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Background &amp; aims <p>Metabolic dysfunction-associated steatohepatitis (MASH) is a multifactorial disease driven by complex molecular mechanisms. Identifying key regulators is critical for developing targeted therapies. Here, we demonstrate the impact of the loss of the apoptosis-antagonizing transcription factor (AATF) on hepatic lipid metabolism and MASH progression.</p> Methods <p>A preclinical mouse model recapitulating human MASH was established by feeding C57Bl/6 mice either a chow diet (CD) or a western diet with sugar water (WD). Hepatic AATF silencing was achieved by tail vein injection of siAATF delivered by adeno-associated virus 8 (AAV8) using a liver-specific thyroxine-binding globulin (TBG) promoter. In addition to histological, biochemical, and molecular biology evaluations, mechanistic insights were obtained through whole transcriptomic and untargeted metabolomic analyses.</p> Results <p>AAV8-mediated specific knockdown of AATF in hepatocytes significantly reduced body weight, liver weight, and insulin resistance in mice fed a western diet (WD). However, no such effects were observed in mice fed a chow diet (CD). Further analyses showed reduced liver injury, steatosis, and steatohepatitis in WDsiAATF mice. Transcriptomic analysis demonstrated that AATF loss alleviated cellular stress, inflammation, and fibrosis in WD-fed mice. Moreover, AATF silencing altered lipid metabolism, notably by decreasing hepatic lipogenesis in WD mice. Interestingly, untargeted metabolomics revealed increased glycerophospholipid biosynthesis and fatty acid β-oxidation in WDsiAATF mice.</p> Conclusion <p>Our findings reveal a previously unrecognized role of AATF as a central regulator of hepatic lipid metabolism in MASH, acting through the AKT–mTORC1 signaling pathway, and establish its inhibition as a promising therapeutic strategy for the treatment of metabolic liver disease.</p> Graphical Abstract <p></p>

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Hepatic loss of AATF attenuates MASH by suppressing AKT–mTORC1 signaling and reprogramming lipid metabolism

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月13日

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  • Akshatha N. Srinivas,
  • Diwakar Suresh,
  • Prajna Anirvan,
  • Manju Moorthy,
  • Gopalkrishna Ramaswamy,
  • Suma M. Nataraj,
  • Prasanna Kumar Santhekadur,
  • Deepak Suvarna,
  • Shivaram P. Singh,
  • Divya P. Kumar

摘要

Background & aims

Metabolic dysfunction-associated steatohepatitis (MASH) is a multifactorial disease driven by complex molecular mechanisms. Identifying key regulators is critical for developing targeted therapies. Here, we demonstrate the impact of the loss of the apoptosis-antagonizing transcription factor (AATF) on hepatic lipid metabolism and MASH progression.

Methods

A preclinical mouse model recapitulating human MASH was established by feeding C57Bl/6 mice either a chow diet (CD) or a western diet with sugar water (WD). Hepatic AATF silencing was achieved by tail vein injection of siAATF delivered by adeno-associated virus 8 (AAV8) using a liver-specific thyroxine-binding globulin (TBG) promoter. In addition to histological, biochemical, and molecular biology evaluations, mechanistic insights were obtained through whole transcriptomic and untargeted metabolomic analyses.

Results

AAV8-mediated specific knockdown of AATF in hepatocytes significantly reduced body weight, liver weight, and insulin resistance in mice fed a western diet (WD). However, no such effects were observed in mice fed a chow diet (CD). Further analyses showed reduced liver injury, steatosis, and steatohepatitis in WDsiAATF mice. Transcriptomic analysis demonstrated that AATF loss alleviated cellular stress, inflammation, and fibrosis in WD-fed mice. Moreover, AATF silencing altered lipid metabolism, notably by decreasing hepatic lipogenesis in WD mice. Interestingly, untargeted metabolomics revealed increased glycerophospholipid biosynthesis and fatty acid β-oxidation in WDsiAATF mice.

Conclusion

Our findings reveal a previously unrecognized role of AATF as a central regulator of hepatic lipid metabolism in MASH, acting through the AKT–mTORC1 signaling pathway, and establish its inhibition as a promising therapeutic strategy for the treatment of metabolic liver disease.

Graphical Abstract