Serum amyloid A activates peroxisome proliferator-activated receptor γ through extracellularly regulated kinase 1/2 and COX-2 expression in hepatocytes.
Serum amyloid A (SAA) is an acute phase protein whose level of expression increases markedly during bacterial infection, tissue damage, and inflammation. The potential beneficial roles of SAA include its involvement in reverse cholesterol transport and possibly extracellular lipid deposition at sites of inflammation and tissue repair. It is an attractive therapeutic target for the treatment of atherosclerosis. Peroxisome proliferator-activated receptor γ (PPARγ) plays a major regulatory role in adipogenesis and in the expression of genes involved in lipid metabolism. Activation of PPARγ leads to multiple changes in gene expression, some of which are believed to be atherogenic while others are antiatherogenic. In this study, we investigated the effects of SAA on PPARγ activation and its downstream target gene expression profiles in HepG2 cells. We demonstrated that SAA could activate PPARγ transcriptional activity. Preincubation of HepG2 cells with SAA enhanced the efflux of cholesterol to HDL and apoA-I. In addition, SAA increased the level of intracellular 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), which is a potent natural ligand for PPARγ. Our data suggested that SAA activated PPARγ through extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent COX-2 expression. Furthermore, SAA-induced cholesterol efflux was suppressed when the ERK1/2 pathway or COX-2 was inhibited. Overall, our study has established, for the first time, a relationship between SAA and PPARγ. Additionally, the data from our study have also provided new insights into the role of SAA in cholesterol efflux.
Li
Hongzhe
H
Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Zhao
Yulan
Y
Zhou
Shuli
S
Heng
Chew-Kiat
CK
D002784:Cholesterol / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D015533:Transcriptional Activation
C477819:15-deoxyprostaglandin J2; D047495:PPAR gamma; D000685:Serum Amyloid A Protein; D002784:Cholesterol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015230:Prostaglandin D2