Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling

Jing Zhong, Xiaofang He, Xinxin Gao, Qiaohong Liu, Yu Zhao, Ying Hong, Weize Zhu, Juan Yan, Yifan Li, Yan Li, Ningning Zheng, Yiyang Bao, Hao Wang, Junli Ma, Wenjin Huang, Zekun Liu, Yuanzhi Lyu, Xisong Ke, Wei Jia, Cen Xie*Yiyang Hu*, Lili Sheng*, Houkai Li*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

12 Citations (Scopus)

Abstract

Nonalcoholic fatty liver disease (NAFLD) is usually characterized with disrupted bile acid (BA) homeostasis. However, the exact role of certain BA in NAFLD is poorly understood. Here we show levels of serum hyodeoxycholic acid (HDCA) decrease in both NAFLD patients and mice, as well as in liver and intestinal contents of NAFLD mice compared to their healthy counterparts. Serum HDCA is also inversely correlated with NAFLD severity. Dietary HDCA supplementation ameliorates diet-induced NAFLD in male wild type mice by activating fatty acid oxidation in hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent way because the anti-NAFLD effect of HDCA is abolished in hepatocyte-specific Pparα knockout mice. Mechanistically, HDCA facilitates nuclear localization of PPARα by directly interacting with RAN protein. This interaction disrupts the formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer. Our results demonstrate the therapeutic potential of HDCA for NAFLD and provide new insights of BAs on regulating fatty acid metabolism.

Original languageEnglish
Article number5451
Number of pages18
JournalNature Communications
Volume14
DOIs
Publication statusPublished - 6 Sept 2023

Scopus Subject Areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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