Nat Commun. 2026 Apr 24. doi: 10.1038/s41467-026-72276-0. Online ahead of print.
ABSTRACT
High plasma cholesterol levels substantially contribute to cardiovascular disease. Hepatic delivery of the microRNA-30c analog C2 decreased plasma cholesterol in apoB-containing lipoproteins in hypercholesterolemic C57BL/6 mice, in African green monkeys that spontaneously developed diabetes and hyperlipidemia and prevented diet-induced hypercholesterolemia in mice with humanized livers. Furthermore, C2 significantly reduced plasma cholesterol and atherosclerosis in LDL receptor knockout mice. C2 did not affect hepatic triglyceride and cholesterol, plasma ALT, AST, CK-MB, ALP, IL-6, TNF-α, and INF-ϒ, thus indicating an absence of tissue lipid accumulation and inflammatory response. In contrast, MTP inhibitor lomitapide significantly reduced plasma lipids and caused hepatic steatosis. Mechanistic studies revealed that C2 reduced hepatic microsomal triglyceride transfer protein expression, secretion of apolipoprotein B-containing lipoproteins and FA synthesis and increased hepatic FA oxidation, plasma bile acids and fecal cholesterol excretion. C2 is a first-in-class microRNA therapeutic that decreases plasma cholesterol and atherosclerosis, without causing hepatic injury and inflammatory response.
PMID:42026066 | DOI:10.1038/s41467-026-72276-0