelial cells and hepatic stellate cells (HSCs). In the present study, the effects of Ex-4 on GLUT4 expression were determined in the liver of ob/ob mice. Ob/ob mice were treated with Ex-4 for 10 weeks. Serum metabolic parameters, hepatic triglyceride levels, and liver tissues were evaluated for hepatic steatosis. The weights of the whole body and liver in ob/ob mice were reduced by long-term Ex-4 treatment. Serum metabolic parameters, hepatic steatosis, and hepatic fibrosis in ob/ob mice were reduced by Ex-4. Particularly, Ex-4 improved hepatic steatosis by enhancing GLUT4 via GLP-1R activation in ob/ob mice. Ex-4 treatment also inhibited hepatic fibrosis by decreasing expression of connective tissue growth factor in HSCs of ob/ob mice. Our data suggest that GLP-1 agonists exert a protective effect on hepatic steatosis and fibrosis in obesity and type 2 diabetes.
Keywords
Exendin-4; Glucose transporter 4; Nonalcoholic fatty liver disease; ob/ob;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Vilsboll T, Holst JJ. Incretins, insulin secretion and Type 2 diabetes mellitus. Diabetologia. 2004;47:357-366.   DOI   ScienceOn
2 Creutzfeldt WO, Kleine N, Willms B, Orskov C, Holst JJ, Nauck MA. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7-36) amide in type I diabetic patients. Diabetes Care. 1996;19: 580-586.   DOI
3 Vilsboll T, Toft-Nielsen MB, Krarup T, Madsbad S, Dinesen B, Holst JJ. Evaluation of beta-cell secretory capacity using glucagon-like peptide 1. Diabetes Care. 2000;23:807-812.   DOI
4 Ding X, Saxena NK, Lin S, Gupta NA, Anania FA. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 2006;43:173-181.   DOI   ScienceOn
5 Van Wagner LB, Rinella ME. The role of insulin-sensitizing agents in the treatment of nonalcoholic steatohepatitis. Therap Adv Gastroenterol. 2011;4:249-263.   DOI
6 Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J, Saxena NK, Anania FA. 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. 2010;51:1584-1592.   DOI   ScienceOn
7 Ben-Shlomo S, Zvibel I, Shnell M, Shlomai A, Chepurko E, Halpern Z, Barzilai N, Oren R, Fishman S. Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMPactivated protein kinase. J Hepatol. 2011;54:1214-1223.   DOI
8 Gupta NA, Kolachala VL, Jiang R, Abramowsky C, Romero R, Fifadara N, Anania F, Knechtle S, Kirk A. The glucagon-like peptide-1 receptor agonist Exendin 4 has a protective role in ischemic injury of lean and steatotic liver by inhibiting cell death and stimulating lipolysis. Am J Pathol. 2012;181: 1693-1701.   DOI
9 Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, Sung IK, Sohn CI, Keum DK, Kim BI. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol. 2006;21:138-143.   DOI   ScienceOn
10 Malhi H, Gores GJ. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:360-369.   DOI   ScienceOn
11 Sheth SG, Gordon FD, Chopra S. Nonalcoholic steatohepatitis. Ann Intern Med. 1997;126:137-145.   DOI   ScienceOn
12 Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113-121.   DOI   ScienceOn
13 Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147-152.   DOI
14 Fruhbeck G, Gomez-Ambrosi J. Modulation of the leptininduced white adipose tissue lipolysis by nitric oxide. Cell Signal. 2001;13:827-833.   DOI
15 Wang Y, Kole HK, Montrose-Rafizadeh C, Perfetti R, Bernier M, Egan JM. Regulation of glucose transporters and hexose uptake in 3T3-L1 adipocytes: glucagon-like peptide-1 and insulin interactions. J Mol Endocrinol. 1997;19:241-248.   DOI
16 Kota BP, Huang TH, Roufogalis BD. An overview on biological mechanisms of PPARs. Pharmacol Res. 2005;51:85-94.   DOI   ScienceOn
17 Trevaskis JL, Griffin PS, Wittmer C, Neuschwander-Tetri BA, Brunt EM, Dolman CS, Erickson MR, Napora J, Parkes DG, Roth JD. Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol. 2012;302:G762-772.   DOI
18 Lee J, Hong SW, Chae SW, Kim DH, Choi JH, Bae JC, Park SE, Rhee EJ, Park CY, Oh KW, Park SW, Kim SW, Lee WY. Exendin-4 improves steatohepatitis by increasing Sirt1 expression in high-fat diet-induced obese C57BL/6J mice. PLoS One. 2012;7:e31394.   DOI
19 Krawczyk M, Bonfrate L, Portincasa P. Nonalcoholic fatty liver disease. Best Pract Res Clin Gastroenterol. 2010;24:695-708.   DOI
20 Brumbaugh DE, Friedman JE. Developmental origins of nonalcoholic fatty liver disease. Pediatr Res. 2014;75:140-147.   DOI
21 Zhao FQ, Keating AF. Functional properties and genomics of glucose transporters. Curr Genomics. 2007;8:113-128.   DOI   ScienceOn
22 Gonzalez-Periz A, Horrillo R, Ferre N, Gronert K, Dong B, Moran-Salvador E, Titos E, Martinez-Clemente M, Lopez-Parra M, Arroyo V, Claria J. Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: a role for resolvins and protectins. FASEB J. 2009;23:1946-1957.   DOI
23 Gao H, Wang X, Zhang Z, Yang Y, Yang J, Li X, Ning G. GLP-1 amplifies insulin signaling by up-regulation of IRbeta, IRS-1 and Glut4 in 3T3-L1 adipocytes. Endocrine. 2007;32:90-95.   DOI
24 Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88:125-172.   DOI   ScienceOn
25 Schepp W, Schmidtler J, Riedel T, Dehne K, Schusdziarra V, Holst JJ, Eng J, Raufman JP, Classen M. Exendin-4 and exendin-(9-39)NH2: agonist and antagonist, respectively, at the rat parietal cell receptor for glucagon-like peptide-1-(7-36)NH2. Eur J Pharmacol. 1994;269:183-191.   DOI
26 Villanueva-Penacarrillo ML, Puente J, Redondo A, Clemente F, Valverde I. Effect of GLP-1 treatment on GLUT2 and GLUT4 expression in type 1 and type 2 rat diabetic models. Endocrine. 2001;15:241-248.   DOI
27 Ding X, Guo L, Zhang Y, Fan S, Gu M, Lu Y, Jiang D, Li Y, Huang C, Zhou Z. Extracts of pomelo peels prevent high-fat diet-induced metabolic disorders in c57bl/6 mice through activating the PPAR${\alpha}$ and GLUT4 pathway. PLoS One. 2013; 8:e77915.   DOI
28 Tang Y, Chen A. Curcumin prevents leptin raising glucose levels in hepatic stellate cells by blocking translocation of glucose transporter-4 and increasing glucokinase. Br J Pharmacol. 2010;161:1137-1149.   DOI
29 Fehmann HC, Jiang J, Schweinfurth J, Wheeler MB, Boyd AE 3rd, Goke B. Stable expression of the rat GLP-I receptor in CHO cells: activation and binding characteristics utilizing GLP-I(7-36)-amide, oxyntomodulin, exendin-4, and exendin (9-39). Peptides. 1994;15:453-456.   DOI
30 Goke R, Fehmann HC, Linn T, Schmidt H, Krause M, Eng J, Goke B. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. J Biol Chem. 1993;268:19650-19655.
31 Shirazi R, Palsdottir V, Collander J, Anesten F, Vogel H, Langlet F, Jaschke A, Schurmann A, Prevot V, Shao R, Jansson JO, Skibicka KP. Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6. Proc Natl Acad Sci U S A. 2013; 110:16199-16204.   DOI
32 Nauck MA, Niedereichholz U, Ettler R, Holst JJ, Orskov C, Ritzel R, Schmiegel WH. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol. 1997;273:E981-988.
33 Kisseleva T, Brenner DA. Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis. J Gastroenterol Hepatol. 2007;22 Suppl 1:S73-78.   DOI   ScienceOn
34 Williams EJ, Gaca MD, Brigstock DR, Arthur MJ, Benyon RC. Increased expression of connective tissue growth factor in fibrotic human liver and in activated hepatic stellate cells. J Hepatol. 2000;32:754-761.   DOI
35 Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait B, Vidaud M, Conti M, Huet S, Ba N, Buffet C, Bedossa P. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology. 2001;34:738-744.   DOI   ScienceOn
36 Svegliati-Baroni G, Saccomanno S, Rychlicki C, Agostinelli L, De Minicis S, Candelaresi C, Faraci G, Pacetti D, Vivarelli M, Nicolini D, Garelli P, Casini A, Manco M, Mingrone G, Risaliti A, Frega GN, Benedetti A, Gastaldelli A. 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. 2011;31:1285-1297.   DOI
37 Postic C, Girard J. The role of the lipogenic pathway in the development of hepatic steatosis. Diabetes Metab. 2008;34:643-648.   DOI
38 Karim S, Adams DH, Lalor PF. Hepatic expression and cellular distribution of the glucose transporter family. World J Gastroenterol. 2012;18:6771-6781.   DOI
39 Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem. 1992;267:7402-7405.
40 Jung TS, Kim SK, Shin HJ, Jeon BT, Hahm JR, Roh GS. ${\alpha}$- lipoic acid prevents non-alcoholic fatty liver disease in OLETF rats. Liver Int. 2012;32:1565-1573.   DOI