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

Damien Chua  ¹ , Zun Siong Low  ² , Joseph Han Sol Kim  ² , Yin Hao Lee  ^{3   4} , Rattanaporn Kiatbumrung  ⁵ , Pornjira Somnark  ⁵ , Min Xu  ⁶ , Yue Shi  ⁶ , Gourav Kaushal  ⁷ , Marcus Ivan Gerard Vos  ² , Aparna Mahadevan  ² , Natalie Hooi  ² , Mathan Raj  ⁸ , Ekaterina Sviriaeva  ² , Beiming Cui  ⁹ , Shaun Tan  ² , Kazuyuki Kasahara  ² , Chun Loong Ho  ⁹ , Walter Wahli  ^{2   10   11} , Kuo Chao Yew  ¹² , Sunny H Wong  ^{2   12} , Christine Cheung  ^{2   13} , Mintu Pal  ¹⁴ , Ru Zhang  ^{15   16   17} , Natthaya Chuaypen  ⁵ , Pisit Tangkijvanich  ⁵ , Hong Sheng Cheng  ¹⁸ , Liang Li  ¹⁹ , Nguan Soon Tan  ^{20   21}

Affiliations

• PMID: 42173835
• DOI: 10.1038/s41467-026-72575-6

Free article

Abstract

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.