Targeting lanosterol synthase alleviates MASLD by promoting fatty acid catabolism.

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Targeting LSS alleviates MASLD development by promoting fatty acid β-oxidation and ketogenesis.