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Original research
ATF4 activation promotes hepatic mitochondrial dysfunction by repressing NRF1–TFAM signalling in alcoholic steatohepatitis
  1. Liuyi Hao1,
  2. Wei Zhong1,2,
  3. Haibo Dong1,
  4. Wei Guo1,
  5. Xinguo Sun1,
  6. Wenliang Zhang1,
  7. Ruichao Yue1,
  8. Tianjiao Li1,
  9. Alexandra Griffiths3,
  10. Ali Reza Ahmadi4,
  11. Zhaoli Sun4,
  12. Zhenyuan Song3,
  13. Zhanxiang Zhou1,2
  1. 1Center for Translational Biomedical Research, UNCG, Kannapolis, North Carolina, USA
  2. 2Department of Nutrition, UNCG, Greensboro, North Carolina, USA
  3. 3Department of Kinesiology and Nutrition, UIC, Chicago, Illinois, USA
  4. 4Department of Surgery, Johns Hopkins Medicine, Baltimore, Maryland, USA
  1. Correspondence to Dr Zhanxiang Zhou, Center for Translational Biomedical Research, UNCG, Kannapolis, NC 28081, USA; z_zhou{at}uncg.edu

Abstract

Objective Mitochondrial dysfunction plays a dominant role in the pathogenesis of alcoholic liver disease (ALD); however, the underlying mechanisms remain to be fully understood. We previously found that hepatic activating transcription factor 4 (ATF4) activation was associated with mitochondrial dysfunction in ALD. This study aimed to investigate the function and mechanism of ATF4 in alcohol-induced hepatic mitochondrial dysfunction.

Design ATF4 activation was detected in the livers of patients with severe alcoholic hepatitis (AH). The role of ATF4 and mitochondrial transcription factor A (TFAM) in alcohol-induced liver damage was determined in hepatocyte-specific ATF4 knockout mice and liver-specific TFAM overexpression mice, respectively.

Results Hepatic PERK-eIF2α-ATF4 ER stress signalling was upregulated in patients with AH. Hepatocyte-specific ablation of ATF4 in mice ameliorated alcohol-induced steatohepatitis. ATF4 ablation also attenuated alcohol-impaired mitochondrial biogenesis and respiratory function along with the restoration of TFAM. Cell studies confirmed that TFAM expression was negatively regulated by ATF4. TFAM silencing in hepatoma cells abrogated the protective effects of ATF4 knockdown on ethanol-mediated mitochondrial dysfunction and cell death. Moreover, hepatocyte-specific TFAM overexpression in mice attenuated alcohol-induced mitochondrial dysfunction and liver damage. Mechanistic studies revealed that ATF4 repressed the transcription activity of nuclear respiratory factor 1 (NRF1), a key regulator of TFAM, through binding to its promoter region. Clinical relevance among ATF4 activation, NRF1–TFAM pathway disruption and mitochondrial dysfunction was validated in the livers of patients with AH.

Conclusion This study demonstrates that hepatic ATF4 plays a pathological role in alcohol-induced mitochondrial dysfunction and liver injury by disrupting the NRF1–TFAM pathway.

  • alcoholic liver disease
  • energy metabolism
  • hepatocyte

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Footnotes

  • Contributors LH and ZZ conceived and designed research; LH, HD, XS, WG, WeiZ, WenZ, RY, TL and ZZ performed experiments and data analysis. ARA and ZS collected human samples and acquired clinical data. All the authors participated in manuscript preparation.

  • Funding This research was supported by the National Institutes of Health grants R01AA018844 (ZZ), R01AA020212 (ZZ), R24AA025017 (ZS) and Postdoctoral Fellowship Award from the American Liver Foundation (LH).

  • Competing interests None declared.

  • Patient consent for publication Not required.

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

  • Data availability statement Data are available on reasonable request.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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