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<p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, but its pathogenesis is unclear. Here we focus on histidine triad nucleotide-binding protein 2 (HINT2), which is expressed in the mitochondria and is involved in hepatic lipid metabolism and mitochondrial protein acetylation. The expression of HINT2 is downregulated in MASLD. HINT2 inhibits free fatty acid-induced lipid accumulation and impairs mitochondrial function in hepatocytes. <i>Hint2</i> knockout exacerbates diet-induced hepatic steatosis, inflammation, fibrosis and mitochondrial damage in mice. The overexpression of <i>Hint2</i> attenuates these alterations. Mechanistically, HINT2 regulates mitochondrial protein acetylation via SIRT3; HINT2 enhances the NAD<sup>+</sup>-dependent activation of sirtuin-3 (SIRT3) by promoting the mitochondrial influx of NAD<sup>+</sup> through solute carrier family 25 member 51 (SLC25A51), thus ameliorating MASLD. Moreover, the downregulation of HINT2 in MASLD is due to YTH N<sup>6</sup>-methyladenosine RNA binding protein 1 (YTHDF1)-mediated regulation. Our results suggest that HINT2 may be an important therapeutic target for MASLD.</p><p></p>

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Histidine triad nucleotide-binding protein 2 attenuates metabolic dysfunction-associated steatotic liver disease through NAD+-dependent sirtuin-3 activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月1日

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  • Qinqiu Wang,
  • Yanjun Guo,
  • Shenghui Chen,
  • Zhening Liu,
  • Xinyu Wang,
  • Hangkai Huang,
  • Qi-en Shen,
  • Ling Yang,
  • Meng Li,
  • Youming Li,
  • Chaohui Yu,
  • Chengfu Xu

摘要

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, but its pathogenesis is unclear. Here we focus on histidine triad nucleotide-binding protein 2 (HINT2), which is expressed in the mitochondria and is involved in hepatic lipid metabolism and mitochondrial protein acetylation. The expression of HINT2 is downregulated in MASLD. HINT2 inhibits free fatty acid-induced lipid accumulation and impairs mitochondrial function in hepatocytes. Hint2 knockout exacerbates diet-induced hepatic steatosis, inflammation, fibrosis and mitochondrial damage in mice. The overexpression of Hint2 attenuates these alterations. Mechanistically, HINT2 regulates mitochondrial protein acetylation via SIRT3; HINT2 enhances the NAD+-dependent activation of sirtuin-3 (SIRT3) by promoting the mitochondrial influx of NAD+ through solute carrier family 25 member 51 (SLC25A51), thus ameliorating MASLD. Moreover, the downregulation of HINT2 in MASLD is due to YTH N6-methyladenosine RNA binding protein 1 (YTHDF1)-mediated regulation. Our results suggest that HINT2 may be an important therapeutic target for MASLD.