Trimethylamine N‐Oxide Aggravates Liver Steatosis through Modulation of Bile Acid Metabolism and Inhibition of Farnesoid X Receptor Signaling in Nonalcoholic Fatty Liver Disease

Abstract

Scope Trimethylamine N‐oxide (TMAO), the metabolite of choline generated by gut microbiota, is associated with nonalcoholic fatty liver disease (NAFLD) and could influence bile acid (BA) metabolism. However, whether TMAO aggravates liver steatosis by modulating BA metabolism and the related mechanisms has not been investigated. Methods and results A case‐control study including biopsy‐proven NAFLD patients (n = 34) and controls (n = 14) is conducted to determine the correlation between TMAO and BA metabolism. Serum levels of total BA and the percentage of farnesoid X receptor (FXR)‐antagonistic BA species are markedly higher in NAFLD patients than in the controls. Serum levels of TMAO positively correlated with the serum levels of total BA and hepatic mRNA expression of cholesterol 7 alpha hydroxylase (CYP7A1). In a murine model, it is found that 18 weeks administration of TMAO impairs liver function and increases hepatic triglyceride accumulation and lipogenesis in mice fed with a high‐fat diet. TMAO increases BA synthesis and shifted hepatic BA composition toward FXR‐antagonistic activity. Knockdown of CYP7A1 via small interfering RNA or activation of FXR by GW4064 blocks the effect of TMAO‐induced lipogenesis in palmitic acid‐treated HepG2 cells. Conclusion TMAO aggravates liver steatosis by suppressing BA‐mediated hepatic FXR signaling.

The Molecular and Mechanistic Insights Based on Gut–Liver Axis: Nutritional Target for Non-Alcoholic Fatty Liver Disease (NAFLD) Improvement

“…The precise mechanisms involving the relationship between TMAO and the initiation and progression of NAFLD remains to be clarified. However, it has been verified that TMAO exacerbates hepatic steatosis by blocking the farnesoid X receptor (FXR) signaling activated by bile acid [49]. By contrast, the activation of FXR signaling have shown a protective effect against NAFLD including liver steatosis and inflammation [50,51].…”

Detection of Early Disease Risk Factors Associated with Metabolic Syndrome: A New Era with the NMR Metabolomics Assessment

“…Some studies reinforced the importance of diet and microbiota in cardio-metabolic health, with the TMAO level emerging as a possible target for therapeutic interventions. Given that CVD risk in humans is linked to circulating levels of TMAO [233], and dietary supplementation with TMAO promotes atherosclerotic CVD in mice [234], a key opportunity for therapeutic research leads to blocking the ability of plasma TMAO to obtain a biological response. More than five hundred Finnish men with MetS was studied, the serum obtained was analyzed by NMR, and the results described a positive correlation between plasma TMAO concentrations and gut microbiota Prevotella and Peptococcaceae, however a negative correlation with Faecalibacterium prausnitzii was detected.…”

Microbial Metabolites: Critical Regulators in NAFLD

“…In animal experiments, substantial data show that TMAO increased hepatic triglyceride accumulation and impaired liver function (Tan et al, 2019). Besides, the potential mechanism that show that TMAO aggravates NAFLD is also investigated.…”

“…In parallel, TMAO also reduces the conversion of cholesterol into BAs, thus affecting lipid absorption and cholesterol homeostasis (Koeth et al, 2013). In addition, TMAO increases BA synthesis and shifts hepatic BA composition mediated by hepatic farnesoid X receptor (FXR) signaling (Tan et al, 2019).…”