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

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。 产生；然而，这与脂肪变性有关。我们发现，miR-30c的过度表达降低了饮食- 诱导C57BL/6J野生型和apoE−/−小鼠高胆固醇血症和动脉粥样硬化。相反， 抑制肝脏miR-30c可增加血浆胆固醇和动脉粥样硬化。基于这些令人兴奋的 已发表的数据，我们假设内源性miR-30c是脂代谢的重要调节因子 MiR-30c缺乏会增加血浆和组织的脂质、血浆细胞因子和动脉粥样硬化。我们会 使用双重敲除(DKO)Mir30c1−/−；Mir30c2−/−和Triple KO来评估这一假说 Mir30c1−/−；Mir30c2−/−；apoE−/−小鼠，饲喂含果糖和不含果糖的饲料和西式饲料。接下来，我们将建立 MiR-30c在高胆固醇血症及早、晚期发病中的直接和特异性作用 不同基因敲除小鼠肝和脾中miR-30c重新表达的动脉粥样硬化病变 战略。此外，使用类似的敲除和重新表达策略，我们将阐明生理学 机制(肝脂蛋白产生、新生脂肪生成和巨噬细胞细胞因子产生) 参与调节高胆固醇血症、脂肪变性、炎症反应和动脉粥样硬化 MIR-30C。此外，我们将评估miR-30c缺陷解除MTP调控的分子假说， 肝细胞中的LPGAT1和ELOVL5；巨噬细胞中的IKKα引起高胆固醇血症，脂肪变性， 以及促炎细胞因子的产生。这些研究将确定内源性miR-30c的重要性。 在调节血浆和组织脂质和细胞因子的产生方面，并将阐明生理学， MiR-30c调控多种生物途径的生化和分子机制。 最后，这些研究将提供有关全身保护作用的新信息以及 肝脏和巨噬细胞特异性miR-30c可对抗饮食诱导的代谢紊乱。

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.