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  • Fatty acids promote fatty liver disease via the dysregulation of 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway

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Hepatology
Original article
Fatty acids promote fatty liver disease via the dysregulation of 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway
  1. Meng Li1,
  2. Chengfu Xu1,
  3. Junping Shi2,
  4. Jiexia Ding1,
  5. Xingyong Wan1,
  6. Dahua Chen1,
  7. Jianguo Gao1,
  8. Chunxiao Li1,
  9. Jie Zhang1,
  10. Yiming Lin1,
  11. Zhenhua Tu3,
  12. Xiaoni Kong4,
  13. Youming Li1,
  14. Chaohui Yu1
  1. 1 Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
  2. 2 Division of Hepatology, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China
  3. 3 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
  4. 4 Department of Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  1. Correspondence to Youming Li and Professor Chaohui Yu, Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; zlym{at}zju.edu.cn, zyyyych{at}zju.edu.cn

Abstract

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.

  • fatty liver
  • liver metabolism
  • hepatocyte
  • hydrogen sulfide
  • oxidative stress

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/gutjnl-2017-313778

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    Footnotes

    • ML, CX and JS contributed equally.

    • Contributors ML and CX designed and performed the study, analysed the data and wrote the paper. JS collected the patient data, analysed the data and critically revised the manuscript. JD, XW, JG, DC, CL, JZ, YL, ZT and XK performed the study. YL and CY designed the study and critically revised the manuscript.

    • Funding This work was supported by the National Natural Science Foundation of China (No 81230012 to YL, 81470838 to CX, and 81570523 to CY). The funders did not play any role in the study design, data collection and analysis, decisions regarding data release or manuscript preparation.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University.

    • Provenance and peer review Not commissioned; externally peer reviewed.