title: Hepatoprotective role of Sestrin2 against chronic ER stress.
abstract: Upon prolonged endoplasmic reticulum (ER) stress, cells attenuate protein translation to prevent accumulation of unfolded proteins. Here we show that Sestrin2 is critical for this process. Sestrin2 expression is induced by an ER stress-activated transcription factor CCAAT-enhancer-binding protein beta (c/EBPβ). Once induced, Sestrin2 halts protein synthesis by inhibiting mammalian target of rapamycin complex 1 (mTORC1). As Sestrin2-deficient cells continue to translate a large amount of proteins during ER stress, they are highly susceptible to ER stress-associated cell death. Accordingly, dietary or genetically induced obesity, which does not lead to any pathological indication other than simple fat accumulation in the liver of wild-type (WT) mice, can provoke Sestrin2-deficient mice to develop severe ER stress-associated liver pathologies such as extensive liver damage, steatohepatitis and fibrosis. These pathologies are suppressed by liver-specific Sestrin2 reconstitution, mTORC1 inhibition or chemical chaperone administration. The Sestrin2-mediated unfolded protein response (UPR) may be a general protective mechanism against ER stress-associated diseases.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Hwan-Woo
authors.initials: HW
authors.lastname: Park
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Haeli
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Ro
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Insook
authors.initials: I
authors.lastname: Jang
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Semple
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Kim
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Myungjin
authors.initials: M
authors.lastname: Kim
authors.affiliation: 1] Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Biological Science, Gachon University of Medicine and Science, Yeonsugu, Incheon 406-799, Republic of Korea.
authors.forename: Myeongjin
authors.initials: M
authors.lastname: Nam
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Deqiang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005234:Fatty Liver / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology; D006706:Homeostasis; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000737:chemistry; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D046912:Multiprotein Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D010544:Peroxidases; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D056811:Unfolded Protein Response; D000084622:Sestrins
chemical_list: D055372:AMP-Activated Protein Kinases; D022782:CCAAT-Enhancer-Binding Protein-beta; D007328:Insulin; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D010544:Peroxidases; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; C465398:SESN2 protein, human; D000084622:Sestrins; C529380:Sesn2 protein, mouse