Hepatic delivery of miroRNA-30c analog reduces plasma cholestrol in mice and monkeys and atherosclerosis in mice without causing liver injury

Despite the many useful drugs that are currently available for this indication, cardiovascular disease remains a major cause of premature mortality worldwide. High plasma cholesterol levels contribute substantially to this problem. Here, we show that hepatic delivery of a microRNA-30c analog C2 reduces plasma cholesterol levels in apoB-containing lipoproteins in hypercholesterolemic C57Bl6 mice, and in African green monkeys that spontaneously developed diabetes and hyperlipidemia. In addition, it prevented diet-induced hypercholesterolemia in FRG-mice with humanized livers. Furthermore, C2 significantly reduced plasma cholesterol and atherosclerosis in LDL receptor knockout mice indicating that the cholesterol-lowering effects of C2 do not rely on the presence of LDL receptors. In all these studies, C2 had no effect on hepatic triglyceride and cholesterol, plasma ALT, AST, CK-MB, ALP, IL-6, TNF-α, and INF-ϒ indicating absence of tissue lipid accumulation, inflammatory and immune responses. Mechanistic studies revealed that C2 reduced hepatic microsomal triglyceride transfer protein activity, hepatic secretion of apolipoprotein B-containing lipoproteins and enhanced fecal cholesterol excretion indicating that this could contribute to lowering of plasma cholesterol. Furthermore, C2 increased hepatic FA oxidation, and reduced hepatic FA synthesis and these mechanisms may contribute to avoidance of hepatic steatosis associated with reduced lipoprotein production. C2 could be a first-in-class microRNA therapeutic to reduce plasma cholesterol and atherosclerosis without causing hepatic injury and inflammatory response.