Abstract 96: The Role of Flavin Monooxygenase 3 (FMO3) in Dietary Choline- and Cholesterol-Driven Atherosclerosis

Abstract

The gut microbiome represents an important endocrine organ generating nutrient metabolites that promote the pathogenesis of cardiovascular disease (CVD), as exemplified by the gut microbe-derived metabolite trimethylamine-N-oxide (TMAO). The meta-organismal TMAO pathway is initiated by ingestion of nutrients present in high fat foods (phosphatidylcholine, choline, and L -carnitine), which are metabolized by gut microbes to generate trimethylamine (TMA). The gut microbial metabolite TMA is further metabolized by the host enzyme flavin monooxygenase 3 (FMO3) to produce TMAO, which signals to drive proatherogenic programs in the host. Our previous work has demonstrated that the TMAO-producing enzyme FMO3 is a central regulator of whole body cholesterol balance and reverse cholesterol transport (RCT). However, the ability of FMO3 to regulate cholesterol balance and RCT is largely dependent on the amount of dietary cholesterol available. Given that the meta-organismal TMAO pathway is highly dependent on dietary cues, we hypothesized that the host enzyme FMO3 may be a central integrator of both choline- and cholesterol-driven atherosclerosis. To determine the role of FMO3 in diet-driven atherosclerosis progression, female hyperlipidemic LDLr -/- mice received either control or FMO3 antisense oligonucleotides (ASO) while being fed a basal control diet or proatherogenic diets containing 1) 0.2% cholesterol, 2) 1.2% choline, or 3) both 0.2% cholesterol and 1.2% choline for 16 weeks. FMO3 knockdown markedly reduced plasma cholesterol under all dietary conditions, yet only reduced plasma triglycerides in the choline-supplemented mice. Unexpectedly, FMO3 knockdown also elevated circulating monocytes and altered T cell subsets in a diet-specific manner, indicating a role for FMO3 in immune cell maturation only when certain nutrients are available in the diet. The relationship to these diet- and FMO3-dependent CVD risk factors to total atherosclerosis lesion area and lesion-associated immune cell burden will also be presented. Collectively, our studies suggest that host enzyme FMO3 plays a central role in integrating dietary cues (choline & cholesterol) to lipid metabolic and immune cell reprogramming that synergize to promote atherosclerosis.