LSS loss of function alleviates NAFLD by activating UPR and promoting fatty acid metabolic transformation

Abnormal cholesterol metabolism is involved in the development of nonalcoholic fatty liver disease (NAFLD). We investigated the role and mechanisms of lanosterol synthase (LSS, one of key enzymes for cholesterol biosynthesis) loss of function in the pathological process of NAFLD. In HFD and MCD induced NAFLD models, obviously reduced steatotic phenotype, hepatic inflammatory injury and hepatocyte ballooning were found in LSS+/- mice when compared with wild-type mice. LSS loss of function alleviates triglyceride (TG) accumulation and hepatic steatosis by transforming fatty acid to ketone bodies. Mechanistically, LSS dysfunction by LSS knockdown or LSS inhibitor RO 48-8071 induces UPR both in endoplasmic reticulum (ER) and mitochondria to mediate attenuating effect on NAFLD development.