Lysophosphatidic Acid Activates Peroxisome Proliferator Activated Receptor-c in CHO Cells That Over-Express

Lysophosphatidic acid (LPA) is an agonist for peroxisome proliferator activated receptor-c (PPARc). Although glycerol-3-phosphate acyltransferase-1 (GPAT1) esterifies glycerol-3-phosphate to form LPA, an intermediate in the de novo synthesis of glycerolipids, it has been assumed that LPA synthesized by this route does not have a signaling role. The availability of Chinese Hamster Ovary (CHO) cells that stably overexpress GPAT1, allowed us to analyze PPARc activation in the presence of LPA produced as an intracellular intermediate. LPA levels in CHO-GPAT1 cells were 6-fold higher than in wild-type CHO cells, and the mRNA abundance of CD36, a PPARc target, was 2-fold higher. Transactivation assays showed that PPARc activity was higher in the cells that overexpressed GPAT1. PPARc activity was enhanced further in CHO-GPAT1 cells treated with the PPARc ligand troglitazone. Extracellular LPA, phosphatidic acid (PA) or a membrane-permeable diacylglycerol had no effect, showing that PPARc had been activated by LPA generated intracellularly. Transient transfection of a vector expressing 1-acylglycerol-3-phosphate acyltransferase-2, which converts endogenous LPA to PA, markedly reduced PPARc activity, as did over-expressing diacylglycerol kinase, which converts DAG to PA, indicating that PA could be a potent inhibitor of PPARc. These data suggest that LPA synthesized via the glycerol-3-phosphate pathway can activate PPARc an