292-OR: Coenzyme A Synthase Knockdown Alleviates Metabolic Dysfunction–Associated Steatohepatitis via Decreasing Cholesterol in Liver Lipid Droplets

Metabolic dysfunction-associated steatohepatitis (MASH) is highly prevalent among patients with type 2 diabetes. Cholesterol is one of several candidates causing hepatic inflammation and fibrosis. We hypothesized that by interrupting the synthesis of cholesterol, we could prevent a choline-deficient L-amino acid-defined high-fat diet (CDAHFD) C57BL/6J MASH mouse model. We found that cholesterol in liver lipid droplets accumulated on day 1, MASH-associated macrophage markers (Gpnmb and Trem2) mRNA expression and plasma ALT increased on day 2, macrophage crown-like-structures emerged on day 3, and fibrosis markers (Col1a1, αSMA) mRNA expression increased on day 7 in the CDAHFD-treated mice. Filipin staining demonstrated free cholesterol accumulation in liver lipid droplets. We next examined whether a N-acetylgalactosamine-modified antisense oligonucleotide (ASO) against coenzyme A synthase (Coasy), which catalyzes a rate controlling step in hepatic cholesterol synthesis, would reduce cholesterol in liver lipid droplets and inflammation/fibrosis in this model. Coasy ASO treatment prevented accumulation of cholesterol in liver lipid droplets (Control=1.02 ± 0.04 mg/g tissue; Coasy=0.68 ± 0.08, P