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

doi:10.1038/s41467-023-41061-8

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 journal › Journal article › peer-review

54 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 language	English
Article number	5451
Number of pages	18
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-41061-8
Publication status	Published - 6 Sept 2023

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Zhong, J., He, X., Gao, X., Liu, Q., Zhao, Y., Hong, Y., Zhu, W., Yan, J., Li, Y., Li, Y., Zheng, N., Bao, Y., Wang, H., Ma, J., Huang, W., Liu, Z., Lyu, Y., Ke, X., Jia, W., ... Li, H. (2023). Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling. Nature Communications, 14(1), Article 5451. https://doi.org/10.1038/s41467-023-41061-8

@article{3042bfb36b3d4c2eb10ee7049520b448,

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

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.",

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

note = "Funding information: We sincerely acknowledge Professor Hu Zhou and his laboratory members (Shanghai Institute of Materia Medica Chinese Academy of Sciences) for their help in the proteomics analysis. This work was supported by the National Natural Science Foundation of China (U21A20413 to H.L., 82273624 to L.S.), Clinical Research Plan of SHDC (SHDC2020CR2049B to Y.H.), Natural Science Foundation of Shanghai (20ZR1453900 to L.S.), Shanghai Excellent Academic Leaders Program (21XD1403500 to H.L.), National Natural Science Foundation of China (82222071 to C.X.), SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program (2022, E2G807H to C.X. and Y.H.) and Shanghai Municipal Science and Technology Major Project (C.X.). Publisher Copyright: {\textcopyright} 2023, Springer Nature Limited.",

year = "2023",

month = sep,

day = "6",

doi = "10.1038/s41467-023-41061-8",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

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Zhong, J, He, X, Gao, X, Liu, Q, Zhao, Y, Hong, Y, Zhu, W, Yan, J, Li, Y, Li, Y, Zheng, N, Bao, Y, Wang, H, Ma, J, Huang, W, Liu, Z, Lyu, Y, Ke, X, Jia, W, Xie, C, Hu, Y, Sheng, L & Li, H 2023, 'Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling', Nature Communications, vol. 14, no. 1, 5451. https://doi.org/10.1038/s41467-023-41061-8

TY - JOUR

T1 - Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling

AU - Zhong, Jing

AU - He, Xiaofang

AU - Gao, Xinxin

AU - Liu, Qiaohong

AU - Zhao, Yu

AU - Hong, Ying

AU - Zhu, Weize

AU - Yan, Juan

AU - Li, Yifan

AU - Li, Yan

AU - Zheng, Ningning

AU - Bao, Yiyang

AU - Wang, Hao

AU - Ma, Junli

AU - Huang, Wenjin

AU - Liu, Zekun

AU - Lyu, Yuanzhi

AU - Ke, Xisong

AU - Jia, Wei

AU - Xie, Cen

AU - Hu, Yiyang

AU - Sheng, Lili

AU - Li, Houkai

N1 - Funding information: We sincerely acknowledge Professor Hu Zhou and his laboratory members (Shanghai Institute of Materia Medica Chinese Academy of Sciences) for their help in the proteomics analysis. This work was supported by the National Natural Science Foundation of China (U21A20413 to H.L., 82273624 to L.S.), Clinical Research Plan of SHDC (SHDC2020CR2049B to Y.H.), Natural Science Foundation of Shanghai (20ZR1453900 to L.S.), Shanghai Excellent Academic Leaders Program (21XD1403500 to H.L.), National Natural Science Foundation of China (82222071 to C.X.), SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program (2022, E2G807H to C.X. and Y.H.) and Shanghai Municipal Science and Technology Major Project (C.X.). Publisher Copyright: © 2023, Springer Nature Limited.

PY - 2023/9/6

Y1 - 2023/9/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85169998955&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-41061-8

DO - 10.1038/s41467-023-41061-8

M3 - Journal article

C2 - 37673856

AN - SCOPUS:85169998955

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5451

ER -

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

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