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<p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to liver morbidity, yet mechanisms linking gut barrier dysfunction to early progression remains poorly defined. We identify intestinal angiopoietin-like 4 (Angptl4) as a central integrator of dietary and microbial signals that governs barrier integrity and hepatic oxidative stress, key early MASLD features. Using intestinal-specific Angptl4 knockout mice, mechanistic in vitro systems, humanized microbiota models, and multi-cohort human studies, we show that intestinal Angptl4 expression is regulated by dietary fatty acids via PPARα signaling and microbiota-derived pattern-recognition pathways, including flagellin-activated-TLR5-EGR1 activation, alongside diet-associated shifts in TLR signaling. These signals destabilize epithelial barriers, amplifying gut-to-liver metabolic and microbial flux. In human cohorts, fecal Angptl4 increases with dysbiosis and metabolic dysfunction, capturing a gut barrier-related dimension distinct from endotoxemia or acute injury. Thus, intestinal Angptl4 emerges as a mechanistic hub linking diet, microbiota, and gut-liver dysfunction, supporting precision barrier-targeted strategies in MASLD.</p>

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Angptl4 integrates dietary and microbial signals to disrupt gut barrier function in MASH

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月22日

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  • Damien Chua,
  • Zun Siong Low,
  • Joseph Han Sol Kim,
  • Yin Hao Lee,
  • Rattanaporn Kiatbumrung,
  • Pornjira Somnark,
  • Min Xu,
  • Yue Shi,
  • Gourav Kaushal,
  • Marcus Ivan Gerard Vos,
  • Aparna Mahadevan,
  • Natalie Hooi,
  • Mathan Raj,
  • Ekaterina Sviriaeva,
  • Beiming Cui,
  • Shaun Tan,
  • Kazuyuki Kasahara,
  • Chun Loong Ho,
  • Walter Wahli,
  • Kuo Chao Yew,
  • Sunny H. Wong,
  • Christine Cheung,
  • Mintu Pal,
  • Ru Zhang,
  • Natthaya Chuaypen,
  • Pisit Tangkijvanich,
  • Hong Sheng Cheng,
  • Liang Li,
  • Nguan Soon Tan

摘要

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to liver morbidity, yet mechanisms linking gut barrier dysfunction to early progression remains poorly defined. We identify intestinal angiopoietin-like 4 (Angptl4) as a central integrator of dietary and microbial signals that governs barrier integrity and hepatic oxidative stress, key early MASLD features. Using intestinal-specific Angptl4 knockout mice, mechanistic in vitro systems, humanized microbiota models, and multi-cohort human studies, we show that intestinal Angptl4 expression is regulated by dietary fatty acids via PPARα signaling and microbiota-derived pattern-recognition pathways, including flagellin-activated-TLR5-EGR1 activation, alongside diet-associated shifts in TLR signaling. These signals destabilize epithelial barriers, amplifying gut-to-liver metabolic and microbial flux. In human cohorts, fecal Angptl4 increases with dysbiosis and metabolic dysfunction, capturing a gut barrier-related dimension distinct from endotoxemia or acute injury. Thus, intestinal Angptl4 emerges as a mechanistic hub linking diet, microbiota, and gut-liver dysfunction, supporting precision barrier-targeted strategies in MASLD.