HLF and PPARα axis regulates metabolic‐associated fatty liver disease through extracellular vesicles derived from the intestinal microbiota
Metabolic-associated fatty liver disease (MAFLD) has become increasingly widespread. The intestine is the primary site of lipid absorption and is important for the homeostasis of lipid metabolism. However, the mechanism underlying the participation of the intestinal tract in the development of MAFLD requires additional investigation. In this study, analysis of the single-cell transcriptome of intestinal tissue from cynomolgus monkeys found that hepatic leukemia factor (HLF) participated in the genetic regulation of intestinal lipid absorption. Results obtained from normal and intestine-specific <i>Hlf</i>-knockout mice confirmed that HLF alleviated intestinal barrier disorders by inhibiting peroxisome proliferator-activated receptor alpha (PPARα) expression. The HLF/PPARα axis alleviated MAFLD by mediating gut microbiota-derived extracellular vesicles (fEVs), thereby inhibiting hepatocyte ferroptosis. Lipidomics and functional experiments verified that taurochenodeoxycholic acid (TCDCA), a conjugated bile acid contained in the fEVs, had a key role in the process. In conclusion, intestinal HLF activity was mediated by fEVs and identified as a novel therapeutic target for MAFLD.
Authors
- Turtushikh Damba (ORCID: https://orcid.org/0000-0003-3141-249X)
- Xinyu Qi
- Jiale Wang (ORCID: https://orcid.org/0000-0001-9883-7295)
- Lin Yu (ORCID: https://orcid.org/0000-0002-9972-3799)
- Jinfeng Zhou (ORCID: https://orcid.org/0000-0003-2479-3968)
- Jingsu Yu
- Menglong Hou
- Yixing Li (ORCID: https://orcid.org/0000-0002-1419-6142)
- Guo Chen (ORCID: https://orcid.org/0000-0003-4895-9192)
- Batbold Batsaikhan (ORCID: https://orcid.org/0000-0003-3109-2166)
- Yunxiao Liang
- Yang Wang (ORCID: https://orcid.org/0000-0001-6790-2242)
- Lei Zhou (ORCID: https://orcid.org/0000-0002-7145-4953)
- Khongorzul Batchuluun (ORCID: https://orcid.org/0000-0001-6176-9313)
- Siqi Liu (ORCID: https://orcid.org/0000-0002-8649-3162)
- Yi Liang (ORCID: https://orcid.org/0000-0003-0269-0255)
- Xiao Yang (ORCID: https://orcid.org/0000-0003-1246-7065)
- Jie Ma (ORCID: https://orcid.org/0000-0002-7344-5145)
- Xue Liang
- Mengkuan Liu
- Xianjin Yang
Institutions
- Guangxi University (CN)
- Mongolian National University of Medical Sciences (MN)
- The People's Hospital of Guangxi Zhuang Autonomous Region (CN)
Publication Details
- Journal
- iMeta
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1002/imt2.70022
- Citations
- 11
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 14.90
Funders
- Deutsches Krebsforschungszentrum
- National Natural Science Foundation of China
- National Key Research and Development Program of China