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MicroRNA-30c analog C2 decreases plasma cholesterol and atherosclerosis without causing liver injury in preclinical studies
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DOI：10.1038/s41467-026-72276-0.png)
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Abstract
En 中文
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. Hepatic delivery of microRNA-30c analog C2 reduced microsomal triglyceride transfer protein, apoB-lipoprotein secretion and fatty acid synthesis; thus increased hepatic fatty acid oxidation, and decreased plasma cholesterol and atherosclerosis.
Keywords:
microRNA-30c
C2 analog
plasma cholesterol
atherosclerosis
hepatic delivery
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