title: Liver X receptor α induces 17β-hydroxysteroid dehydrogenase-13 expression through SREBP-1c.
abstract: Liver X receptors, including LXRα and LXRβ, are known to be master regulators of liver lipid metabolism. Activation of LXRα increases hepatic lipid storage in lipid droplets (LDs). 17β-Hydroxysteroid dehydrogenase-13 (17β-HSD13), a recently identified liver-specific LD-associated protein, has been reported to be involved in the development of nonalcoholic fatty liver disease. However, little is known about its transcriptional regulation. In the present study, we aimed at determining whether 17β-HSD13 gene transcription is controlled by LXRs. We found that treatment with T0901317, a nonspecific LXR agonist, increased both 17β-HSD13 mRNA and protein levels in cultured hepatocytes. It also significantly upregulated hepatic 17β-HSD13 expression in wild-type (WT) and LXRβ-/-mice but not in LXRα-/-mice. Basal expression of 17β-HSD13 in the livers of LXRα-/-mice was lower than that in the livers of WT and LXRβ-/-mice. Moreover, induction of hepatic 17β-HSD13 expression by T0901317 was almost completely abolished in SREBP-1c-/-mice. Bioinformatics analysis revealed a consensus sterol regulatory element (SRE)-binding site in the promoter region of the 17β-HSD13 gene. A 17β-HSD13 gene promoter-driven luciferase reporter and ChIP assays further confirmed that the 17β-HSD13 gene was under direct control of SREBP-1c. Collectively, these findings demonstrate that LXRα activation induces 17β-HSD13 expression in a SREBP-1c-dependent manner. 17β-HSD13 may be involved in the development of LXRα-mediated fatty liver.
authors.affiliation: Center for Nephrology and Urology, Department of Physiology, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China.|AstraZeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Health Science Center, Shenzhen, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Su
authors.affiliation: Center for Nephrology and Urology, Department of Physiology, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas.
authors.forename: Yu-Bing
authors.initials: YB
authors.lastname: Dai
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
authors.forename: Chun-Jiong
authors.initials: CJ
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.|Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China; and.
authors.forename: Hu
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.affiliation: Center for Nephrology and Urology, Department of Physiology, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China.|AstraZeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Health Science Center, Shenzhen, China.
authors.forename: Xiong-Zhong
authors.initials: XZ
authors.lastname: Ruan
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas.|Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China; and.|Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Stockholm, Sweden.
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.affiliation: AstraZeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Health Science Center, Shenzhen, China.|Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China; and.
authors.forename: You-Fei
authors.initials: YF
authors.lastname: Guan
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China; and wserien@163.com.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zhang
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D066292:Lipid Droplets / Q000378:metabolism; D000071518:Liver X Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D015533:Transcriptional Activation; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D015067:17-Hydroxysteroid Dehydrogenases; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase
keywords: 17β-HSD13; SCDR9; gene knockout; lipid droplet; nonalcoholic fatty liver disease; nuclear receptor