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.

中文翻译：

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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

目的 肝细胞中游离脂肪酸 (FFA) 的积累会引起脂毒性，导致非酒精性脂肪肝 (NAFLD)。本研究旨在探讨 FFA 通过调节 3-巯基丙酮酸硫转移酶 (MPST)（一种调节内源性硫化氢 (H2S) 生物合成的关键酶）参与 NAFLD 发病机制的潜在机制。设计 在小鼠和 NAFLD 患者中评估了肝脏 MPST 表达。多种分子方法用于研究 MPST 调节对体内和体外肝脏脂肪变性的影响。结果 用 FFA 对肝细胞进行体外处理后，MPST 表达上调，这部分依赖于 NF-κB/p65。在高脂肪饮食 (HFD) 喂养的小鼠和 NAFLD 患者中，肝脏 MPST 表达显着增加。通过腺病毒递送 MPST 短发夹 RNA 或 Mpst 基因的杂合缺失部分敲低 MPST，可显着改善 HFD 喂养小鼠的肝脏脂肪变性。一致地，MPST 的抑制也减少了 L02 细胞中 FFA 诱导的脂肪积累。有趣的是，MPST 的抑制显着增强而不是减少了 H2S 的产生，而 MPST 过表达显着抑制了 H2S 的产生。免疫共沉淀实验表明 MPST 直接与胱硫醚 γ-裂解酶 (CSE) 相互作用并对其进行负调节，CSE 是肝脏中 H2S 产生的主要来源。从机制上讲，MPST 通过抑制 CSE/H2S 并随后上调甾醇调节元件结合蛋白 1c 通路、C-Jun N 端激酶磷酸化和肝脏氧化应激来促进脂肪变性。结论 FFAs 上调 MPST 的肝脏表达，随后抑制 CSE/H2S 通路，导致 NAFLD。MPST 可能是 NAFLD 的潜在治疗靶点。