title: Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s-PPARα axis signalling.
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.
authors.affiliation: 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].
authors.forename: Mengle
authors.initials: M
authors.lastname: Shao
authors.affiliation: 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].
authors.forename: Bo
authors.initials: B
authors.lastname: Shan
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Deng
authors.affiliation: 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.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: 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].
authors.forename: Ting
authors.initials: T
authors.lastname: Mao
authors.affiliation: 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].
authors.forename: Yifu
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
authors.affiliation: National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jingya
authors.initials: J
authors.lastname: Li
authors.affiliation: National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Molecular and Integrative Physiology, the University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Liangyou
authors.initials: L
authors.lastname: Rui
authors.affiliation: 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.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000222:Adaptation, Physiological; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D005215:Fasting / Q000097:blood / Q000378:metabolism; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D005227:Fatty Acids; D047493:PPAR alpha; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014280:Triglycerides; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D005947:Glucose; D020155:3-Hydroxybutyric Acid