Mechanosensing by Piezo1 in gastric ghrelin cells contributes to hepatic lipid homeostasis in mice.

Ghrelin is an orexigenic peptide released by gastric ghrelin cells that contributes to obesity and hepatic steatosis. The mechanosensitive ion channel Piezo1 in gastric ghrelin cells inhibits the synthesis and secretion of ghrelin in response to gastric mechanical stretch. We sought to modulate hepatic lipid metabolism by manipulating Piezo1 in gastric ghrelin cells. Mice with a ghrelin cell–specific deficiency of Piezo1 (Ghrl-Piezo1^−/−) had hyperghrelinemia and hepatic steatosis when fed a low-fat or high-fat diet. In these mice, hepatic lipid accumulation was associated with changes in gene expression and in protein abundance and activity expected to increase hepatic fatty acid synthesis and decrease lipid β-oxidation. Pharmacological inhibition of the ghrelin receptor improved hepatic steatosis in Ghrl-Piezo1^−/− mice, thus confirming that the phenotype of these mice was due to overproduction of ghrelin caused by inactivation of Piezo1. Gastric implantation of silicone beads to induce mechanical stretch of the stomach inhibited ghrelin synthesis and secretion, thereby helping to suppress fatty liver development induced by a high-fat diet in wild-type mice but not in Ghrl-Piezo1^−/− mice. Our study elucidates the mechanism by which Piezo1 in gastric ghrelin cells regulate hepatic lipid accumulation, providing insights into potential treatments for fatty liver. Editor's summary: The appetite-stimulating hormone ghrelin promotes hepatic lipid accumulation. Zhang et al. investigated the regulation of hepatic lipid homeostasis by Piezo1, a mechanosensitive ion channel that is activated when food ingestion stretches the stomach and that suppresses ghrelin production. Mice lacking Piezo1 in ghrelin-producing cells in the stomach developed hepatic steatosis, which was reversed by pharmacologically blocking the ghrelin receptor. Gastric bead implantation, which mimicked the mechanical stretch induced by food intake, reduced hepatic steatosis in control mice on a normal diet or with diet-induced obesity but not in the conditional knockout mice. Thus, Piezo1 in ghrelin-producing cells could be targeted to treat metabolic dysfunction–associated steatotic liver disease, the most prevalent liver disorder worldwide. —Wei Wong [ABSTRACT FROM AUTHOR]