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microRNA-30c reduces plasma cholesterol in homozygous familial hypercholesterolemic and type 2 diabetic mouse models
Sara Irani1,2,3, Jahangir Iqbal2, W James Antoni3
1School of Graduate Studies, Molecular and Cell Biology Program The State University of New York Downstate Medical Center, Brooklyn, NY.
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.
Insights
MicroRNA-30c effectively lowers high plasma cholesterol in various mouse models of metabolic disorders, including diabetes and diet-induced hypercholesterolemia. This approach reduces atherosclerosis risk without impacting triglyceride or glucose levels.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- High plasma cholesterol is a risk factor for atherosclerosis, often linked to metabolic disorders.
- Reducing lipoprotein production can lower plasma lipids but may cause steatosis.
- MicroRNA (miR)-30c has previously shown potential in lowering hypercholesterolemia and atherosclerosis.
Purpose of the Study:
- To investigate the effect of hepatic miR-30c delivery on plasma lipids, transaminases, and hepatic lipids in different hypercholesterolemic mouse models.
- To evaluate miR-30c's efficacy in diet-induced and diabetic hypercholesterolemia.
- To explore the mechanistic pathways through which miR-30c influences lipid metabolism.
Main Methods:
- Hepatic delivery of miR-30c in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice fed a chow diet.
- Administration of miR-30c to Western diet-fed LDL receptor-deficient (Ldlr-/-) mice.
- Analysis of plasma lipids (cholesterol, triglycerides), glucose, transaminases, and hepatic lipids.
- Assessment of hepatic microsomal triglyceride transfer protein activity and lipid synthesis.
Main Results:
- Hepatic miR-30c reduced plasma cholesterol by approximately 28% and VLDL/LDL cholesterol by 25% in ob/ob and db/db mice, without altering triglyceride or glucose levels.
- miR-30c treatment led to lower plasma transaminases and creatine kinase activity in these models.
- In Ldlr-/- mice, miR-30c significantly lowered plasma cholesterol and atherosclerosis, with no impact on plasma triglyceride, glucose, or transaminases.
- Hepatic lipids remained similar between control and miR-30c-treated groups.
- Mechanistic studies revealed that miR-30c reduced hepatic microsomal triglyceride transfer protein activity and lipid synthesis.
Conclusions:
- Hepatic miR-30c administration effectively reduces plasma cholesterol in multiple models of diet-induced and diabetic hypercholesterolemia.
- miR-30c demonstrates potential as a therapeutic agent for lowering plasma cholesterol in various metabolic disorders, irrespective of the hypercholesterolemia's origin.
- The mechanism involves the downregulation of hepatic microsomal triglyceride transfer protein activity and lipid synthesis, without inducing steatosis or affecting glucose homeostasis.
