The nuclear receptor family PPAR is a group of ligand-activated transcription factors. The first member of this family, PPAR a, was identified as a mediator of the actions of hypolipidemic agents to induce the proliferation of peroxisomes in rodent liver. PPAR family was later implicated in versatile biological processes, including lipid homeostasis, regulation of inflammatory responses, macrophage differentiation and its functions. Moreover, PPAR seems closely linked to the diseases troubling modern people, such as diabetes, atherosclerosis and cancer. This has led enthusiastic research interests in the fields of not only basic biology, but also medical and pharmaceutical sciences. PPAR is probably activated by various lipid ligands, and mainly regulates in many tissues the expression of genes involved in lipid metabolism. The natural ligands and genuine functions of PPAR are still to be made clear. Accumulation of fundamental knowledge of the PPAR functions and development of novel ligands are expected to lead to efficient remedies.
This paper overview the general aspects of PPAR structure-function studies, from the history of its discovery to the applications in future.

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Peroxisome proliferator-activated receptors, PPARs, are members of nuclear hormone recptor superfamily implicated in energy homeostatis including lipid metabolism. On activation by binding of ligand, these ligand-PPARs complexes as transcription factors stimulated gene expression by binding to the promoter of target genes. The different structural domains of PPARs are present in terms of activation mechanisms, namely ligand binding-, phosphorylation-and cofactor interaction-domain, PPAR has three isoforms, a, /3 (5) and y, and each isoform shows different ligand specificity and tissue distribution. In ligands activating PPARs many structural divers compounds, such as fatty acids, eicosanoids, hypolipidemic drugs and thiazolidinediones (TZD) are involved. Threfore, it has been recognized that PPARs relate to cellular energy homeostasis as a regulatory factor of lipid metabolism. The name, PPAR is originated from “peroxisome proliferators”. Peroxisome proliferators are a large group of chemicals which, when fed to rodents, results in a characteristic hepatomegaly, peroxisome proliferation in parenchymal cells, and induction of non-genotoxic hepatocarcinoma. As a mechanim of peroxisome proliferator-induced carcinogenesis, oxidative stress and disruption of the regulation of cell growth/development process has been noticed. Now, it is elucidated that PPAR plays an essential role in peroxisome proliferator-induced hepatocarcinogenesis through the study using a knockout mouse.

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SREBPs (Sterol Regulatory Element-binding Proteins) regulate the transcription of genes encoding proteins and enzymes involved in cholesterol or fatty acid metabolism. There exist two isoforms, SREBP-1 and-2, with 47% amino acid homology. Unlike other members of the basic helix-loop-helix leucine zipper (bHLH-Zip) family, SREBPs are synthesized as precursors bound to the ER membrane and nuclear envelope. The transcriptionally active NH₂-terminal portion including the bHLH-Zip domain is released from the membrane by two-step proteolysis. Among the SREBP family members, SREBP 1 mainly regulates fatty acid metabolism. The alternative splicing generates SREBP la and lc, the latter lacks 24 amino acids in the NH₂-terminal transactivation domain, thereby being a weaker transcription factor than la. Their responsive genes include fatty acid synthase, acetyl CoA carboxylase, ATP citrate-lyase, stearoyl CoA desaturase, glycerol-3-phosphate acyltransferase gene. Recent studies demonstrate that unsaturated fatty acids downregulate the SREBP 1 activities, but that the precise regulatory mechanism remains unclear. It is noted that both cholesterol and fatty acid metabolism are coordinately regulated through the actions of the SREBPs.

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To date, there have been accumulated the numerous reports suggesting the significant roles of sphingomyelin metabolism in the intracellular signal transduction such as the apoptosis pathway. Despite extensive studies, however, the precise function of each enzyme is still obscure and some of observations appear to be controversial. The confusions could be partially due to the insufficient information concerning molecular species, structures, and functions of sphingomyelin metabolic enzymes. Therefore, in this article, I tried to overview the pathophysiological significance of sphingomyelin metabolic enzymes from the viewpoint of protein structures. Serine palmitoyltransferase which is responsible for the first step in the sphingomyelin synthetic pathway, and sphingomyelinase and ceramidase which are responsible for the first and second steps in the sphingomyelin hydrolytic pathway are mainly described.

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All aerobic organisms from bacteria to mammals use oxgen to generate energy but at the same time produce various reactive oxygen species (ROS). The ROS causes cell injury by interacting with nucleic acid, proteins, lipids and carbohydrates, occasionally leading to cell death (necrosis and apoptosis). Therefore, these organisms are endowed with extensive antioxidant defensive mechanisms against the damaging effects caused by ROS. The protective enzymes include superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT), whereas the non-enzymatic protective substances include a-tocopherol, /3-carotene and flavonoids. The oxidative stress due to imbalance of the redox governed by levels of the oxidative and antioxidative molecules undergoes changes in the intracellular signal transduction. Hydrogen peroxide (H₂O₂) is often employed as a model molecule of ROS, since it can easily permeate the plasma membrane and the oxidative state can be modulated. This article will focus on the H₂O₂-mediated lipid signaling with special reference to phospholipase D (PLD) and also will discuss some other topics in lipid signaling.

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