MicroRNA-30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion

This study identifies miR-30c as a regulator of both microsomal triglyceride transfer protein, needed for the secretion of APOB-containing lipoproteins such as low-density lipoproteins, and a number of other genes involved in lipid biosynthesis. In mice, miR-30c regulates hepatic lipid biosynthesis and lipoprotein secretion such that hepatic overexpression of miR-30c reduces plasma cholesterol and triglyceride concentrations and decreases atherosclerotic plaque burden. Hyperlipidemia is a risk factor for various cardiovascular and metabolic disorders. Overproduction of lipoproteins, a process that is dependent on microsomal triglyceride transfer protein (MTP), can contribute to hyperlipidemia. We show that microRNA-30c (miR-30c) interacts with the 3′ untranslated region of MTP mRNA and induces its degradation, leading to reductions in MTP activity and in apolipoprotein B (APOB) secretion. miR-30c also reduces lipid synthesis independently of MTP. Hepatic overexpression of miR-30c reduced hyperlipidemia in Western diet–fed mice by decreasing lipid synthesis and the secretion of triglyceride-rich ApoB-containing lipoproteins and decreased atherosclerosis in Apoe −/− mice. Furthermore, inhibition of hepatic miR-30c by anti–miR-30c increased hyperlipidemia and atherosclerosis. Therefore, miR-30c coordinately reduces lipid biosynthesis and lipoprotein secretion, thereby regulating hepatic and plasma lipid concentrations. Raising miR-30c levels might be useful in treating hyperlipidemias and associated disorders.