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 gamma (PPAR gamma) plays a major regulatory role in adipogenesis and in the expression of genes involved in lipid metabolism. Activation of PPAR gamma 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 PPAR gamma activation and its downstream target gene expression profiles in HepG2 cells. We demonstrated that SAA could activate PPAR gamma 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-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), which is a potent natural ligand for PPAR gamma. Our data suggested that SAA activated PPAR gamma 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 PPAR gamma. Additionally, the data from our study have also provided new insights into the role of SA A in cholesterol efflux.