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
Open accessAbstract
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)
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The energy-sensing kinase AMPK has major effects on cellular metabolism and inflammation.
“The energy-sensing kinase AMPK has major effects on cellular metabolism and inflammation.”
From Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications (2024) · cites this paper as [42]
The Discussion (page not provided) describes GLP-1 receptor signaling through AKT, PDK-1 and PKC, rather than AMPK. Searches for AMPK and AMP-activated protein kinase found no passage in our copy addressing its effects on cellular metabolism or inflammation. (LLM, conf=0.76)
Experimental — accuracy not yet measuredTreatment of Huh7 and HepG2 hepatoma cells with exenatide decreased intracellular lipid accumulation by enhancing fatty acid oxidation and reducing lipogenesis.
“Treatment of Huh7 and HepG2 hepatoma cells with exenatide decreased intracellular lipid accumulation [181,182] by enhancing fatty acid oxidation and reducing lipogenesis [160,161,179,183].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [181]
GLP-1 ligands promote phosphorylation of AKT and other crucial molecules (PDK-1 and PKC-ζ) downstream of IRS-2.
“GLP-1 ligands are able to promote the phosphorylation of AKT and other crucial molecules (PDK-1 and PKC-ζ) downstream of IRS-2 [83].”
From GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives (2023) · cites this paper as [83]
Exendin-4 significantly reduces hepatic accumulation of triglycerides in mouse models and human hepatocytes.
“Preclinical studies showed that exendin-4, a GLP-1R agonist derived from the saliva of the Gila monster, was able to significantly reduce the hepatic accumulation of triglycerides both in mouse models [82] and in human hepatocytes [83] by activating the signaling cascade downstream of the insulin receptor (see below).”
From GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives (2023) · cites this paper as [83]
In obese mice, administration of GLP-1 agonists reduced hepatic steatosis, an effect replicated in humans.
“Moreover, in obese mice, the administration of GLP-1 agonists reduced hepatic steatosis [48], an effect that has also been replicated in humans [47,49].”
From Adipose Tissue: A Novel Target of the Incretin Axis? A Paradigm Shift in Obesity-Linked Insulin Resistance (2024) · cites this paper as [49]
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- Authors
- Gupta, N. A., Mells, J., Dunham, R. M., Grakoui, A., Handy, J., Saxena, N. K., & Anania, F. A.
- Affiliations
- Emory University (US)
- Corresponding author
- Gupta, Nitika Arora
- Venue
- Hepatology
- Published
- 2010-05
- Volume
- 51
- Issue
- 5
- Pages
- 1584-1592
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC2862093
- OpenAlex
- W1968002849
- Cited by
- 532
- References
- 39
- Citations by year
- 2026: 34 · 2025: 38 · 2024: 39 · 2023: 31 · 2022: 31 · 2021: 34 · 2020: 43 · 2019: 25 · 2018: 26 · 2017: 34 · 2016: 42 · 2015: 25 · 2014: 38 · 2013: 33 · 2012: 35
- FWCI
- 21.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research Institute
- U.S. Public Health Service (P30A1050409, A1070101)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK077137, R24DK064399, K01DK076742, R01DK075397, R01DK062092, R03DK089130)
- National Center for Research Resources (RR-00 165, P51RR000165)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- GLP-1 receptor, exendin-4, hepatic steatosis, hepatocytes, insulin signaling, PDK1, Akt, protein kinase C zeta, triglyceride accumulation, non-alcoholic fatty liver disease, G protein-coupled receptors, receptor internalization
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Exenatide, Protein Kinase C zeta, Fatty Liver, Humans, Insulin, Peptides, Protein Kinase C, Venoms, Signal Transduction, Protein Serine-Threonine Kinases, Receptors, Glucagon, Hepatocytes, Proto-Oncogene Proteins c-akt, Glucagon-Like Peptide 1, 3-Phosphoinositide-Dependent Protein Kinases
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