Alcohol Exposure Alters the Ghrelin System: In Vitro Mechanistic Insights Into Impaired Glucose Sensing and Enhanced Ghrelin Secretion.

BACKGROUND

Ghrelin, a stomach-derived orexigenic peptide, typically rises during fasting to stimulate food intake. Chronic alcohol consumption elevates circulating ghrelin, which induces alcohol craving and increases intake in clinical and preclinical models. By increasing alcohol drive, ghrelin contributes to alcohol use disorder (AUD) and accelerates alcohol-associated liver disease (ALD) by inhibiting insulin secretion and promoting adipose lipolysis. However, the cellular mechanisms by which ethanol dysregulates ghrelin secretion remain unclear. This study investigated how ethanol modulates ghrelin production and disrupts nutrient sensing in ghrelin-secreting cells.

METHODS

Stomach (SG-1) and pancreatic (PG-1) ghrelinoma cells were treated with 25 mM or 50 mM ethanol for 48 h, after which ghrelin synthesis and secretion were measured. Further, the interaction between ethanol and other physiological regulators (glucose [10 mM], insulin [20 mM], and palmitic acid [400 μM]) of ghrelin secretion was evaluated. Intracellular glycolytic rate was characterized using Seahorse-XFe analysis.

RESULTS

Chronic ethanol exposure (48 h) significantly increased ghrelin secretion and the mRNA encoding for ghrelin and ghrelin O-acyltransferase (GOAT), an enzyme that activates ghrelin. Under normal conditions, high glucose effectively suppressed ghrelin secretion; however, ethanol pretreatment blunted this inhibitory effect. While palmitic acid alone had no effect, its combination with ethanol synergistically enhanced ghrelin secretion. Mechanistically, ethanol-pretreated cells exhibited a metabolic impairment characterized by increased glucose uptake but significantly reduced basal glycolysis, proton efflux rate (PER), and compensatory glycolytic capacity. This metabolic failure was linked to the profound downregulation of the rate-limiting enzymes glucokinase, hexokinase, and pyruvate kinase.

CONCLUSIONS

Ethanol drives increased ghrelin by disrupting the glucose-sensing machinery within ghrelin-secreting cells. By suppressing key glycolytic enzymes, ethanol uncouples the cell from glucose, mimicking a state of starvation despite nutrient availability. Targeting these metabolic pathways may provide a novel therapeutic strategy for the interconnected pathologies of AUD and ALD.