Acta Pharmacologica Sinica 2006 September; 27 (9): 1146-1152; doi: 10.1111/j.1745-7254.2006.00359.x

Aim: To investigate whether oxidized low-density lipoprotein (ox-LDL) modulates peroxisome proliferator-activated receptor g (PPARg) activity through phosphorylation in macrophages, and the effect of PPARg phosphorylation on macrophages-derived foam cell formation.

Methods: After exposing the cultured THP-1 cells to ox-LDL in the presence or absence of different mitogen-activated protein kinase (MAPK) inhibitors, PPARg and phosphorylated PPARg protein levels were detected by Western blot. MAPK activity was analyzed using MAP Kinase Assay Kit. Intracellular cholesterol accumulation was assessed by Oil red O staining and cholesterol oxidase enzymatic method. The mRNA level of PPARg target gene was determined by reverse transcription-polymerase chain reaction (RT-PCR).

Results: ox-LDL evaluated PPARg phosphorylation status and subsequently decreased PPARg target gene expression in a dose-dependent manner. ox-LDL also induced MAPK activation. Treatment of THP-1 cells with c-Jun N-terminal kinase-, but not p38- or extracellular signal-regulated kinase-MAPK inhibitor, significantly suppressed PPARg phosphorylation induced by ox-LDL, which in turn inhibited foam cell formation.

Conclusion: In addition to its ligand-dependent activation, ox-LDL modulates PPARg activity through phosphorylation, which is mediated by MAPK activation. PPARg phosphorylation mediated by MAPK facilitates foam cell formation from macrophages exposed to ox-LDL.

Keywords: peroxisome proliferator-activated receptor g; phosphorylation; macrophages; LDL lipoprotein