Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis

Abstract

oxidation of trimethylamine (TMA) to trimethylamine-Noxide (TMAO) ( 1 ). TMA is a gas that has a characteristic "fi shy" odor that is produced entirely from the catabolism of dietary choline or carnitine by gut microbiota and then absorbed into the circulation ( 2, 3 ). Rare loss-of-function mutations of FMO3 have been shown to be a cause of "fi sh malodor syndrome" or trimethylaminuria, characterized by high levels of TMA ( 4-6 ). The incidence of trimethylaminuria caused by FMO3 mutations in Caucasian populations is estimated to be 1 in 10,000 ( 4 ). Some but not all trimethylaminuria patients have hypertension ( However, common polymorphisms of the FMO3 gene are not associated with hypertension in the Caucasian population ( 7 ). To the best of our knowledge, whether loss-of-function FMO3 gene mutations infl uence metabolic traits such as plasma lipid, glucose, or insulin levels has not been reported. Recently, TMAO was shown to be signifi cantly associated with coronary artery disease (CAD) in a large cohort of human subjects ( 3 ). A follow-up study confi rmed Abstract We performed silencing and overexpression studies of fl avin containing monooxygenase (FMO) 3 in hyperlipidemic mouse models to examine its effects on trimethylamine N -oxide (TMAO) levels and atherosclerosis. Knockdown of hepatic FMO3 in LDL receptor knockout mice using an antisense oligonucleotide resulted in decreased circulating TMAO levels and atherosclerosis. Surprisingly, we also observed signifi cant decreases in hepatic lipids and in levels of plasma lipids, ketone bodies, glucose, and insulin. FMO3 overexpression in transgenic mice, on the other hand, increased hepatic and plasma lipids. Global gene expression analyses suggested that these effects of FMO3 on lipogenesis and gluconeogenesis may be mediated through the PPAR and Kruppel-like factor 15 pathways. In vivo and in vitro results were consistent with the concept that the effects were mediated directly by FMO3 rather than trimethylamine/TMAO; in particular, overexpression of FMO3 in the human hepatoma cell line, Hep3B, resulted in signifi cantly increased glucose secretion and lipogenesis. Our results indicate a major role for FMO3 in modulating glucose and lipid homeostasis in vivo, and they suggest that pharmacologic inhibition of FMO3 to reduce TMAO levels would be confounded by metabolic interactions. -