Glucagon-Like Peptide-1 Receptor Is Present on Human... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

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

Gupta, Nitika Arora1,2,*,†; Mells, Jamie3,†; Dunham, Richard M.4; Grakoui, Arash4; Handy, Jeffrey5; Saxena, Neeraj Kumar5; Anania, Frank A.5

1_Department of Pediatrics, Emory University School of Medicine, Atlanta, GA_

2_Children's Healthcare of Atlanta, Transplant Services, Atlanta, GA_

3_Nutrition and Health Sciences Program, Graduate Division of Biological and Biomedical Sciences, Emory University School of Medicine, Atlanta, GA_

4_Division of Infectious Diseases, Microbiology, and Immunology, Department of Medicine, Emory Vaccine Center, Atlanta, GA_

5_Division of Digestive Diseases, Emory University School of Medicine, Atlanta, GA_

†Address reprint requests to: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA 30322. Email:[email protected]; fax: 404-727-4069

Received 29 May 2009; Accepted 28 December 2009

Published online 1 February 2010 in Wiley InterScience (www.interscience.wiley.com).

Supported by US Public Health Service Awards R24 DK064399, R01 DK062092, K01 DK076742, and R01 DK 075397; EVC/CFAR Flow Cytometry Core (P30 A1050409); a Cancer Research Institute Investigator award; Yerkes Research Center Base Grant RR 00165; and US Public Health Service Grant A1070101.

Potential conflict of interest: Nothing to report.

*These authors contributed equally to this work.

Additional Supporting Information may be found in the online version of this article.

Abstract

Glucagon-like peptide 1 (GLP-1) is a naturally occurring peptide secreted by the L cells of the small intestine. GLP-1 functions as an incretin and stimulates glucose-mediated insulin production by pancreatic β cells. In this study, we demonstrate that exendin-4/GLP-1 has a cognate receptor on human hepatocytes and that exendin-4 has a direct effect on the reduction of hepatic steatosis in the absence of insulin. Both glucagon-like peptide 1 receptor (GLP/R) messenger RNA and protein were detected on primary human hepatocytes, and receptor was internalized in the presence of GLP-1. Exendin-4 increased the phosphorylation of 3-phosphoinositide-dependent kinase-1 (PDK-1), AKT, and protein kinase C ζ (PKC-ζ) in HepG2 and Huh7 cells. Small interfering RNA against GLP-1R abolished the effects on PDK-1 and PKC-ζ. Treatment with exendin-4 quantitatively reduced triglyceride stores compared with control-treated cells. Conclusion: This is the first report that the G protein–coupled receptor GLP-1R is present on human hepatocytes. Furthermore, it appears that exendin-4 has the same beneficial effects in vitro as those seen in our previously published in vivo study in ob/ob mice, directly reducing hepatocyte steatosis. Future use for human nonalcoholic fatty liver disease, either in combination with dietary manipulation or other pharmacotherapy, may be a significant advance in treatment of this common form of liver disease. (Hepatology 2010)