Characterizing ghrelin’s role in dysregulating GLP-1-mediated function and promoting the development of alcohol-associated liver disease

This study investigated the complex interplay between two gut hormones, glucagon-like peptide-1 (GLP-1) and ghrelin and their role in the development of alcohol-associated liver disease (ALD). Previous studies conducted in our laboratory and others have shown that chronic alcohol exposure leads to increased serum ghrelin and GLP-1 levels. Paradoxically, despite increased GLP-1, insulin resistance and disrupted hepatic lipid metabolism was noted in chronic ethanol fed animals. These results suggested impaired GLP-1-mediated protective function in the presence of high ghrelin. Our recent studies also revealed that growth hormone secretagogue receptor (GHSR, which is the ghrelin receptor) knockout (GHSR-KO) rats fed ethanol were more insulin sensitive and were resistant to develop ALD despite reduced serum GLP-1 compared to ethanol-fed wildtypes. Based on these considerations, we hypothesized that alcohol-induced increases in ghrelin-GHSR interaction impairs GLP-1-mediated functions. We employed both in vivo and in vitro approaches, including chronic ethanol feeding of wild-type and GHSR-KO rats, ghrelin administration to chow-fed rats, GSHR and GLP-1 receptor (GLP-1R)-transfected hepatocytes, murine enteroendocrine GLUTag and HEK293T cells utilizing several techniques to test our hypothesis. Chronic ethanol feeding in wildtype rats increased GLP-1 and GLP-1R levels, while ethanol-fed GHSR-KO rats did not show this increase. Ghrelin promoted GHSR and GLP-1R interaction/dimerization, thereby reducing GLP-1 effects. Furthermore, in-silico molecular docking analysis identified specific amino acid residues in the transmembrane regions of both receptors that are predicted to mediate this interaction. Alcohol-induced increases in ghrelin modulate GLP-1-mediated functions through GHSR-GLP-1R interactions. Targeting this interaction could offer a potential therapeutic strategy for ALD. Chronic alcohol-induced increased ghrelin modulates GLP-1 function (insulin sensitivity and hepatic steatosis) by interfering with GLP-1R mediated signaling via GHSR-GLP-1R dimerization. Targeting GHSR/GLP-1R interaction offers potential therapy for alcohol-associated liver disease. • Alcohol exposure impairs GLP-1 function despite increasing GLP-1/GLP-1R levels. • Alcohol-induced enhanced ghrelin inhibits GLP-1 activity via GHSR/GLP-1R interaction. • This interaction involves increased receptor co-localization and dimerization. • Targeting GHSR/GLP-1R may offer a new therapy alcohol-associated liver disease.