Trimethylamine-N-oxide (TMAO)-induced atherosclerosis is associated with bile acid metabolism

Abstract

BackgroundRecently, trimethylamine-N-oxide (TMAO) plasma levels have been proved to be associated with atherosclerosis development. Among the targets aimed to ameliorating atherosclerotic lesions, inducing bile acid synthesis to eliminate excess cholesterol in body is an effective way. Individual bile acid as endogenous ligands for the nuclear receptor has differential effects on regulating bile acid metabolism. It is unclear whether bile acid profiles are mechanistically linked to TMAO-induced development of atherosclerosis.MethodsMale apoE−/− mice were fed with control diet containing 0.3% TMAO for 8 weeks. Aortic lesion development and serum lipid profiles were determined. Bile acid profiles in bile, liver and serum were measured by liquid chromatographic separation and mass spectrometric detection (LC-MS). Real-time PCRs were performed to analyze mRNA expression of genes related to hepatic bile acid metabolism.ResultsThe total plaque areas in the aortas strongly increased 2-fold (P < 0.001) in TMAO administration mice. The levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) in TMAO group were also significantly increased by 25.5% (P = 0.044), 31.2% (P = 0.006), 28.3% (P = 0.032), respectively. TMAO notably changed bile acid profiles, especially in serum, the most prominent inductions were tauromuricholic acid (TMCA), deoxycholic acid (DCA) and cholic acid (CA). Mechanically, TMAO inhibited hepatic bile acid synthesis by specifically repressing the classical bile acid synthesis pathway, which might be mediated by activation of small heterodimer partner (SHP) and farnesoid X receptor (FXR).ConclusionsThese findings suggested that TMAO accelerated aortic lesion formation in apoE−/− mice by altering bile acid profiles, further activating nuclear receptor FXR and SHP to inhibit bile acid synthesis by reducing Cyp7a1 expression.

Prevention of Vascular Inflammation by Pterostilbene via Trimethylamine‐N‐Oxide Reduction and Mechanism of Microbiota Regulation

“…FMO3 is regulated by a hepatic bile acid‐activated nuclear receptor farnesoid X receptor (FXR) . Specifically, primary bile acid such as cholic acid stimulates FMO3 expression . Antibiotic administration suppressed secondary bile acids production and caused a buildup of primary bile acids like cholic acid as antibiotics administration group showed an increase of FMO3 mRNA level similar to carnitine group (Figure ).…”

Carnitine in Human Muscle Bioenergetics: Can Carnitine Supplementation Improve Physical Exercise?

“…However, so far, no scientific basis supports improvement in exercise performance for healthy individuals or athletes after carnitine supplementation. Moreover, considering that carnitine metabolism produces TMAO which has been recently recognized as a novel risk factor for cardiovascular diseases [104][105][106][107][108], the use of uncontrolled amounts of carnitine as supplements must be carefully reviewed.…”

“…Painfully, TMAO has been demonstrated to promote atherosclerosis and to increase cardiovascular risk in animals [102]. In human studies, a significant positive correlation has been found between fasting plasma TMAO levels and major cardiovascular events [8,[104][105][106][107][108]. Thus, due to the production of TMAO, the beneficial effect of carnitine is controversial and deserves more attention.…”

Gut microbiota in atherosclerosis: focus on trimethylamine N‐oxide

“…Disruption of normal bile acid metabolism leads to atherosclerosis. It was showed that TMAO inhibited the hepatic bile acids synthesis by downregulating cholesterol 7α‑hydroxylase (Cyp7a1) expression, which is the key enzyme of this pathway (). Nevertheless, the exact regulatory mechanism remains to be elucidated, since current concerning about whether the influence of TMAO on the cellular metabolism is direct or indirect remains controversial.…”