title: Downregulation of liver X receptor-alpha in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines.
abstract: The acute-phase response (APR) suppresses type II nuclear hormone receptors and alters the expression of their target genes involved in lipid metabolism in the liver and heart. Therefore, we examined the expression of liver X receptor/retinoid X receptor (LXR/RXR) and their target genes in kidney from mice treated with lipopolysaccharide (LPS) and in human proximal tubular HK-2 cells treated with interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). We found that LXRalpha and RXRalpha expression was suppressed by LPS in kidney and by IL-1beta or TNF-alpha in HK-2 cells. The decrease in LXRalpha/RXRalpha expression was associated with a decrease in the expression of several LXRalpha target genes [apolipoprotein E (apoE), ABCA1, ABCG1, and sterol-regulatory element binding protein-1c (SREBP-1c)] and a decrease in ligand-induced apoE expression. Moreover, IL-1beta and TNF-alpha significantly reduced liver X receptor response element (LXRE)-driven transcription as measured by LXRE-linked luciferase activity. However, overexpression of LXRalpha/RXRalpha only partially restored the cytokine-mediated reduction in LXRE-linked luciferase activity. Additionally, expression of the LXR coactivators peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC1alpha) and steroid receptor coactivator-2 (SRC-2) was decreased by IL-1beta or TNF-alpha. We conclude that the APR suppresses the expression of both nuclear receptors LXRalpha/RXRalpha and several LXRalpha coactivators in kidney, which could be a mechanism for coordinately regulating the expression of multiple LXR target genes that play important roles in lipid metabolism in kidney during the APR.
authors.affiliation: Department of Medicine, University of California San Francisco, CA 94121, USA.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Wang
authors.forename: Arthur H
authors.initials: AH
authors.lastname: Moser
authors.forename: Judy K
authors.initials: JK
authors.lastname: Shigenaga
authors.forename: Carl
authors.initials: C
authors.lastname: Grunfeld
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Feingold
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D015152:Blotting, Northern; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D051548:Histone Acetyltransferases; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000166:cytology*; D008070:Lipopolysaccharides / Q000378:metabolism*; D000071518:Liver X Receptors; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015233:Models, Statistical; D056920:Nuclear Receptor Coactivator 1; D057093:Orphan Nuclear Receptors; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D016207:Cytokines; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D006360:Heat-Shock Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D047490:Retinoid X Receptor alpha; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D008156:Luciferases; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1