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 () and Houkai Li ()
Additional contact information
Jing Zhong: Shanghai University of Traditional Chinese Medicine
Xiaofang He: Shanghai University of Traditional Chinese Medicine
Xinxin Gao: Shanghai University of Traditional Chinese Medicine
Qiaohong Liu: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine
Yu Zhao: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine
Ying Hong: Shanghai University of Traditional Chinese Medicine
Weize Zhu: Shanghai University of Traditional Chinese Medicine
Juan Yan: Shanghai University of Traditional Chinese Medicine
Yifan Li: Shanghai University of Traditional Chinese Medicine
Yan Li: Shanghai University of Traditional Chinese Medicine
Ningning Zheng: Shanghai University of Traditional Chinese Medicine
Yiyang Bao: Shanghai University of Traditional Chinese Medicine
Hao Wang: Shanghai University of Traditional Chinese Medicine
Junli Ma: Shanghai University of Traditional Chinese Medicine
Wenjin Huang: Shanghai University of Traditional Chinese Medicine
Zekun Liu: Shanghai University of Traditional Chinese Medicine
Yuanzhi Lyu: University of California, Davis
Xisong Ke: Shanghai University of Traditional Chinese Medicine
Wei Jia: Center for Translational Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Cen Xie: Chinese Academy of Sciences
Yiyang Hu: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine
Lili Sheng: Shanghai University of Traditional Chinese Medicine
Houkai Li: Shanghai University of Traditional Chinese Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41061-8

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