FMO3 and its metabolite TMAO contribute to the formation of gallstones
FMO3 and its metabolite TMAO contribute to the formation of gallstones
复制标题
FMO3 及其代谢物 TMAO 有助于胆结石的形成
DOI：
10.1016/j.bbadis.2019.06.016
复制
发表时间：
2019-10-01
影响因子：
6.2
通讯作者：
Jiang, Zhaoyan
中科院分区：
文献类型：
--
作者：
Chen, Yaoyao;Weng, Zhenkun;Jiang, Zhaoyan
氧化三甲胺（TMAO）是一种由三甲胺（TMA）衍生而来的代谢产物。三甲胺首先由肠道微生物群产生，随后在肝脏中被含黄素单加氧酶3（FMO3）氧化。由于氧化三甲胺在调节脂质代谢中发挥作用，它可能促进动脉粥样硬化等疾病的发展。在本研究中，我们发现人体血浆中氧化三甲胺水平较高与胆结石疾病的存在呈正相关。我们进一步发现，喂食致石饮食（LD）的胆结石易感小鼠品系C57BL / 6J肝脏中FMO3表达增加，血浆氧化三甲胺水平升高，而胆结石抗性小鼠品系AKR / J则无此现象。在小鼠饮食中补充氧化三甲胺或其前体胆碱，会增加肝脏FMO3表达和血浆氧化三甲胺水平，并诱导肝脏胆小管胆固醇转运蛋白ATP结合盒（Abc）g5和g8的表达。体外实验中，用氧化三甲胺孵育的肝细胞中观察到ABCG5和ABCG8表达上调。此外，喂食添加0.3%氧化三甲胺的致石饮食的AKR / J小鼠，胆结石发病率上升至70%，而仅喂食致石饮食的AKR / J小鼠胆结石发病率为0%。这与氧化三甲胺诱导的肝脏Abcg5和g8表达增加有关。我们的研究表明，氧化三甲胺可能与肝脏Abcg5 / g8表达增加、胆汁胆固醇分泌过多以及胆结石形成有关。
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.