| Atherosclerosis is a progressive condition that can develop over the course of decades, and eventually lead to cardiovascular disease, which is the leading cause of death in the world. Metabolic imbalance in the liver can cause dyslipidemia (abnormal levels of lipids) and aberrant levels of metabolites such as trimethylamine N-oxide (TMAO), both of which are associated with increased risk of atherosclerosis. Understanding the genetic influences and molecular networks that govern these processes is necessary to identify candidates for more effective therapeutics.;MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of gene expression in various biological and pathological processes, and have been shown to be dysregulated in atherosclerosis. Most previous mouse studies of miRNAs in atherosclerosis have a common limitation in that they have utilized single inbred strains to study individual miRNAs of interest. These have left important knowledge gaps in the field that motivate new studies to understand the response of miRNAs to atherogenic diets in diverse genetic backgrounds. Also, because miRNAs are purported to function cooperatively in groups, it is important to not simply focus investigative efforts on the actions of single miRNAs. My research directly addresses these gaps in the field. Specifically, I utilized an unbiased systems genetics approach in a genetically diverse mouse cohort from the Diversity Outbred (DO) resource to identify co-regulated modules of hepatic miRNAs, or rather groups of miRNAs in the liver that exhibit a shared response to a pro-atherogenic diet. I also quantified the extent of association between the miRNA groups, gene modules, and several cardiometabolic traits. Notably, we found that one particular group of miRNAs, comprising members such as miR-146, miR-27, miR-24, miR-199, and miR-181, is strongly correlated with circulating levels of low-density lipoprotein cholesterol.;The majority of previous studies on the cardiovascular disease risk factor and liver metabolite TMAO focus on its regulation by the gut microbiota as well as some host liver enzymes. However, there have been very few studies to investigate the effects of host genetics on circulating TMAO levels. To understand the genetic influences on TMAO, I performed quantitative trait loci mapping in the same DO cohort mentioned above. I identified a novel association between a locus on chromosome 12 and circulating TMAO levels. Also, I identified miR-146 as a strong candidate regulator of TMAO, which was corroborated in additional animal models (a mouse and non-human primate model) of cardiometabolic dysfunction.;The findings from this body of work contribute to the field by addressing two major knowledge gaps, and warrant further study and validation in the context of atherosclerosis. |
