title: Porphyromonas gingivalis lipopolysaccharide increases lipid accumulation by affecting CD36 and ATP-binding cassette transporter A1 in macrophages.
abstract: Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS) promotes macrophage-derived foam cell formation, however, the mechanisms are not well established. In macrophages, lipid uptake is mediated by scavenger receptors including SR-A and CD36, while the cholesterol efflux is mediated by ATP-binding cassette transporter G1 (ABCG1), ABCA1 and SR-BI. We further investigated the mechanisms underlying the dysregulation by P. gingivalis LPS of these regulators resulting in the promotion of lipid accumulation in THP-1-derived macrophages. Our results showed that P. gingivalis LPS exacerbated lipid accumulation in oxidized low-density lipoprotein (oxLDL)-treated macrophages. However, cholesterol efflux was inhibited by P. gingivalis LPS in THP-1-derived macrophages. In oxLDL-untreated macrophages, P. gingivalis LPS treatment caused an increase in CD36 mRNA and protein levels, and a decrease in ABCA1 mRNA and protein levels, while having no effect on SR-A, SR-BI or ABCG1 expression. Upregulation of CD36 by P. gingivalis LPS resulted from activation of c-Jun/AP-1, and this was confirmed by the inhibition of increased CD36 expression after AP-1 inhibition using SP600125. However, the decreased protein stability of ABCA1 by P. gingivalis LPS was a result of increased calpain activity. Moreover, small hairpin RNA (shRNA) targeting heme oxygenase-1 (HO-1) augmented the P. gingivalis LPS-induced atherogenic effects on the expression of c-Jun/AP-1, CD36, ABCA1 and calpain activity. Accordingly, P. gingivalis LPS-regulated promotion of lipid accumulation in foam cells was also exacerbated by HO-1 shRNA. These results indicate that P. gingivalis LPS confers a exacerbation effect on the formation of foam cells by a novel HO-1-dependent mediation of cholesterol efflux and lipid accumulation in macrophages.
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China.
authors.forename: Xiu-Ying
authors.initials: XY
authors.lastname: Li
authors.forename: Chun
authors.initials: C
authors.lastname: Wang
authors.forename: Xue-Rong
authors.initials: XR
authors.lastname: Xiang
authors.forename: Fang-Chun
authors.initials: FC
authors.lastname: Chen
authors.forename: Cong-Ming
authors.initials: CM
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D050356:Lipid Metabolism / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016966:Porphyromonas gingivalis / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D051547:Heme Oxygenase-1