Intestinal TM6SF2 protects against metabolic dysfunction-associated steatohepatitis through the gut-liver axis

Xiang Zhang; Harry Cheuk-Hay Lau; Suki Ha; Chuanfa Liu; Cong Liang; Hye Won Lee; Queena Wing-Yin Ng; Yi Zhao; Fenfen Ji; Yunfei Zhou; Yasi Pan; Yang Song; Yating Zhang; Jennie Ching Yin Lo; Alvin Ho Kwan Cheung; Jianfeng Wu; Xiaoxing Li; Hongzhi Xu; Chi Chun Wong; Vincent Wai-Sun Wong; Jun Yu

doi:10.1038/s42255-024-01177-7

Intestinal TM6SF2 protects against metabolic dysfunction-associated steatohepatitis through the gut-liver axis

Nat Metab. 2025 Jan 8. doi: 10.1038/s42255-024-01177-7. Online ahead of print.

Authors

Xiang Zhang¹, Harry Cheuk-Hay Lau¹, Suki Ha¹, Chuanfa Liu¹, Cong Liang², Hye Won Lee³, Queena Wing-Yin Ng¹, Yi Zhao^{1

2}, Fenfen Ji¹, Yunfei Zhou¹, Yasi Pan¹, Yang Song^{1

4}, Yating Zhang¹, Jennie Ching Yin Lo¹, Alvin Ho Kwan Cheung⁵, Jianfeng Wu⁶, Xiaoxing Li², Hongzhi Xu⁴, Chi Chun Wong¹, Vincent Wai-Sun Wong⁷, Jun Yu⁸

Affiliations

¹ Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
² Institute of Precision Medicine, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
³ Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea.
⁴ Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, China.
⁵ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁶ State Key Laboratory of Cellular Stress Biology, School of Medicine, Xiamen University, Xiamen, China.
⁷ Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. wongv@cuhk.edu.hk.
⁸ Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. junyu@cuhk.edu.hk.

PMID: 39779889
DOI: 10.1038/s42255-024-01177-7

Abstract

Transmembrane-6 superfamily member 2 (TM6SF2) regulates hepatic fat metabolism and is associated with metabolic dysfunction-associated steatohepatitis (MASH). TM6SF2 genetic variants are associated with steatotic liver disease. The pathogenesis of MASH involves genetic factors and gut microbiota alteration, yet the role of host-microbe interactions in MASH development remains unclear. Here, we discover that mice with intestinal epithelial cell-specific knockout of Tm6sf2 (Tm6sf2^ΔIEC) develop MASH, accompanied by impaired intestinal barrier and microbial dysbiosis. Transplanting stools from Tm6sf2^ΔIEC mice induces steatohepatitis in germ-free recipient mice, whereas MASH is alleviated in Tm6sf2^ΔIEC mice co-housed with wild-type mice. Mechanistically, Tm6sf2-deficient intestinal cells secrete more free fatty acids by interacting with fatty acid-binding protein 5 to induce intestinal barrier dysfunction, enrichment of pathobionts, and elevation of lysophosphatidic acid (LPA) levels. LPA is translocated from the gut to the liver, contributing to lipid accumulation and inflammation. Pharmacological inhibition of the LPA receptor suppresses MASH in both Tm6sf2^ΔIEC and wild-type mice. Hence, modulating microbiota or blocking the LPA receptor is a potential therapeutic strategy in TM6SF2 deficiency-induced MASH.

Abstract

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