Emerging roles of flavin monooxygenase 3 in cholesterol metabolism and atherosclerosis

Abstract

Purpose of review: Atherosclerosis and associated cardiovascular disease still remain the largest cause of mortality worldwide. Several recent studies have discovered that metabolism of common nutrients by gut microbes can produce a proatherogenic metabolite called trimethylamine-N-oxide (TMAO). The goal of this review is to discuss emerging evidence that the hepatic enzyme that generates TMAO, flavin monooxygenase 3 (FMO3), plays a regulatory role in maintaining whole body cholesterol balance and atherosclerosis development.

Recent findings: Several independent studies have recently uncovered a link between either FMO3 itself or its enzymatic product TMAO with atherosclerosis and hepatic insulin resistance. These recent studies show that inhibition of FMO3 stimulates macrophage reverse cholesterol transport and protects against atherosclerosis in mice.

Summary: A growing body of work demonstrates that nutrients present in high-fat foods (phosphatidylcholine, choline and L-carnitine) can be metabolized by the gut microbial enzymes to generate trimethylamine, which is then further metabolized by the host enzyme FMO3 to produce proatherogenic TMAO. Here, we discuss emerging evidence that the TMAO-producing enzyme FMO3 is centrally involved in the pathogenesis of atherosclerosis by regulating cholesterol metabolism and insulin resistance, and how these new insights provide exciting new avenues for cardiovascular disease therapies.

Figure 1

The trimethylamine-N-oxide (TMAO) generating enzyme flavin monooxygenase 3 (FMO3) regulates hepatic drug metabolism, diabetes and insulin signaling, cholesterol balance, and atherosclerosis development.