Curriculum in Genetics and Molecular Biology, University of North Carolina Chapel Hill, Chapel Hill, North Carolina.
Department of Genetics, School of Medicine, University of North Carolina Chapel Hill, Chapel Hill, North Carolina.
Physiol Genomics. 2017 Nov 1;49(11):618-629. doi: 10.1152/physiolgenomics.00050.2017. Epub 2017 Sep 15.
Chronically altered levels of circulating lipids, termed dyslipidemia, is a significant risk factor for a number of metabolic and cardiovascular morbidities. MicroRNAs (miRNAs) have emerged as important regulators of lipid balance, have been implicated in dyslipidemia, and have been proposed as candidate therapeutic targets in lipid-related disorders including atherosclerosis. A major limitation of most murine studies of miRNAs in lipid metabolic disorders is that they have been performed in just one (or very few) inbred strains, such as C57BL/6. Moreover, although individual miRNAs have been associated with lipid phenotypes, it is well understood that miRNAs likely work together in functional modules. To address these limitations, we implemented a systems genetics strategy using the Diversity Outbred (DO) mouse population. Specifically, we performed gene and miRNA expression profiling in the livers from ~300 genetically distinct DO mice after 18 wk on either a high-fat/high-cholesterol diet or a high-protein diet. Large-scale correlative analysis of these data with a wide range of cardio-metabolic end points revealed a co-regulated module of miRNAs significantly associated with circulating low-density lipoprotein cholesterol (LDL-C) levels. The hubs of this module were identified as miR-199a, miR-181b, miR-27a, miR-21_-_1, and miR-24. In sum, we demonstrate that a high-fat/high-cholesterol diet robustly rewires the miRNA regulatory network, and we identify a small group of co-regulated miRNAs that may exert coordinated effects to control circulating LDL-C.
慢性改变的循环脂质水平,称为血脂异常,是许多代谢和心血管疾病的重要危险因素。microRNAs (miRNAs) 已成为脂质平衡的重要调节因子,与血脂异常有关,并被提议作为包括动脉粥样硬化在内的脂质相关疾病的候选治疗靶点。大多数关于 miRNA 在脂质代谢紊乱中的小鼠研究的一个主要限制是,它们仅在一种(或很少几种)近交系中进行,例如 C57BL/6。此外,尽管个别 miRNAs 与脂质表型相关,但人们清楚地知道,miRNAs 可能在功能模块中协同工作。为了解决这些限制,我们使用多样性杂交 (DO) 小鼠群体实施了系统遗传学策略。具体来说,我们在高脂/高胆固醇饮食或高蛋白饮食 18 周后,对约 300 只遗传上不同的 DO 小鼠的肝脏进行基因和 miRNA 表达谱分析。对这些数据与广泛的心脏代谢终点进行大规模相关分析显示,与循环低密度脂蛋白胆固醇 (LDL-C) 水平显著相关的 miRNA 存在一个受调控的模块。该模块的枢纽被鉴定为 miR-199a、miR-181b、miR-27a、miR-21_1 和 miR-24。总之,我们证明高脂肪/高胆固醇饮食可以强有力地重塑 miRNA 调控网络,并且我们鉴定了一小群受调控的 miRNAs,它们可能通过协调作用来控制循环 LDL-C。