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<p>Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a prevalent chronic liver disorder with complex pathogenesis and limited therapeutic options. Here, we identify the solute carrier SLC13A3 as a critical regulator of MASLD progression. In a mouse model fed a high-fat, high-cholesterol, and high-fructose (HFHCHF) diet, hepatic SLC13A3 expression was significantly upregulated and positively correlated with disease severity. Liver-specific overexpression of <i>Slc13a3</i> exacerbated hepatic steatosis, lipid accumulation, and metabolic dysfunction, whereas <i>Slc13a3</i> knockdown attenuated these pathological phenotypes. Targeted metabolomic analysis revealed that SLC13A3 modulates hepatic NAD<sup>+</sup> levels, thereby influencing the expression of key lipid metabolism genes, including <i>SREBF1</i>, <i>CD36</i>, <i>PPARγ</i>, and <i>SCD1</i>. These findings highlight a previously unrecognized role of SLC13A3 in MASLD pathogenesis and suggest its potential as a therapeutic target.</p>

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Liver-specific SLC13A3 modulation alleviates MASLD by regulating NAD+ metabolism

  • 期刊论文

  • 发表日期：

    2026年2月14日

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  • Jiangxia Du,
  • Minhui Shen,
  • Yuan Mu,
  • Shuoran Peng,
  • Zhifei Xu,
  • Xiaochun Yang,
  • Bo Yang,
  • Peihua Luo,
  • Hao Yan,
  • Qiaojun He

摘要

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a prevalent chronic liver disorder with complex pathogenesis and limited therapeutic options. Here, we identify the solute carrier SLC13A3 as a critical regulator of MASLD progression. In a mouse model fed a high-fat, high-cholesterol, and high-fructose (HFHCHF) diet, hepatic SLC13A3 expression was significantly upregulated and positively correlated with disease severity. Liver-specific overexpression of Slc13a3 exacerbated hepatic steatosis, lipid accumulation, and metabolic dysfunction, whereas Slc13a3 knockdown attenuated these pathological phenotypes. Targeted metabolomic analysis revealed that SLC13A3 modulates hepatic NAD+ levels, thereby influencing the expression of key lipid metabolism genes, including SREBF1, CD36, PPARγ, and SCD1. These findings highlight a previously unrecognized role of SLC13A3 in MASLD pathogenesis and suggest its potential as a therapeutic target.