Abstract 577: MicroRNA-30c Reduces Plasma Cholesterol in Different Hypercholesterolemic and Hyperglycemic Mouse Models

Abstract

High plasma cholesterol levels are found in several metabolic disorders and their reductions are advocated to reduce risk of atherosclerosis. A way to lower plasma lipids is to curtail lipoprotein assembly and secretion; however, this is associated with steatosis. We have shown that microRNA-30c (miR-30c) reduces Western diet-induced hypercholesterolemia and atherosclerosis in C57BL/6J and Apoe -/- mice with no obvious adverse effects by reducing hepatic lipoprotein production and lipid synthesis. Here, we tested the effect of miR-30c on plasma lipids, transaminases and hepatic lipids in five different mouse models. Hepatic delivery of miR-30c reduced MTP activity but did not affect plasma cholesterol, triglyceride and glucose in chow-fed C57Bl6J and streptozotocin-induced diabetic, normolipidemic mice. However, hepatic delivery of miR-30c to chow fed leptin deficient ( ob/ob ) and leptin receptor deficient ( db/db ) hypercholesterolemic and hyperglycemic type 2 diabetic mice reduced cholesterol in total plasma and VLDL/LDL by ~ 28%and ~ 25%, respectively, without affecting phospholipid, triglyceride and glucose levels. Interestingly, these mice had lower plasma transaminases and creatine kinases indicating possible beneficial effects. Mechanistic studies showed that miR-30c reduced hepatic MTP activity and lipid synthesis. Moreover, miR-30c significantly lowered plasma cholesterol and atherosclerosis in Western-diet fed low density lipoprotein receptor knockout mice with no effect on plasma triglyceride, glucose and transaminases, suggesting that miR-30c can be a potential therapeutic agent for homozygous familial hypercholesterolemia. In all these studies, hepatic lipid levels were similar in control and miR-30c injected mice. These studies indicate that miR-30c reduces plasma cholesterol in diet-induced and diabetic hyperholesterolemic mice but not in normocholesterolemic mice. Thus, miR-30c may be beneficial in lowering plasma cholesterol in different metabolic disorders independent of the origin of hypercholesterolemia.