Lysophosphatidic Acid Activates Peroxisome Proliferator Activated Receptor-γ in CHO Cells That Over-Express Glycerol 3-Phosphate Acyltransferase-1

Lysophosphatidic acid (LPA) is an agonist for peroxisome proliferator activated receptor-gamma (PPAR gamma). 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 PPAR gamma 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 PPAR gamma target, was 2-fold higher. Transactivation assays showed that PPAR gamma activity was higher in the cells that overexpressed GPAT1. PPAR gamma activity was enhanced further in CHO-GPAT1 cells treated with the PPAR gamma ligand troglitazone. Extracellular LPA, phosphatidic acid (PA) or a membrane-permeable diacylglycerol had no effect, showing that PPAR gamma 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 PPAR gamma activity, as did over-expressing diacylglycerol kinase, which converts DAG to PA, indicating that PA could be a potent inhibitor of PPAR gamma. These data suggest that LPA synthesized via the glycerol-3-phosphate pathway can activate PPAR gamma and that intermediates of de novo glycerolipid synthesis regulate gene expression.