Effects of miR-30c deficiency on plasma cholesterol and atherosclerosis

miR-30c 缺陷对血浆胆固醇和动脉粥样硬化的影响

• 批准号: 10424970
• 负责人: M Mahmood Hussain
• 金额: $ 26.95万
• 依托单位: NYU LONG ISLAND SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10424970
• 关键词: Effects; miR; 30c; deficiency; plasma

High plasma cholesterol levels, a major risk factor for atherosclerosis, can be reduced by inhibiting lipoprotein production; however, this is associated with steatosis. We showed that over expression of miR-30c lowers diet- induced hypercholesterolemia and atherosclerosis in C57BL/6J wild type and Apoe−/− mice. Conversely, inhibition of hepatic miR-30c increased plasma cholesterol and atherosclerosis. Based on these exciting published data, we hypothesize that endogenous miR-30c is an important regulator of lipid metabolism and that miR-30c deficiency will enhance plasma and tissue lipids, plasma cytokines and atherosclerosis. We will evaluate this hypothesis using double knockout (DKO) Mir30c1−/−;Mir30c2−/− and triple KO Mir30c1−/−;Mir30c2−/−;Apoe−/− mice fed chow and western diets with and without fructose. Next, we will establish the direct and specific role of miR-30c in the development of hypercholesterolemia and early and advanced atherosclerotic lesions by re-expressing miR-30c in the liver and spleen of these knockout mice using different strategies. Further, using similar knockout and re-expression strategies, we will elucidate physiological mechanisms (hepatic lipoprotein production, de novo lipogenesis and macrophage cytokine production) involved in the regulation of hypercholesterolemia, steatosis, inflammatory response and atherosclerosis by miR-30c. Moreover, we will evaluate the molecular hypothesis that miR-30c deficiency deregulates MTP, LPGAT1 and ELOVL5 in hepatocytes; and IKKα in macrophages to cause hypercholesterolemia, steatosis, and pro-inflammatory cytokine production. These studies will establish the importance of endogenous miR-30c in the regulation of plasma and tissue lipids and cytokine production, and will elucidate physiological, biochemical and molecular mechanisms involved in the regulation of various biological pathways by miR-30c. At the end, these studies will furnish novel information concerning the protective role of whole body as well as liver- and macrophage-specific miR-30c against diet-induced metabolic disorders.

高血浆胆固醇水平是动脉粥样硬化的主要危险因素，可以通过抑制脂蛋白来降低

项目成果

Human MicroRNA-33b Promotes Atherosclerosis in Apoe-/- Mice.

人类 MicroRNA-33b 促进 Apoe-/- 小鼠的动脉粥样硬化。

• DOI: 10.1161/atvbaha.118.311617
• 发表时间: 2018
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Hussain,MMahmood;Goldberg,IraJ
• 通讯作者: Goldberg,IraJ

Human MicroRNA-548p Decreases Hepatic Apolipoprotein B Secretion and Lipid Synthesis.

• DOI: 10.1161/atvbaha.117.309247
• 发表时间: 2017-05
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Zhou L;Hussain MM
• 通讯作者: Hussain MM

Sphingolipids and Lipoproteins in Health and Metabolic Disorders.

• DOI: 10.1016/j.tem.2017.03.005
• 发表时间: 2017-07
• 期刊: Trends in endocrinology and metabolism: TEM
• 作者: Iqbal J;Walsh MT;Hammad SM;Hussain MM
• 通讯作者: Hussain MM