Location: Obesity and Metabolism ResearchTitle: microRNA-146a-5p association with the cardiometabolic disease risk factor TMAO
|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: Physiological Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/2/2019
Publication Date: 2/1/2019
Citation: Coffey, A.R., Smallwood, T.L., Albright, J., Hua, K., Kanke, M., Pomp, D., Bennett, B.J., Sethupathy, P. 2019. microRNA-146a-5p association with the cardiometabolic disease risk factor TMAO. Physiological Genomics. 51(2):59-71. https://doi.org/10.1152/physiolgenomics.00079.2018.
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 regulator of plasma TMAO levels located on Chr 12 that interact with miR-146a, a miRNA associated with atherosclerosis.
Technical Abstract: TMAO is a product of gut microbial metabolism that is further processed in the liver, and excreted into circulation. It has been associated with an increase in cardiovascular disease risk and atherosclerotic lesion formation. Genetic regulators of TMAO levels are largely unknown. In the present study, we used a genetically diverse mouse population from the Diversity Outbred (DO) resource to measure baseline and post-atherogenic or -control diet TMAO levels, and perform quantitative trait loci (QTL) mapping. We identified a novel QTL on Chromosome 12 for pre- and post-diet TMAO levels. We also used liver gene expression from the same mice to identify several mRNAs, including Numb, with overlapping expression QTL. We also analyzed liver microRNA expression patterns across the DO mice and identified specific microRNAs, most notably miR-146a/b, that are highly up-regulated in the livers of mice fed an atherogenic diet, and are strongly positively correlated with TMAO. Interestingly, we observed a significant inverse correlation between miR-146a/b and Numb, supporting a regulatory interaction between the two that has been validated previously in other contexts. We provided further support for a putative link between miR-146a/b and TMAO through analysis of the liver-specific insulin-receptor knockout (LIRKO) mouse model, which exhibits significantly elevated levels of circulating TMAO. Our findings suggest that one or more genes at the Chr12 locus, as well as miR-146a/b, may be closely related to the control of TMAO levels in atherosclerosis.