Targeting lanosterol synthase alleviates MASLD by promoting fatty acid catabolism

Abnormal cholesterol metabolism is involved in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). We investigated the role and mechanisms of lanosterol synthase (LSS) loss of function in the pathological process of MASLD. MASLD models were induced by methionine-and choline-deficient diet (MCD) feeding in LSS+/− mice or wild type mice given LSS inhibitor RO48-8071. Transcriptomics analysis was performed to analyze differentially expressed genes in mice model. Lipidomic Profiling revealed the overall composition of lipid classes in MCD induced MASLD model. In vitro experiments using a MCDE (identical medium completely deficient of methionine and choline) induced cell model assessed the effect of LSS knockdown on MASLD development. Quantitative real-time PCR (qRT-PCR) and Western blot were employed to evaluate the differential expression of interested genes. In MCD induced MASLD models, obviously reduced steatotic phenotype, hepatic inflammatory injury and hepatocyte ballooning were found in LSS+/− mice. LSS loss of function alleviates liver injury and hepatic steatosis via reducing fatty deposition and triglyceride accumulation in hepatocytes. Mechanistically, LSS dysfunction promotes fatty acid β-oxidation and ketogenesis in liver cells to mediate attenuating effect on MASLD development. Targeting LSS alleviates MASLD development by promoting fatty acid β-oxidation and ketogenesis.