title: Deletion of sphingosine kinase 1 ameliorates hepatic steatosis in diet-induced obese mice: Role of PPARγ.
abstract: Sphingolipid metabolites have emerged playing important roles in the pathogenesis of nonalcoholic fatty liver disease, whereas the underlying mechanism remains largely unknown. In the present study, we provide both in vitro and in vivo evidence showing a pathogenic role of sphingosine kinase 1 (SphK1) in hepatocellular steatosis. We found that levels of SphK1 expression were significantly increased in steatotic hepatocytes. Enforced overexpression of SphK1 or treatment with sphingosine 1-phosphate (S1P) markedly enhanced hepatic lipid accumulation. In contrast, the siRNA-mediated knockdown of SphK1 or S1P receptors, S1P2 and S1P3, profoundly inhibited lipid accumulation in hepatocytes. Moreover, Sphk1(-/-) mice exhibited a significant amelioration of hepatosteatosis under diet-induced obese (DIO) conditions, compared to wild-type littermates. In addition, DIO-induced up-regulation of PPARγ and its target genes were significantly reduced by SphK1 deficiency. Furthermore, treatment of hepatocytes with S1P induces a dose-dependent increase in PPARγ expression at the transcriptional level. Blockage of S1P receptors and the Akt-mTOR signaling profoundly inhibited S1P-induced PPARγ expression. Notably, down-regulation of PPARγ by using its siRNA significantly diminished the pro-steatotic effect of SphK1/S1P. Thus, the study demonstrates a new pathway connecting SphK1 and PPARγ involved in the pathogenesis of hepatocellular steatosis.
authors.affiliation: Centenary Institute, The University of Sydney, Sydney, Australia.
authors.forename: Jinbiao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Endocrinology and Metabolism, Zhongshan Hospital, and Institute of Chronic Metabolic Diseases, Fudan University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Centenary Institute, The University of Sydney, Sydney, Australia.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Centenary Institute, The University of Sydney, Sydney, Australia.
authors.forename: Dominik
authors.initials: D
authors.lastname: Kaczorowski
authors.affiliation: Centenary Institute, The University of Sydney, Sydney, Australia.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: McCaughan
authors.affiliation: Centenary Institute, The University of Sydney, Sydney, Australia.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Gamble
authors.affiliation: Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Don
authors.affiliation: Department of Endocrinology and Metabolism, Zhongshan Hospital, and Institute of Chronic Metabolic Diseases, Fudan University, Shanghai, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Centenary Institute, The University of Sydney, Sydney, Australia.
authors.forename: Mathew A
authors.initials: MA
authors.lastname: Vadas
authors.affiliation: Centenary Institute, The University of Sydney, Sydney, Australia; Department of Endocrinology and Metabolism, Zhongshan Hospital, and Institute of Chronic Metabolic Diseases, Fudan University, Shanghai, China. Electronic address: xiapu_fudan@163.com.
authors.forename: Pu
authors.initials: P
authors.lastname: Xia
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004041:Dietary Fats / Q000009:adverse effects; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000099157:Sphingosine Kinase
chemical_list: D004041:Dietary Fats; D008246:Lysophospholipids; D047495:PPAR gamma; D017853:Phosphotransferases (Alcohol Group Acceptor); D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D058570:TOR Serine-Threonine Kinases; D000099157:Sphingosine Kinase; C501285:S1pr3 protein, mouse; C060506:sphingosine 1-phosphate; C546843:mTOR protein, mouse
keywords: Hepatocytes; Nonalcoholic fatty liver disease; PPARγ; Sphingolipids; Sphingosine kinase 1