HFD-induced downregulation of TRPV2 mediates hepatic steatosis via p21 signaling

Abstract The global prevalence and incidence of nonalcoholic fatty liver disease (NAFLD) exhibit a growing trend. Although its underlying mechanism is still unknown, NAFLD is characterized by a significant accumulation of lipids. Here we report that high-fat diet (HFD) feeding HFD induced hepatic steatosis in mice, accompanied by a reduction in the expression and function of hepatic TRPV2. By conditional knockout TRPV2 in hepatocytes, we found that HFD-induced hepatic steatosis was exacerbated. In vitro model of NAFLD, we found TRPV2 regulated the lipid accumulation in HepG2 cells, and TRPV2 activation inhibited the expression of p21 and p16 which are cellular senescence markers. Finally, we found administration of probenecid, TRPV2 agonist, impaired HFD-induced hepatic steatosis and suppressed HFD-induced elevation in p21 and p16. Collectively, our findings imply that hepatic TRPV2 protects against the accumulation of lipids by modulating p21 signaling.