Deficiency of Epithelial PIEZO1 Alleviates Liver Steatosis Induced by High-Fat Diet in Mice

PIEZO1 has been found to play a vital role in regulating intestinal epithelial cells (IEC) function and maintaining intestinal barrier in recent years. Therefore, IEC PIEZO1 might exert a significant impact on liver metabolism through the gut-liver axis, but there is no research on this topic currently. Classic high-fat diet (HFD) model and mice with IEC-specific deficiency of PIEZO1 (<i>Piezo1</i> ^ΔIEC) were used to explore the problem. IEC PIEZO1 deletion significantly alleviated liver steatosis, without change on glucose tolerance and energy expenditure. Fibroblast growth factor 15/19 (FGF15/19) was downregulated in IEC and portal vein of <i>Piezo1</i> ^ΔIEC mice, which was associated with phenotypic change. After supplementary of exogenous FGF19, the effect of improving liver steatosis brought by PIEZO1 deletion was blocked. Notably, PIEZO1 depletion-induced FGF15 reduction was not dependent on classic bile acids (BAs) - farnesoid X receptor (FXR) pathway, but attributed to impaired retinol metabolism and lower content of retinoic acid (RA). Subsequently, addition of RA but not retinol benefited inducing FGF15 production in ileal organoid from <i>Piezo1</i> ^ΔIEC mice. Altogether, IEC PIEZO1 represents a promising target for therapy of hepatic steatosis via the gut-liver axis.