Abstract
High plasma cholesterol levels are found in several metabolic disorders and their reductions are advocated to reduce the risk of atherosclerosis. A way to lower plasma lipids is to curtail lipoprotein production; however, this is associated with steatosis. We previously showed that microRNA (miR)-30c lowers diet-induced hypercholesterolemia and atherosclerosis in C57BL/6J and Apoe−/− mice. Here, we tested the effect of miR-30c on plasma lipids, transaminases, and hepatic lipids in different mouse models. Hepatic delivery of miR-30c to chow-fed leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) hypercholesterolemic and hyperglycemic mice reduced cholesterol in total plasma and VLDL/LDL by ∼28% and ∼25%, respectively, without affecting triglyceride and glucose levels. And these mice had lower plasma transaminases and creatine kinase activities than controls. Moreover, miR-30c significantly lowered plasma cholesterol and atherosclerosis in Western diet-fed Ldlr−/− mice with no effect on plasma triglyceride, glucose, and transaminases. In these studies, hepatic lipids were similar in control and miR-30c-injected mice. Mechanistic studies showed that miR-30c reduced hepatic microsomal triglyceride transfer protein activity and lipid synthesis. Thus miR-30c reduced plasma cholesterol in several diet-induced and diabetic hypercholesterolemic mice. We speculate that miR-30c may be beneficial in lowering plasma cholesterol in different metabolic disorders independent of the origin of hypercholesterolemia.
Highlights
High plasma cholesterol levels are found in several metabolic disorders and their reductions are advocated to reduce the risk of atherosclerosis
We have previously shown that hepatic overexpression of miR-30c reduces hepatic microsomal triglyceride transfer protein (MTP) activity, plasma cholesterol, atherosclerosis, and hepatic lipoprotein production in diet-induced male and female C56BL/6J and Apoe / mice [19, 20]
We hypothesized that miR-30c would impede the progression of hypercholesterolemia and atherosclerosis in Ldlr / mice that are deficient in the Ldlr gene and serve as a model to study homozygous familial hypercholesterolemia (HoFH) [27]
Summary
High plasma cholesterol levels are found in several metabolic disorders and their reductions are advocated to reduce the risk of atherosclerosis. The widely prescribed statins and the newly emerging proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors act on the lipoprotein clearance pathway to lower LDL cholesterol Both of these drugs enhance the removal of plasma lipoproteins by increasing hepatic expression of LDL receptor (LDLR) [3, 4]. Available drugs that act on this pathway are the apoB antisense oligonucleotide, mipomersen, and the MTP inhibitor, lomitapide These drugs increase plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), markers of liver injury, and cause hepatic steatosis [10,11,12,13,14,15].
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