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.
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 beta 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 zeta (PKC-zeta) in HepG2 and Huh7 cells. Small interfering RNA against GLP-1R abolished the effects on PDK-1 and PKC-zeta. Treatment with exendin-4 quantitatively reduced triglyceride stores compared with control-treated cells.


CONCLUSIONS
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.
Gupta
Nitika Arora
NA
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA. narorag@emory.edu
Mells
Jamie
J
Dunham
Richard M
RM
Grakoui
Arash
A
Handy
Jeffrey
J
Saxena
Neeraj Kumar
NK
Anania
Frank A
FA
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000077270:Exenatide; D005234:Fatty Liver / Q000503:physiopathology* / Q000517:prevention & control; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018027:Receptors, Glucagon / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014688:Venoms / Q000494:pharmacology; D000099221:Protein Kinase C zeta
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010455:Peptides; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D018027:Receptors, Glucagon; D014688:Venoms; D000099221:Protein Kinase C zeta; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse