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

Abstract

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

Adipose-Specific Knockout of Seipin/Bscl2 Results in Progressive Lipodystrophy

“…Loss of SEIPIN function can change the quantity and/or distribution of certain lipids, such as PA (21). PAs could inhibit adipocyte differentiation by serving as highaffinity PPAR-g antagonists (31). In support of this hypothesis, Rosi treatment significantly improved a number of metabolic profiles of the ASKO mice and also rescued the adipogenic defect in Seipin 2/2 mouse embryonic fibroblasts, as shown recently (Fig.…”

Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum

“…PA has previously been shown to accumulate in tissues of lipin-1-deficient mice and contribute to impaired adipose tissue development and peripheral neuropathy in those animals (13,14). Recent studies have implicated tissue PA content in several aspects of metabolic homeostasis, including reductions in the expression and activation of peroxisome proliferator-activated receptor-γ (14,34), activation of ERK signaling (13), inhibition of mammalian target of rapamycin complex 2 (35), inflammatory signaling (36), and others (reviewed in ref. 37).…”

Lipin-1 Phosphatidic Phosphatase Activity Modulates Phosphatidate Levels to Promote Peroxisome Proliferator-activated Receptor γ (PPARγ) Gene Expression during Adipogenesis

“…In addition to their roles as building blocks for TAG biosynthesis, the intermediates in the glycerol phosphate pathway are bioactive lipids. A recent study on the rate-limiting enzyme of the pathway, GPAT1, demonstrated that the product of this enzyme (lysophosphatidic acid) increases PPAR␥ activity in Chinese hamster ovary cells, as assessed by a luciferase reporter assay (19). In contrast, overexpression of AGPAT2, the subsequent enzyme in the glycerolipid pathway, which utilizes lysophosphatidic acid as a substrate and converts it to PA, attenuated PPAR␥ activity.…”

“…PPAR␥ activity can be modulated by endogenous lipid ligands, including activation by oxidized fatty acids, and inhibition of PPAR␥ activity by cyclic phosphatidic acid (10,16,17). In addition, recent evidence indicates that enzymes of the glycerol 3-phosphate pathway for triglyceride biosynthesis may have roles in PPAR␥ activation and/or adipogenic gene expression (18,19). The activity of glycerol-3-phosphate acyltransferases, acylglycerol acyltransferases, and the lipin phosphatidate phosphatases (PAP) sequentially convert glycerol 3-phosphate to lysophosphatidic acid (glycerol-3-phosphate acyltransferases), then to phosphatidic acid (acylglycerol acyltransferases), and to diacylglycerol (lipins) (reviewed in Refs.…”