FMO3 and its metabolite TMAO contribute to the formation of gallstones

Jun 29, 2019Biochimica et biophysica acta. Molecular basis of disease

FMO3 and its product TMAO may contribute to gallstone formation

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Abstract

High plasma TMAO levels were positively associated with gallstone disease in humans.

TMAO is produced from trimethylamine by gut bacteria and further oxidized in the liver.
Increased hepatic expression of FMO3 and elevated plasma TMAO levels were observed in gallstone-susceptible mice fed a lithogenic diet.
Dietary TMAO or its precursor choline may increase hepatic FMO3 expression and plasma TMAO levels.
Supplementation with TMAO led to a 70% incidence of gallstones in gallstone-resistant mice on a lithogenic diet.
Increased expression of cholesterol transporters Abcg5 and Abcg8 in the liver is associated with TMAO treatment.

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Trimethylamine-N-oxide (TMAO) is a metabolite derived from trimethylamine (TMA), which is first produced by gut microbiota and then oxidized by flavin-containing monooxygenase 3 (FMO3) in the liver. TMAO may contribute to the development of diseases such as atherosclerosis because of its role in regulating lipid metabolism. In this study, we found that high plasma TMAO levels were positively associated with the presence of gallstone disease in humans. We further found increased hepatic FMO3 expression and elevated plasma TMAO level in a gallstone-susceptible strain of mice C57BL/6J fed a lithogenic diet (LD), but not in a gallstone-resistant strain of mice AKR/J. Dietary supplementation of TMAO or its precursor choline increased hepatic FMO3 expression and plasma TMAO levels and induced hepatic canalicular cholesterol transporters ATP binding cassette (Abc) g5 and g8 expression in mice. Up-regulation of ABCG5 and ABCG8 expression was observed in hepatocytes incubated with TMAO in vitro. Additionally, in AKR/J mice fed a LD supplemented with 0.3% TMAO, the incidence of gallstones rose up to 70% compared with 0% in AKR/J mice fed only a LD. This was associated with increased hepatic Abcg5 and g8 expression induced by TMAO. Our study demonstrated TMAO could be associated with increased hepatic Abcg5/g8 expression, biliary cholesterol hypersecretion and gallstone formation.

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FMO3 and its metabolite TMAO contribute to the formation of gallstones

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