title: Cross-talk between TLR4-MyD88-NF-κB and SCAP-SREBP2 pathways mediates macrophage foam cell formation.
abstract: Myeloid differentiation factor 88 (MyD88) and NF-κB play central roles in mediating signal transduction of the Toll-like receptor (TLR) superfamily in human macrophages. The feedback regulation of LDL receptor (LDLR) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) are mediated by the sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP)-SREBP2 pathway and are key regulatory elements for cholesterol homeostasis in human cells. This study was designed to investigate cross-talk between TLR4-MyD88-NF-κB and SCAP-SREBP2 pathways in macrophage foam cell formation. phorbol 12-myristate 13-acetate-activated THP-1 macrophages were transfected with negative control or MyD88 small interfering (si)RNA. Transfected cells were incubated with LPS in the absence or presence of LDL or IκB kinase (IKK) inhibitor (BMS-345541). Intracellular cholesterol content was assessed. mRNA and protein expression of LDLR, HMG-CoAR, SCAP, and SREBP2 were examined by real-time RT-PCR and Western blot analysis. Intracellular translocation of SCAP in the organelles was detected by immunofluorecence and confocal microscopy. We demonstrated that LPS-induced cholesterol accumulation was attenuated by applying siRNA against MyD88 in the absence or presence of LDL. LPS increased both gene and protein expression of LDLR and HMG-CoAR by increasing expression and abnormal translocation of SCAP from the endoplasmic reticulum to the Golgi. These effects were blocked by knockdown of MyD88 or blockade of IKK or by knockdown of SCAP, suggesting that the cross-talk between NF-κB and SCAP plays an important role in macrophage foam cell formation and that interfering with the cross-talk might be a potential approach in preventing LPS-induced macrophage foam cell formation.
authors: John Moorhead Renal Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, London, United Kingdom.
authors: Lung-Chih
authors: LC
authors: Li
authors: Zac
authors: Z
authors: Varghese
authors: John F
authors: JF
authors: Moorhead
authors: Chien-Te
authors: CT
authors: Lee
authors: Jin-Bor
authors: JB
authors: Chen
authors: Xiong Z
authors: XZ
authors: Ruan
mesh_terms: D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D021381:Protein Transport; D011810:Quinoxalines / Q000494:pharmacology; D034741:RNA, Small Interfering; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; C507779:MYD88 protein, human; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011810:Quinoxalines; D034741:RNA, Small Interfering; D011973:Receptors, LDL; C497390:SREBF2 protein, human; C102196:SREBP cleavage-activating protein; D051782:Sterol Regulatory Element Binding Protein 2; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D051550:I-kappa B Kinase