Location: Obesity and Metabolism ResearchTitle: Systems genetics identifies a co-regulated module of liver microRNAs associated with plasma LDL cholesterol in murine diet-induced dyslipidemia
|COFFEY, ALISHA - University Of North Carolina|
|SMALLWOOD, TANGI - University Of North Carolina|
|ALBRIGHT, JODY - University Of North Carolina|
|HUA, KUNJIE - University Of North Carolina|
|KANKE, MATT - University Of North Carolina|
|POMP, DANIEL - University Of North Carolina|
|SETHUPATHY, PRAVEEN - University Of North Carolina|
Submitted to: PLoS Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/12/2017
Publication Date: 9/15/2017
Citation: Coffey, A.R., Smallwood, T.L., Albright, J., Hua, K., Kanke, M., Pomp, D., Bennett, B.J., Sethupathy, P. 2017. Systems genetics identifies a co-regulated module of liver microRNAs associated with plasma LDL cholesterol in murine diet-induced dyslipidemia. PLoS Genetics. 49(11):618-629. https://doi.org/10.1152/physiolgenomics.00050.2017.
Interpretive Summary: microRNAs (miRNAs), which are small non-coding RNAs that fine-tune gene expression primarily at the post-transcriptional level, have emerged as key players in many processes, including those involved with lipid homeostasis. Several hepatic miRNAs are diet responsive and have been associated with atherosclerosis and hyperlipidemia. In the present study, we utilized a cohort of almost 300 DO mice to interrogate the hepatic network of miRNAs associated with circulating lipid levels in diet-induced dyslipidemia. We identify a key co-regulated module of miRNAs that is strongly associated with LDL cholesterol (LDL-C), which is a significant risk factor for many downstream morbidities, including atherosclerosis and metabolic disease.
Technical Abstract: 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 weeks 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 endpoints 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 re-wires the miRNA regulatory network, and we identify a small group of co-regulated miRNAs that may exert coordinated effects to control circulating LDL-C.