Fatty acids promote fatty liver disease via the dysregulation of 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway.
Fatty acids promote fatty liver disease via the dysregulation of 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway.
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脂肪酸通过 3-巯基丙酮酸硫转移酶/硫化氢途径的失调促进脂肪肝疾病。
作者：
Li M;Xu C;Shi J;Ding J;Wan X;Chen D;Gao J;Li C;Zhang J;Lin Y;Tu Z;Kong X;Li Y;Yu C
目的游离脂肪酸（FFAs）在肝细胞内蓄积引起脂毒性，导致非酒精性脂肪性肝病（NAFLD）的发生。本研究旨在探讨FFA通过调节内源性硫化氢（H2S）生物合成的关键酶3-巯基丙酮酸硫转移酶（MPST）参与NAFLD发病的潜在机制。设计在小鼠和NAFLD患者中评估肝脏MPST表达。多种分子方法被用于研究MPST调节在体内和体外对肝脂肪变性的影响。结果FFAs可上调MPST的表达，其作用部分依赖于NF-κB/p65。肝脏MPST表达在高脂饮食（HFD）喂养的小鼠和NAFLD患者中显著增加。通过腺病毒递送MPST短发夹RNA或Mpst基因的杂合缺失部分敲除MPST显著改善HFD喂养小鼠的肝脂肪变性。因此，MPST的抑制也减少FFA诱导的L02细胞中的脂肪积累。有趣的是，抑制MPST显着增强而不是减少H2S的生产，而MPST过表达显着抑制H2S的生产。免疫共沉淀实验表明，MPST直接相互作用，并负调控胱硫醚γ-裂解酶（CSE），在肝脏中的H2S生产的主要来源。从机制上讲，MPST通过抑制CSE/H2S和随后上调固醇调节元件结合蛋白1c途径、C-Jun N-末端激酶磷酸化和肝脏氧化应激来促进脂肪变性。结论FFAs通过上调肝脏MPST的表达，抑制CSE/H2S通路，导致NAFLD的发生。MPST可能是NAFLD潜在的治疗靶点。
Objective Accumulation of free fatty acids (FFAs) in hepatocytes induces lipotoxicity, leading to non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate the underlying mechanisms by which FFA contributes to the pathogenesis of NAFLD via the regulation of 3-mercaptopyruvate sulfurtransferase (MPST), a key enzyme that regulates endogenous hydrogen sulfide (H2S) biosynthesis. Design Hepatic MPST expression was evaluated in mice and patients with NAFLD. A variety of molecular approaches were used to study the effects of MPST regulation on hepatic steatosis in vivo and in vitro. Results In vitro treatment of hepatocytes with FFAs upregulated MPST expression, which was partially dependent on NF-κB/p65. Hepatic MPST expression was markedly increased in high fat diet (HFD)-fed mice and patients with NAFLD. Partial knockdown of MPST via adenovirus delivery of MPST short hairpin RNA or heterozygous deletion of the Mpst gene significantly ameliorated hepatic steatosis in HFD-fed mice. Consistently, inhibition of MPST also reduced FFA-induced fat accumulation in L02 cells. Intriguingly, inhibition of MPST significantly enhanced rather than decreased H2S production, whereas MPST overexpression markedly inhibited H2S production. Co-immunoprecipitation experiments showed that MPST directly interacted with and negatively regulated cystathionine γ-lyase (CSE), a major source of H2S production in the liver. Mechanistically, MPST promoted steatosis via inhibition of CSE/H2S and subsequent upregulation of the sterol regulatory element-binding protein 1c pathway, C-Jun N-terminal kinase phosphorylation and hepatic oxidative stress. Conclusions FFAs upregulate hepatic expression of MPST and subsequently inhibit the CSE/H2S pathway, leading to NAFLD. MPST may be a potential therapeutic target for NAFLD.
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影响因子：
18.9
作者：
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作者：
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