Peroxisome proliferator-activated receptor delta(PPAR-delta), or (PPAR-beta), also known as Nuclear hormone receptor 1(NUC1) is a nuclear receptor that in humans is encoded by the PPARD gene. [5]
This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) family. It was first identified in Xenopus in 1993. [6]
PPAR-delta is a nuclear hormone receptor that governs a variety of biological processes and may be involved in the development of several chronic diseases, including diabetes, obesity, atherosclerosis, and cancer. [7] [8]
In muscle PPARD expression is increased by exercise, resulting in increased oxidative (fat-burning) capacity and an increase in type I fibers. [9] Both PPAR-delta and AMPK agonists are regarded as exercise mimetics. [10] In adipose tissue PPAR-β/δ increases both oxidation as well as uncoupling of oxidative phosphorylation. [9]
PPAR-delta may function as an integrator of transcription repression and nuclear receptor signaling. It activates transcription of a variety of target genes by binding to specific DNA elements. Well described target genes of PPARδ include PDK4, ANGPTL4, PLIN2, and CD36. The expression of this gene is found to be elevated in colorectal cancer cells. [11] The elevated expression can be repressed by adenomatosis polyposis coli (APC), a tumor suppressor protein involved in the APC/beta-catenin signaling pathway. Knockout studies in mice suggested the role of this protein in myelination of the corpus callosum, epidermal cell proliferation, and glucose [12] and lipid metabolism. [13]
This protein has been shown to be involved in differentiation, lipid accumulation, [14] directional sensing, polarization, and migration in keratinocytes. [15]
Studies into the role of PPAR-delta in cancer have produced contradictory results. Although there is some controversy, the majority of studies have suggested that PPAR-delta activation could result in changes that are favorable to cancer progression. [16] PPAR-delta favours tumour angiogenesis. [17]
PPAR-delta is highly expressed in many tissues, including colon, small intestine, liver and keratinocytes, as well as in heart, spleen, skeletal muscle, lung, brain and thymus. [18]
Knockout mice lacking the ligand binding domain of PPAR-delta are viable. However, these mice are smaller than the wild type both neo and postnatally. In addition, fat stores in the gonads of the mutants are smaller. The mutants also display increased epidermal hyperplasia upon induction with TPA. [19]
PPAR-delta is activated in the cell by various fatty acids and fatty acid derivatives. [7] Examples of naturally occurring fatty acids that bind with and activate PPAR-delta include arachidonic acid and certain members of the 15-hydroxyicosatetraenoic acid family of arachidonic acid metabolites including 15(S)-HETE, 15(R)-HETE, and 15-HpETE. [20] Several high affinity ligands for PPAR-delta have been developed, including GW501516 and GW0742, which play an important role in research. In one study utilizing such a ligand, it has been shown that agonism of PPARδ changes the body's fuel preference from glucose to lipids. [21] Initially, PPAR-delta agonists were considered promising therapies as an exercise mimetic that could treat metabolic syndrome, but later on more evidence was uncovered about their possible pro-cancer effects. [16]
The atypical antidepressant Tianeptine has been shown to be a high-efficacy PPAR-delta agonist. [22]
Although its drug development was discontinued due to animal studies suggesting an increased risk of cancer, GW501516 has been used as a performance enhancing drug. [25] It and other PPAR-delta agonists are banned in sports. [26] [27]
Peroxisome proliferator-activated receptor delta has been shown to interact with HDAC3 [28] [29] and NCOR2. [29]
The thiazolidinediones, abbreviated as TZD, also known as glitazones after the prototypical drug ciglitazone, are a class of heterocyclic compounds consisting of a five-membered C3NS ring. The term usually refers to a family of drugs used in the treatment of diabetes mellitus type 2 that were introduced in the late 1990s.
In the field of molecular biology, the peroxisome proliferator–activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism, and tumorigenesis of higher organisms.
The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.
The fatty-acid-binding proteins (FABPs) are a family of transport proteins for fatty acids and other lipophilic substances such as eicosanoids and retinoids. These proteins are thought to facilitate the transfer of fatty acids between extra- and intracellular membranes. Some family members are also believed to transport lipophilic molecules from outer cell membrane to certain intracellular receptors such as PPAR. The FABPs are intracellular carriers that “solubilize” the endocannabinoid anandamide (AEA), transporting AEA to the breakdown by FAAH, and compounds that bind to FABPs block AEA breakdown, raising its level. The cannabinoids are also discovered to bind human FABPs that function as intracellular carriers, as THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. Levels of fatty-acid-binding protein have been shown to decline with ageing in the mouse brain, possibly contributing to age-associated decline in synaptic activity.
Peroxisome proliferator-activated receptor gamma, also known as the glitazone reverse insulin resistance receptor, or NR1C3 is a type II nuclear receptor functioning as a transcription factor that in humans is encoded by the PPARG gene.
Obesogens are certain chemical compounds that are hypothesised to disrupt normal development and balance of lipid metabolism, which in some cases, can lead to obesity. Obesogens may be functionally defined as chemicals that inappropriately alter lipid homeostasis and fat storage, change metabolic setpoints, disrupt energy balance or modify the regulation of appetite and satiety to promote fat accumulation and obesity.
Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1, is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the PPARA gene. Together with peroxisome proliferator-activated receptor delta and peroxisome proliferator-activated receptor gamma, PPAR-alpha is part of the subfamily of peroxisome proliferator-activated receptors. It was the first member of the PPAR family to be cloned in 1990 by Stephen Green and has been identified as the nuclear receptor for a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes.
Liver X receptor alpha (LXR-alpha) is a nuclear receptor protein that in humans is encoded by the NR1H3 gene.
Estrogen-related receptor alpha (ERRα), also known as NR3B1, is a nuclear receptor that in humans is encoded by the ESRRA gene. ERRα was originally cloned by DNA sequence homology to the estrogen receptor alpha, but subsequent ligand binding and reporter-gene transfection experiments demonstrated that estrogens did not regulate ERRα. Currently, ERRα is considered an orphan nuclear receptor.
Angiopoietin-like 4 is a protein that in humans is encoded by the ANGPTL4 gene. Alternatively spliced transcript variants encoded with different isoforms have been described. This gene was previously referred to as ANGPTL2, HFARP, PGAR, or FIAF but has been renamed ANGPTL4.
Peroxisome proliferator-activated receptor gamma coactivator 1-beta is a protein that in humans is encoded by the PPARGC1B gene.
Oleoylethanolamide (OEA) is an endogenous peroxisome proliferator-activated receptor alpha (PPAR-α) agonist. It is a naturally occurring ethanolamide lipid that regulates feeding and body weight in vertebrates ranging from mice to pythons.
GW501516 is a PPARδ receptor agonist that was invented in a collaboration between Ligand Pharmaceuticals and GlaxoSmithKline in the 1990s. It entered into clinical development as a drug candidate for metabolic and cardiovascular diseases, but was abandoned in 2007 because animal testing showed that the drug caused cancer to develop rapidly in several organs.
PPAR agonists are drugs which act upon the peroxisome proliferator-activated receptor. They are used for the treatment of symptoms of the metabolic syndrome, mainly for lowering triglycerides and blood sugar.
Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, and lipid modulator.
Pirinixic acid is a peroxisome proliferator-activated receptor alpha (PPARα) agonist that is under experimental investigation for prevention of severe cardiac dysfunction, cardiomyopathy and heart failure as a result of lipid accumulation within cardiac myocytes. Treatment is primarily aimed at individuals with an adipose triglyceride lipase (ATGL) enzyme deficiency or mutation because of the essential PPAR protein interactions with free fatty acid monomers derived from the ATGL catalyzed lipid oxidation reaction. It was discovered as WY-14,643 in 1974.
Tetradecylthioacetic acid (TTA) is a synthetic fatty acid used as a nutritional supplement.
GW0742 is a PPARδ/β agonist that has been investigated for drug use by GlaxoSmithKline.
A selective PPAR modulator (SPPARM) is a selective receptor modulator of the peroxisome proliferator-activated receptor (PPAR). Examples include SPPARMs of the PPARγ, BADGE, EPI-001, INT-131, MK-0533, and S26948.
Walter Wahli, born on 23 May 1946 in Moutier, Switzerland, is a distinguished biologist and professor. He has held academic positions at the University of Lausanne and at Nanyang Technological University of Singapore. Wahli's research has contributed to the understanding of metabolic regulation through gene expression. He is particularly recognized for his work on nuclear receptors, specifically the Peroxisome proliferator-activated Receptors (PPARs), which play a crucial role in regulating the body's energy balance.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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