Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a frequent complication of type 2 diabetes. However, the molecular mechanisms responsible for the development of MASH are unknown. Loss of function mutations in the lipid droplet proteins Comparative Gene Identification-58 (CGI-58) and Cell Death-inducing DNA fragmentation factor-like effector B (CIDEB) promote and protect against MASH, respectively. We hypothesized that the discrete impact of these proteins on MASH is due to the alteration of lipid droplet morphology followed by cholesterol content. We tested these hypotheses using antisense oligonucleotides (ASO) to knock down the expression of CGI-58 or CideB in the liver of a choline-deficient L-amino acid-defined high-fat diet (CDAHFD) mouse MASH model. CGI-58 ASO treatment increased plasma ALT, macrophage crown-like structures, and liver inflammation/fibrosis marker expression, which were associated with increased lipid droplet size and liver lipid droplet cholesterol content. Co-treatment with an ASO against glycerol-3-phosphate acyltransferase, mitochondrial (Gpam) decreased liver lipid droplet cholesterol and prevented CGI-58 ASO-induced MASH. In contrast, CideB ASO treatment in CDAHFD mice prevented liver inflammation and fibrosis and reduced liver lipid droplet size and lipid droplet cholesterol content. These protective effects of the CideB ASO were all abrogated with cholesterol supplementation to the diet. Conclusions: Knockdown of CGI-58 promotes liver inflammation and fibrosis by increasing liver lipid droplet size and lipid droplet cholesterol content, whereas knockdown of CideB protects against the development of liver inflammation and fibrosis by reducing liver lipid droplet size and cholesterol content. Furthermore, CIDEB and GPAM are potential therapeutic targets for MASH. Disclosure I. Sakuma: None. R.C. Gaspar: None. A. Nasiri: None. M. Kahn: None. J. Zheng: None. M. Guerra: None. D. Yimlamai: None. S. Murray: Employee; Ionis Pharmaceuticals. M. Perelis: Employee; Ionis Pharmaceuticals. W. Barnes: Employee; Ionis Pharmaceuticals. D.F. Vatner: None. K. Petersen: None. V. Samuel: None. G.I. Shulman: None.