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

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

doi:10.1038/ncomms4528

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

Nat Commun. 2014 Mar 27:5:3528. doi: 10.1038/ncomms4528.

Authors

Mengle Shao¹, Bo Shan², Yang Liu³, Yiping Deng³, Cheng Yan³, Ying Wu³, Ting Mao², Yifu Qiu², Yubo Zhou⁴, Shan Jiang⁵, Weiping Jia⁵, Jingya Li⁴, Jia Li⁴, Liangyou Rui⁶, Liu Yang³, Yong Liu³

Affiliations

¹ 1] 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, Shanghai 200031, China [2] [3].
² 1] 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, Shanghai 200031, China [2].
³ 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, Shanghai 200031, China.
⁴ National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁵ Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
⁶ Department of Molecular and Integrative Physiology, the University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.

PMID: 24670948
DOI: 10.1038/ncomms4528

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3-Hydroxybutyric Acid / metabolism
Adaptation, Physiological
Analysis of Variance
Animals
Cells, Cultured
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Endoribonucleases / genetics
Endoribonucleases / metabolism*
Fasting / blood
Fasting / metabolism
Fatty Acids / blood
Fatty Acids / metabolism
Glucose / metabolism
HEK293 Cells
Humans
Immunoblotting
Lipid Metabolism
Liver / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxidation-Reduction
PPAR alpha / genetics
PPAR alpha / metabolism*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Regulatory Factor X Transcription Factors
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction*
Transcription Factors / genetics
Transcription Factors / metabolism*
Triglycerides / blood
Triglycerides / metabolism
X-Box Binding Protein 1

Substances

DNA-Binding Proteins
Fatty Acids
PPAR alpha
Regulatory Factor X Transcription Factors
Transcription Factors
Triglycerides
X-Box Binding Protein 1
XBP1 protein, human
Xbp1 protein, mouse
Ern1 protein, mouse
Protein Serine-Threonine Kinases
Endoribonucleases
Glucose
3-Hydroxybutyric Acid