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Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s–PPARα axis signalling

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  • Mengle Shao

    (Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of the Chinese Academy of Sciences
    Present address: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA)

  • Bo Shan

    (Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of the Chinese Academy of Sciences)

  • Yang Liu

    (Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of the Chinese Academy of Sciences)

  • Yiping Deng

    (Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of the Chinese Academy of Sciences)

  • Cheng Yan

    (Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of the Chinese Academy of Sciences)

  • Ying Wu

    (Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of the Chinese Academy of Sciences)

  • Ting Mao

    (Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of the Chinese Academy of Sciences
    Present address: China Novartis Institutes for BioMedical Research Co., Ltd., Shanghai 201203, China)

  • Yifu Qiu

    (Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of the Chinese Academy of Sciences
    Present address: Cardiovascular Research Institute, University of California, San Francisco, California 94158, USA)

  • Yubo Zhou

    (National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Shan Jiang

    (Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital)

  • Weiping Jia

    (Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital)

  • Jingya Li

    (National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Jia Li

    (National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Liangyou Rui

    (the University of Michigan Medical School)

  • Liu Yang

    (Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of the Chinese Academy of Sciences)

  • Yong Liu

    (Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of the Chinese Academy of Sciences)

Abstract

Although the mammalian IRE1α-XBP1 branch of the cellular unfolded protein response has been implicated in glucose and lipid metabolism, the exact metabolic role of IRE1α signalling in vivo remains poorly understood. Here we show that hepatic IRE1α functions as a nutrient sensor that regulates the metabolic adaptation to fasting. We find that prolonged deprivation of food or consumption of a ketogenic diet activates the IRE1α-XBP1 pathway in mouse livers. Hepatocyte-specific abrogation of Ire1α results in impairment of fatty acid β-oxidation and ketogenesis in the liver under chronic fasting or ketogenic conditions, leading to hepatosteatosis; liver-specific restoration of XBP1s reverses the defects in IRE1α null mice. XBP1s directly binds to and activates the promoter of PPARα, the master regulator of starvation responses. Hence, our results demonstrate that hepatic IRE1α promotes the adaptive shift of fuel utilization during starvation by stimulating mitochondrial β-oxidation and ketogenesis through the XBP1s–PPARα axis.

Suggested Citation

  • Mengle Shao & Bo Shan & Yang Liu & Yiping Deng & Cheng Yan & Ying Wu & Ting Mao & Yifu Qiu & Yubo Zhou & Shan Jiang & Weiping Jia & Jingya Li & Jia Li & Liangyou Rui & Liu Yang & Yong Liu, 2014. "Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s–PPARα axis signalling," Nature Communications, Nature, vol. 5(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4528
    DOI: 10.1038/ncomms4528
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    Cited by:

    1. Fei Xiao & Haizhou Jiang & Zi Li & Xiaoxue Jiang & Shanghai Chen & Yuguo Niu & Hanrui Yin & Yousheng Shu & Bo Peng & Wei Lu & Xiaoying Li & Zhigang Li & Shujue Lan & Xiaoyan Xu & Feifan Guo, 2023. "Reduced hepatic bradykinin degradation accounts for cold-induced BAT thermogenesis and WAT browning in male mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Aitor Almanza & Katarzyna Mnich & Arnaud Blomme & Claire M. Robinson & Giovanny Rodriguez-Blanco & Sylwia Kierszniowska & Eoghan P. McGrath & Matthieu Gallo & Eleftherios Pilalis & Johannes V. Swinnen, 2022. "Regulated IRE1α-dependent decay (RIDD)-mediated reprograming of lipid metabolism in cancer," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Jing Yan & Yuemei Zhang & Hairong Yu & Yicen Zong & Daixi Wang & Jiangfei Zheng & Li Jin & Xiangtian Yu & Caizhi Liu & Yi Zhang & Feng Jiang & Rong Zhang & Xiangnan Fang & Ting Xu & Mingyu Li & Jianzh, 2022. "GPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages," Nature Communications, Nature, vol. 13(1), pages 1-22, December.

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