Hepatocyte PIEZO1 Negatively Regulates Lipogenesis and Ameliorates MASLD by Sensing Membrane Tension and Activating AMPK

ABSTRACT Liver is a central organ for lipid metabolism. Disruption of lipid homeostasis leads to lipid accumulation in hepatocytes, which is a feature of metabolic dysfunction‐associated steatotic liver disease (MASLD). Mechanical force and mechanosensitive proteins have been found to play a crucial role in energy metabolism. However, their role in hepatic lipid metabolism remains unclear. In this study, mechanosensitive ion channel PIEZO1 is detected in hepatocytes, and downregulated in the liver of MASLD patients and high‐fat diet (HFD)‐induced MASLD mouse model. Under HFD feeding, mice with hepatocyte‐specific Piezo1 deletion exhibit severer triglyceride accumulation, upregulation of de novo lipogenesis genes, and decreased phosphorylation of AMPK and RAPTOR in the liver. In contrast, injection of PIEZO1 activator Yoda1 alleviates triglyceride accumulation, downregulates lipogenesis genes and enhances phosphorylation of AMPK and RAPTOR in HFD‐fed C57BL/6 mice. Knockdown of PIEZO1 in HepG2 leads to upregulation of lipogenesis genes and impairs AMPK‐RAPTOR pathway, while Yoda1 or hypotonic treatment do the reverse. The effects of PIEZO1 knockdown and Yoda1 treatment can be abolished by AMPK activator and CaMKK2/AMPK inhibitors, respectively. These findings suggest that PIEZO1 can respond to changes in membrane tension and activate AMPK, thereby inhibiting lipogenesis and maintaining lipid homeostasis.