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.

CD36 is upregulated in mice with periodontitis and metabolic syndrome and involved in macrophage gene upregulation by palmitate

“…We tested our hypothesis that SFA, which is rich in the HFD used in our animal study and involved in the pathogenesis of MetS (Phillips et al , ), acts with LPS to upregulate CD36 expression in macrophages. The finding from this study supports our hypothesis as it showed that while either palmitate or LPS‐stimulated CD36 expression, which is in agreement with the previous reports (Chabowski et al , ; Li et al , ; Pararasa et al , ), the combination of palmitate and LPS stimulated CD36 expression to a higher level. As it is known that SFA is increased in MetS patients (Rivellese et al , ; Tuomilehto, ) and MetS mice (Morselli et al , ), and LPS is increased in patients with periodontitis, palmitate and LPS are likely to act in concert to stimulate CD36 expression in patients or mice with both MetS and periodontitis.…”

Silencing Triggering Receptors Expressed on Myeloid Cells-1 Impaired the Inflammatory Response to Oxidized Low-Density Lipoprotein in Macrophages

“…The role of SRA and CD36 in recognition and internalization of modified lipoproteins has been extensively studied [20]. However, the role of TLRs, the major receptors that detect and respond to bacteria and its product, has been less studied in the inflammatory response to oxLDL.…”

Periodontitis: from microbial immune subversion to systemic inflammation

“…Such autoantibodies can be induced in response to bacterial epitopes — such as those found in P. gingivalis arginine-specific gingipains and T. denticola phosphoglycerate kinase — that bear homology to the TLRVYK peptide of the phospholipid-binding serum protein β2-glycoprotein-I 119,120 . Furthermore, P. gingivalis enhances low-density lipoprotein-uptake and foam cell formation by upregulating CD36 (a scavenger receptor mediating lipid uptake) and downregulating ATP-binding cassette transporter A1 (which mediates the efflux of cholesterol from macrophages) 121,122 . In a similar context, the pathogen induces vascular smooth-muscle-cell proliferation leading to neo-intima formation, and stimulates production of matrix metalloproteinases that contribute to plaque rupture and thrombotic vessel occlusion 6 ( FIG.…”