%0 Journal Article
%T PPAR¦Ă Networks in Cell Signaling: Update and Impact of Cyclic Phosphatidic Acid
%A Tamotsu Tsukahara
%J Journal of Lipids
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/246597
%X Lysophospholipid (LPL) has long been recognized as a membrane phospholipid metabolite. Recently, however, the LPL has emerged as a candidate for diagnostic and pharmacological interest. LPLs include lysophosphatidic acid (LPA), alkyl glycerol phosphate (AGP), cyclic phosphatidic acid (cPA), and sphingosine-1-phosphate (S1P). These biologically active lipid mediators serve to promote a variety of responses that include cell proliferation, migration, and survival. These LPL-related responses are mediated by cell surface G-protein-coupled receptors and also intracellular receptor peroxisome proliferator-activated receptor gamma (PPAR¦Ă). In this paper, we focus mainly on the most recent findings regarding the biological function of nuclear receptor-mediated lysophospholipid signaling in mammalian systems, specifically as they relate to health and diseases. Also, we will briefly review the biology of PPAR¦Ă and then provide an update of lysophospholipids PPAR¦Ă ligands that are under investigation as a therapeutic compound and which are targets of PPAR¦Ă relevant to diseases. 1. Introduction Peroxisome proliferator-activated receptor gamma (PPAR¦Ă) is a member of the nuclear hormone receptor superfamily, many of which function as ligand-activated transcription factors [1]. Synthetic agonists of PPAR¦Ă include the thiazolidinedione (TZD) class of drugs, which are widely used to improve insulin sensitivity in type II diabetes. Despite the beneficial effects of PPAR¦Ă on glucose and lipid homeostasis, excess PPAR¦Ă activity can be deleterious. These classical PPAR¦Ă agonists elicit a variety of side effects, including weight gain, edema, increased fat mass, and tumor formation in rodents [2]. In contrast, there have been many reports in which the putative physiological agonists of PPAR¦Ă have been identified [3¨C5]. LPA is a naturally occurring phospholipid with growth-like effects in almost every mammalian cell type. LPAs elicit their biological responses through eight plasma membrane receptors [6] and intracellularly through the PPAR¦Ă [3, 4]. Although LPA derived from hydrolysis of plasma membrane phospholipids is established as a ligand for G-coupled cell surface LPA receptor, studies suggested that LPA might also enter cells to activate PPAR¦Ă. PPAR¦Ă plays a role in regulating lipid and glucose homeostasis, cell proliferation, apoptosis, and inflammation [7, 8]. These pathways have a direct impact on human diseases in obesity, diabetes, atherosclerosis, and cancer [9¨C11]. On the other hand, cyclic phosphatidic acid (cPA), similar in structure to LPA, can be generated
%U http://www.hindawi.com/journals/jl/2013/246597/