title: Sphingosine Kinase 1 Protects Hepatocytes from Lipotoxicity via Down-regulation of IRE1α Protein Expression.
abstract: Aberrant deposition of fat including free fatty acids in the liver often causes damage to hepatocytes, namely lipotoxicity, which is a key pathogenic event in the development and progression of fatty liver diseases. This study demonstrates a pivotal role of sphingosine kinase 1 (SphK1) in protecting hepatocytes from lipotoxicity. Exposure of primary murine hepatocytes to palmitate resulted in dose-dependent cell death, which was enhanced significantly in Sphk1-deficient cells. In keeping with this, expression of dominant-negative mutant SphK1 also markedly promoted palmitate-induced cell death. In contrast, overexpression of wild-type SphK1 profoundly protected hepatocytes from lipotoxicity. Mechanistically, the protective effect of SphK1 is attributable to suppression of ER stress-mediated pro-apoptotic pathways, as reflected in the inhibition of IRE1α activation, XBP1 splicing, JNK phosphorylation, and CHOP induction. Of note, SphK1 inhibited the IRE1α pathway by reducing IRE1α expression at the transcriptional level. Moreover, S1P mimicked the effect of SphK1, suppressing IRE1α expression in a receptor-dependent manner. Furthermore, enforced overexpression of IRE1α significantly blocked the protective effect of SphK1 against lipotoxicity. Therefore, this study provides new insights into the role of SphK1 in hepatocyte survival and uncovers a novel mechanism for protection against ER stress-mediated cell death.
authors.affiliation: From the Signal Transduction Program, Centenary Institute, University of Sydney, Sydney, NSW 2042, Australia and.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Qi
authors.affiliation: the Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: From the Signal Transduction Program, Centenary Institute, University of Sydney, Sydney, NSW 2042, Australia and.
authors.forename: Jinbiao
authors.initials: J
authors.lastname: Chen
authors.affiliation: From the Signal Transduction Program, Centenary Institute, University of Sydney, Sydney, NSW 2042, Australia and.
authors.forename: Lan
authors.initials: L
authors.lastname: Dai
authors.affiliation: From the Signal Transduction Program, Centenary Institute, University of Sydney, Sydney, NSW 2042, Australia and.
authors.forename: Dominik
authors.initials: D
authors.lastname: Kaczorowski
authors.affiliation: the Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: From the Signal Transduction Program, Centenary Institute, University of Sydney, Sydney, NSW 2042, Australia and the Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China xiapu_fudan@163.com.
authors.forename: Pu
authors.initials: P
authors.lastname: Xia
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D004722:Endoribonucleases / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019308:Palmitic Acid / Q000009:adverse effects* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D000071717:X-Box Binding Protein 1; D000099157:Sphingosine Kinase
chemical_list: D004268:DNA-Binding Proteins; D004722:Endoribonucleases; D004791:Enzyme Inhibitors; D048670:MAP Kinase Kinase 4; D019308:Palmitic Acid; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D000099157:Sphingosine Kinase; C000605544:Xbp1 protein, mouse; C510185:Ern1 protein, mouse
keywords: IRE1α; endoplasmic reticulum stress (ER stress); hepatocytes; lipotoxicity; sphingolipid; sphingosine kinase (SphK); unfolded protein response (UPR)