Trimethylamine-N-oxide (TMAO), a microbial choline metabolism byproduct that is processed in the liver and excreted into circulation, is associated with increased atherosclerotic lesion formation and cardiovascular disease risk. Genetic regulators of TMAO levels are largely unknown. In the present study, we used 288 mice from a genetically heterogeneous mouse population [Diversity Outbred (DO)] to determine hepatic microRNA associations with TMAO in the context of an atherogenic diet. We also validated findings in two additional animal models of atherosclerosis: liver-specific insulin receptor knockout mice fed a chow diet (LIRKO) and African green monkeys fed high-fat/high-cholesterol diet. Small RNA-sequencing analysis in DO mice, LIRKO mice, and African green monkeys identified only one hepatic microRNA (miR-146a-5p) that is aber-rantly expressed across all three models. Moreover, miR-146a-5p levels are associated with circulating TMAO after atherogenic diet in each of these models. We also performed high-resolution genetic mapping and identified a novel quantitative trait locus on Chromosome 12 for TMAO levels. This interval includes two genes, Numb and Dlst, which are inversely correlated with both miR-146a and TMAO and are predicted targets of miR-146a. Both of these genes have been validated as direct targets of miR-146a, though in other cellular contexts. This is the first report to our knowledge of a link between miR-146 and TMAO. Our findings suggest that miR-146-5p, as well as one or more genes at the Chromosome 12 QTL (possibly Numb or Dlst), is strongly linked to TMAO levels and likely involved in the control of atherosclerosis.
|Number of pages||13|
|State||Published - Feb 2019|
Bibliographical noteFunding Information:
This research was supported in part by National Institutes of Health Grants R01HL-128572 (B. J. Bennett), P30DK-056350 (B. J. Bennett and D. Pomp), R01DK-105965 (P. Sethupathy), a pilot grant from the Nutrition Research Institute (B. J. Bennett and P. Sethupathy), and a National Science Foundation Graduate Research Fellowship Program DGE-1144081 (A. R. Coffey). This work was supported by United States Department of Agriculture (USDA)/ Agriculture Research Service/Western Human Nutrition Research Center project funds (2032-51000-004-00D). USDA is an equal opportunity provider and employer.
© 2019, American Physiological Society. All rights reserved.
- Diversity Outbred mice
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