Peroxisome Proliferator-Activated Receptors, PPARs

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The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors is composed of three family members: PPARα, PPARβ/δ (most commonly identified as PPARδ), and PPARγ. This transcription factor family was first identified in studies examining the cholesterol-lowering effects of fibrates. The fibrates effect their cholesterol lowering response via increased hepatic fatty acid oxidation. This increase in oxidation results from proliferation of the density of peroxisomes in hepatocytes. Hence the identification of the target of fibrates as the peroxisome proliferator-activated receptor (PPAR). Whereas, PPARα is indeed a transcription factor whose activation results in proliferation of peroxisomes, the activation of PPARδ or PPARγ does not lead to peroxisome proliferation. Thus, the latter two members of the family are related only by amino acid sequence identity not by absolute function.

The PPARs form permissive heterodimers with the RXRs and as such can regulate gene expression either upon binding PPAR ligands or RXR ligands. The PPAR/RXR heterodimers bind to PPAR-responsive elements (PPREs) in target DNA that consist of direct repeats (DRs) with the core sequence AGG(A/T)CA separated by one or two base-pairs, designated DR1 and DR2, respectively. The domain structures of the PPARs are similar to other members of the nuclear receptor family of transcriptional regulators. Each PPAR has a DNA-binding domain (DBD) and a ligand-binding domain (LBD). Both the DBD and LBD are highly conserved among the three PPARs. The LBD of the PPARs is large and can accommodate a variety of endogenous lipids that includes fatty acids, eicosanoids, derivatives of the essential fatty acid linoleic acid, as well as oxidized and nitrated fatty acids. Although each of these different types of lipid have been shown to bind to PPARs, the concentration required is generally higher than would be encountered in vivo and thus, whether any represent the physiological ligand is still yet to be conclusively determined.

In the absence of ligand the PPAR/RXR heterodimer resides in the nucleus bound to PPREs in a complex with transcriptional co-repressors such as silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and nuclear receptor co-repressor (N-CoR). Nuclear receptors that reside in the nucleus in the absence of activating ligand are classified as type II nuclear receptors, whereas, nuclear receptors that reside in the cytosol until engaging ligand are classified as type I nuclear receptors. Upon ligand binding to PPARs there is a conformational change in the complex that facilitates a co-repressor for co-activator complex exchange and transcriptional activation of target genes. One of the primary co-activators of the PPARs is peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α). Following the identification of PGC-1α, two additional related co-activators were characterized. These related co-activators are identified as PGC-1β (also called PGC-1-related estrogen receptor-α coactivator; PERC) and PGC-1-related co-activator (PRC). PGC-1α and PGC-1β are highly expressed in brown adipose tissue (BAT), slow-twitch skeletal muscle, and heart, all tissues with high oxidative capacity.

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Individual Members of the PPAR Family













The first family member identified was PPARα and it was found by virtue of it binding to the fibrate class of anti-hyperlipidemic drugs and resulting in the proliferation of peroxisomes in hepatocytes, hence the derivation of the name of the protein. Given its relationship to the steroid/thyroid hormone superfamily of nuclear receptors the PPARα gene is also identified as NR1C1. Subsequently to its identification as the receptor for the fibrates is was shown that PPARα is the endogenous receptor for polyunsaturated fatty acids (PUFAs). More information on PPARα ligands is found below. PPARα is highly expressed in the liver, skeletal muscle, heart, and kidney. Its function in the liver is to induce hepatic peroxisomal fatty acid oxidation during periods of fasting. Expression of PPARα is also seen in macrophage foam cells and vascular endothelium. Its role in these cells is thought to be the activation of anti-inflammatory and anti-atherogenic effects.

The human PPARα gene is located on chromosome 22q12–q13.1 spanning just over 93kb, encompassing 8 exons that encode a protein of 468 amino acids. The coding region of the PPARα protein begins in exon 3, thus the first two exons and part of exon 3 constitute the 5'-untranslated region of the gene. As described above, the PPARα protein contains a DBD and a LBD. The DBD encompasses amino acids 101–166 in the human protein. The LBD encompasses amino acids 280–468. In addition, the protein contains two transcriptional activation function domains identified as AF-1 and AF-2. The AF-1 domain reside in the N-terminal region of the protein whereas, the AF-2 domain overlaps with the LBD. The activity of the AF-2 domain is repressed until ligand-binding.

Expression of the PPARα gene (symbol = PPARA) is highest in tissues with active fatty acid catabolism. This includes liver, heart, BAT, small and large intestine, and skeletal muscle. The role of PPARα in these tissues is to exert its effects on overall fatty acid catabolism. In the liver PPARα exerts a dominant effect on both fatty acid catabolism and ketone body production. In order for PPARα to exert its effects on lipid metabolism it must itself be targeted for transcriptional activation. Expression of the PPARα gene is regulated by numerous stimuli including stress, insulin release, leptin release from adipose tissue and hormone action such as that exerted by growth hormone. In the liver PPARα expression is activated in response to starvation which allows for increased expression of PPARα target genes in the liver leading to increased catabolism of fatty acids as they enter the liver. Transcription factors that regulate expression of the PPARα gene include hepatocyte nuclear factor 4 (HNF4) which is an activator and chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) which is a repressor of PPARα expression. Both of these transcription factors bind to a direct repeat type 1 element (DR1) in the PPARα gene promoter region that is composed of two copies of the sequence AGG(A/T)CA separated by a single nucleotide. The PPARα target genes listed in the following Table do not constitute a complete list, but are intended to represent many of the genes discussed in other pages of this site.

PPARα Target Genes of Lipid Homeostasis

Mitochondrial β-Oxidation
Gene Name Function / Comments
ACAA2 acetyl-CoA acyltransferase 2; mitochondrial β-ketothiolase catalyzing last step of β-oxidation of fatty acids
ACADM acyl-CoA dehydrogenase, medium-chain; medium-chain acyl-CoA dehydrogenase (MCAD); catalyzes first reaction of mitochondrial β-oxidation
ACADS acyl-CoA dehydrogenase, short-chain; short-chain acyl-CoA dehydrogenase (SCAD); catalyzes first reaction of mitochondrial β-oxidation
ACADVL acyl-CoA dehydrogenase, medium-chain; very long-chain acyl-CoA dehydrogenase (VLCAD); catalyzes first reaction of mitochondrial β-oxidation; high specificity for palmitoyl-CoA
CACT carnitine-acylcarnitine translocase; transports acetyl-carnitine from mitochondria to cytosol; also called SLC25A20
CPT1A carnitine palmitoyltransferase 1A; outer mitochondrial membrane fatty acylcarnitine transporter, predominant expression is in liver
CPT2 carnitine palmitoyltransferase 2; inner mitochondrial membrane fatty acylcarnitine transporter
HADHA hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase α-subunit; enzyme complex called the mitochondrial trifunctional protein (MTP); complex contains 4 α- and 4 β-subunits and catalyzes the last 3 steps of mitochondrial fatty acid β-oxidation
HADHB β-subunit of mitochondrial trifunctional protein (MTP)
Peroxisomal β-Oxidation
Gene Name Function / Comments
ACAA1 acetyl-CoA acyltransferase 1; peroxisomal 3-oxoacyl-CoA thiolase; peroxisomal equivalent of the mitochondrial thiolase activity
ACOX1 acyl-CoA oxidase 1; catalyzes the first step of peroxisomal fatty acid β-oxidation
ECH1 peroxisomal enoyl-CoA hydratase
Microsomal ω-Hydroxylation/Oxidation
Gene Name Function / Comments
ALDH9A1 aldehyde dehydrogenase, family 9, subfamily A, member 1; catalyzes the dehydrogenation of γ-aminobutyraldehyde to γ-aminobutyric acid (GABA)
CYP4A11 cytochrome P450, subfamily 4A, polypeptide 11; primary lauric acid ω-hydroxylase expressed in human liver
Gene Name Function / Comments
ACACB acetyl-CoA carboxylase 2 (ACC2); acetyl-CoA carboxylase-β (beta); associated with CPT-1 on outer mitochondrial membrane; synthesis of malonyl-CoA results in immediate inhibition of fatty acid transport into mitochondria
AGPAT2 1-acylglycerol-3-phosphate acyltransferase 2; lysophosphatidic acid acyltransferase-β (LPAAT-β); catalyzes conversion of lysophosphatidic acid to phosphatidic acid which can then be utilized in the synthesis of triglycerides
FADS1 fatty acid desaturase 1, (delta) Δ5-desaturase: D5D
FADS2 fatty acid desaturase 2, (delta) Δ6-desaturase: D6D
ELOVL6 elongation of very long-chain fatty acids-like 6; long-chain fatty acyl elongase (LCE); expressed in tissues with high lipid content; involved in fatty acid elongation
GPAM glycerol-3-phosphate acyltransferase (GPAT), mitochondrial; is one of two GPAT enzymes in humans, the other is found in the ER; synthesizes the initial committed step in glycerolipid biosynthesis
SCD1 stearoyl-CoA desaturase 1, (delta) Δ9-desaturase
Gene Name Function / Comments
HMGCS2 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase; HMG-CoA synthase, mitochondrial; catalyzes the conversion of acetoacetate to HMG-CoA during ketone body synthesis
Lipid Binding & Transport / Lipoproteins
Gene Name Function / Comments
APOA1 apolipoprotein A-I; major apoprotein of HDL, serves as a cofactor for lecithin:cholesterol acyltransferase (LCAT) which is involved in transfer of cholesterol from peripheral tissues to HDL in process referred to as reverse cholesterol transport
APOC3 apolipoprotein C-III; apoprotein of HDL and apoB-containing lipoproteins; enhances the catabolism of HDL, impairs catabolism and liver uptake of apoB-containing lipoproteins
FATP2 fatty acid transport protein 2; very long-chain acyl-CoA synthetase (VLACS); solute carrier family 27, member 2 (SLC27A2); integral membrane protein involved in uptake of long-chain and very long-chain fatty acids along simultaneous with CoA activation
FATP4 fatty acid transport protein 4; acyl-CoA synthetase very long-chain family, member 5 (ACSVL5); solute carrier family 27, member 4 (SLC27A4); only FATP expressed in intestine; integral membrane protein involved in uptake of dietary long-chain and very long-chain fatty acids
LIPC hepatic lipase, hepatic triglyceride lipase (HTGL); synthesized by heptocytes and bound to hepatic endothelial surfaces via heparin sulfate proteoglycans (HSPGs); catalyzes hydrolysis of fatty acids at the sn1 position of phospholipids and of mono-, di-, and triacylglycerides associated with a variety of lipoproteins
LPL lipoprotein lipase, bound to vascular endothelial cell surfaces; predominantly expressed in cardiac and skeletal muscle and adipose tissue; catalyzes hydrolysis of fatty acids at the sn1 and sn2 position of phospholipids and of mono-, di-, and triacylglycerides associated with a variety of lipoproteins
PLTP phospholipid transfer protein, lipid transfer protein II; associated with HDL involved in phospholipid transfer between HDL and LDL
VLDLR very low density lipoprotein receptor; expressed in tissues with active fatty acid metabolism, but not expressed in liver; plays a crucial role in triglyceride synthesis
Cholesterol Metabolism
Gene Name Function / Comments
ABCA1 ATP-binding cassette, subfamily A, member 1; transfers cholesterol from intracellular locations, such as in marcrophages, to apoA-I in HDL in process of reverse cholesterol transport; defects in gene result in Tangier disease
ABCB4 ATP-binding cassette, subfamily B, member 4; involved in biliary phosphatidylcholine transport
CYP7A1 cytochrome P450, subfamily 7A, polypeptide 1, cholesterol 7α-hydroxylase; initiates the classic pathway of bile acid synthesis; rate-limiting enzyme
CYP8B1 cytochrome P450, subfamily 8b, polypeptide 1, sterol 12α-hydroxylase; controls the ratio of the bile acids, cholic acid and chenodeoxycholic acid, in the bile
LXR liver X receptor

As indicated above, the activity of PPARα, at target gene promoter sites, is regulated by the presence of co-repressors and co-activators. Upon ligand binding co-repressors are replaced by co-activators and gene activation is effected. Numerous co-activators have been identified that interact with PPARα upon ligand binding. The list of co-activators is currently 11 but more may be identified as functional in tissue- and context-specific situations. Within the liver numerous co-activators have been found in a large complex with PPARα/RXR heterodimers. Several of the co-activators possess histone acetyltransferase (HAT) activity with histone acetylation resulting in the altered chromatin structure necessary for transcriptional activation. In addition to PGC-1α and PGC-1β described above, known co-activators of PPARα include cAMP-response element-binding protein (CREB)-binding protein/p300 (CBP/p300), steroid receptor co-activator-1 (SRC-1), PPAR-interacting protein (PRIP), and coactivator-associated arginine methyltransferase-1 (CARM-1).

In addition to regulation of PPARα activity by control of the expression of the PPARA gene, the protein is subjected to post-translational modifications that regulate its transcription regulating potential. The primary regulating modification is phosphorylation. PPARα is phosphorylated on specific serine residues and as a result its transcriptional activation activity is nearly doubled. Insulin mediates increases in phosphorylation of Ser12 and Ser21 in PPARα. Additional signaling pathways that lead to increased PPARα phosphorylation include stress, p38 mitogen-activated protein kinase (MAPK) and PKC. Evidence suggests that the phosphorylation of PPARα by PKC plays a significant role in statin drug-mediated acute anti-inflammatory effects.

There are numerous ligands that have been shown to activate PPARα. These ligands fall into two distinct categories identified as synthetic xenobiotics (exogenous ligands) and biological molecules (endogenous ligands). The original synthetic ligands identified were those of the fibrate class of plasma triglyceride and cholesterol lowering drugs. Indeed, experiments designed to define the mechanism of action of the fibrates were how the PPARs, starting with PPARα, were originally identified. In addition to the fibrates, industrial plasticizers such as di-(2-ethylhexyl)-phthalate (DEHP) used in the manufacture of polyvinyl chloride (PVC) plastics, certain pesticides and herbicides, industrial solvents, as well as food flavoring compounds have been shown to bind to and activate PPARα. The result of all of these diverse chemical compounds activating PPARα is increased peroxisome proliferation in hepatocytes and massive increases in transcriptional activation of fatty acid oxidizing genes.

Numerous fatty acids and fatty acid derivatives serve as endogenous ligands for PPARα. Dietary saturated and unsaturated fatty acids function as direct activators of PPARα. Endogenously derived fatty acids and fatty acid derivatives are likely to be the physiologically relevant ligands of PPARα. Numerous lipid metabolizing enzymes generate PPARα ligands. These include cyclooxygenases (COXs), cytochrome P450 enzymes, and several lipoxygenases (LOXs). The first enzyme demonstrated to be involved in the metabolism of PPARα ligands was fatty acyl-CoA oxidase 1 (ACOX1), the first and rate limiting enzyme of peroxisomal β-oxidation of fatty acids. When this enzyme is knocked out in mice there is profound activation of hepatic PPARα. Other enzymes of fatty acid catabolism have been shown to be involved in the degradation of endogenously derived PPARα agonists. On the other hand, enzymes of fatty acid synthesis such as fatty acid synthase (FAS), several lipoxygenases (LOXs), and fatty acyl-CoA synthetase (FACS) have all been shown to generate endogenous PPARα ligands. The leukotriene, LTB4 has been shown to be a ligand for PPARα which provides a connection between lipid homeostasis and inflammatory processes elicited by LTB4. Products of cytochrome P450 enzymes such as 19- and 20-hydroxyeicosatetraenoic acid (19- and 20-HETE) are also able to activate PPARα.

The first genes demonstrated to contain a PPRE element able to bind PPARα/RXR heterodimers were ACOX1 and peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (L-bifunctional protein: LBP). Of the genes that are currently known to be targets of PPARα action they can be divided into functional categories that include lipid metabolism, inflammation, cell cycle and signal transduction, metabolism of xenobiotics, and other processes. To date over 115 genes have been shown to be regulated by activation of the PPARα/RXR heterdimeric transcription factor complex. Some notable genes include the liver X receptor α (LXRα) gene, lipoprotein lipase (LPL), steroyl-CoA desaturase 1 (SCD1), mitochondrial hydroxymethylglutaryl-CoA (HMG-CoA) synthase, medium-chain acyl-CoA dehydrogenase (MCAD), and carnitine palmitoyltransferase-1 (CPT-1) all of which are involved in various aspects of lipid metabolism. Of significance is the fact that expression of PPARα is in part controlled by itself as the PPARα gene contains a PPRE responsive to PPARα/RXR activation. In characterizing the targets of PPARα action it is clear that this transcription factor functions primarily as a catabolic regulator of energy expenditure.

The liver is the primary organ in the regulation of whole body energy homeostasis via its ability to modulate fatty acid and glucose metabolism. That PPARα is a major player in hepatic energy homeostasis is apparent from the genes and pathways that are targets of it action. Liver fatty acid oxidation occurs primarily in the mitochondria and peroxisomes with some capacity in the endoplasmic reticulum. Several mitochondrial β-oxidation enzymes are activated by PPARα including long-chain acyl-CoA synthetases and CPT-1. As indicated above, ACOX1, responsible for the initial step in peroxisomal β-oxidation of very-long-chain fatty acids was the first identified target of PPARα. LBP, described above, is another peroxisomal β-oxidation enzyme induced by PPARα. Activation of PPARα also exerts hypolipidemic effects primarily in the liver but also in skeletal muscle and macrophages. The apolipoprotein C-III (apoC-III) inhibits the activity of lipoprotein lipase and lipoprotein remnant clearance. When PPARα is activated the activity level of apoC-III is decreased. In addition, activation of PPARα results in increased LPL activity in the liver and skeletal muscle leading to increased triglyceride clearance. Activation of PPARα induces the expression of the macrophage cholesterol efflux transporter, ABCA1, as well as the receptor on macrophages to which HDL particle bind, scavenger receptor-B1 (SR-B1). The result of both of these activities is increased reverse cholesterol transport. The apolipoproteins A-I and A-II (apoA-I and apoA-II), found associated with HDLs, are direct targets of PPARα and both play important roles in reverse cholesterol transport. ApoA-I activates HDL-associated lecithin:cholesterol acyltransferase (LCAT) and apoA-II increase the activity of hepatic LPL activity.

When studying the effects of PPARα knock-out in mice it was found that they became severely hypoglycemic within a short period of time upon fasting. This observation provided a link between PPARα-regulated lipid homeostasis and glucose homeostasis. Upon fasting adipose tissue triglycerides are hydrolyzed in order to provide the liver with fatty acids that can be oxidized for energy production and the glycerol backbone that can be utilized for de novo glucose production via gluconeogenesis. In order for glycerol to serve as a substrate for gluconeogenesis several hepatic genes are required to be induced. These include glycerol kinase, glycerol-3-phosphate dehydrogenase (GPDH), and the glycerol transporters aquaporin 3 and aquaporin 9. The expression of each of these genes is dependent upon PPARα activation. Thus, the hypoglycemia observed in the PPARα-deficient mice underscores the importance of the glycerol backbone of stored triglycerides in overall glucose homeostasis in fasting individuals. Another important target of PPARα, with respect to glucose homeostasis, is TRB3. TRB3 is an inhibitor of PKB/AKT which is an important serine/threonine kinase involved in numerous signaling events downstream of the insulin receptor. For more precise information on PKB/AKT visit the Insulin Function page.

The ability of PPARα activation to lead to increased cholesterol efflux from macrophages is significant with respect to the role of activated macrophages and inflammatory events leading to atherosclerosis. As indicated above LTB4, a potent pro-inflammatory eicosanoid produced primarily in activated neutrophils, is a ligand for PPARα. The net effect of LTB4 activation of PPARα is a reduction in the level of the PUFAs that serve as the substrates for LTB4 synthesis as a result of increased fatty acid oxidation. Thus, LTB4 serves to limit its own production via activation of PPARα. PPARα ligands also result in reduced levels of several additional pro-inflammatory molecules such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Activation of PPARα also leads to reduced levels of COX-2 and inducible nitric oxide synthase (iNOS) thereby, reducing production of and response to pro-inflammatory signals, respectively.

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PPARγ was originally identified as being expressed in differentiating adipocytes. It is now recognized as a master regulator of adipogenesis and is most abundantly expressed in adipose tissue. PPARγ was identified as the target of the thiazolidinedione (TZD) class of insulin-sensitizing drugs. The mechanism of action of the TZDs is a function of the activation of PPARγ and the consequent induction of genes necessary for differentiation of adipocytes. This effect of PPARγ leads to increased fat storage and secretion of insulin-sensitizing adipocytokines such as adiponectin from adipocytes. Given its relationship to the steroid/thyroid hormone superfamily of nuclear receptors the PPARγ gene is also identified as NR1C3.

The human PPARγ gene (symbol PPARG) is located on chromosome 3p25 spanning over 100kb and composed of 9 exons encoding at least four isoforms (although only two are of biological significance) due to alternative mRNAs and translational start codon usage. The principal protein products of the PPARG gene are identified as PPARγ1 and PPARγ2. PPARγ1 is encoded for by exons A1 and A2 then common exons 1 through 6. PPARγ2 is encoded by exon B and common exons 1 through 6. Like all nuclear receptors the PPARγ proteins contain a DBD and a LBD. In addition, like PPARα, the PPARγ proteins contain a ligand-dependent activation function domain (identified as AF-2) and a ligand-independent activation function domain (identified as AF-1). The AF-2 domain resides in the LBD and the AF-1 domain is in the N-terminal region of the PPARγ proteins. PPARγ2 protein contains an additional 30 N-terminal amino acids relative to PPARγ1 and these additional amino acids confer a 5–6-fold increase in the transcription-stimulating activity of AF-1 when compared to the same domain in the PPARγ1 protein. Expression of PPARγ1 is nearly ubiquitous. PPARγ2 is expressed near exclusively in white adipose tissue (WAT) where it is involved in lipid storage and in BAT where it is involved in energy dissipation.

Like PPARα, PPARγ forms an obligate heterodimer with members of the RXR family and the heterodimers bind to PPREs that consist of a repeating hexanucleotide sequence (AGGTCA) separated by 1 (DR1) or 2 (DR2) nucleotides within the promoter region of target genes. As indicated above the activity of PPARγ, at target gene promoter sites, is regulated by the presence of co-repressors and co-activators. Upon ligand binding co-repressors are replaced by co-activators and gene activation is effected. Numerous co-activators (such as CBP/p300 and SRC-1) have been identified that interact with PPARγ upon ligand binding. Numerous ligands have been identified that can activate PPARγ. These include the naturally occurring lipids prostaglandin J2 (PGJ2), the essential fatty acid linolenic acid, the PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and 9(S)-hydroxy-octadecadienoic acid (HODE), and several hydroxyeicosatetraenoic acids (HETEs).

The transcriptional activity of PPARγ is regulated by post-translational modifications that include phosphorylation, SUMOylation, and unbiquitination. For information on SUMO and ubiquitin modification of proteins visit the Protein Modifications page. By far phosphorylation is the most important post-translational modification affecting PPARγ activity. Growth factors and insulin all result in phosphorylation of serine residues in the AF-1 domain. Ser84 in PPARγ1 and Ser114 in PPARγ2 have been shown to be phosphorylated by several MAPKs including p38MAPK, Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). Phosphorylation by these MAPKs results in inhibition of both ligand-dependent and ligand-independent transactivation of the protein. AMPK also has been shown to phosphorylate and inhibit PPARγ activity.

During adipocyte differentiation several upstream genes are required for the activation of the PPARG gene. These include the CCAAT/enhancer-binding proteins β and δ (C/EBPβ and C/EBPδ), SREBP-1c, Krüppel-like factor-5 (KLF5), KLF15, zinc-finger protein 423 (Zfp423), and early B-cell factor (Ebf1). In the process of adipocyte differentiation PPARγ activates nearly all of the genes required for this process. These genes include aP2 which is required for transport of free fatty acids (FFAs) and perilipin which is a protein covering the surface of mature lipid droplets in adipocytes. Additional genes regulated by PPARγ that are involved in lipid metabolism or glucose homeostasis include lipoprotein lipase (LPL), several acyl-CoA synthetases (e.g. ACS1 and ACS2), acetyl-CoA acetyltransferase 1 (ACAT1), several phospholipase A (PLA) genes, the adipocytokine adiponectin, the gluconeogenic enzyme PEPCK, and glycerol-3-phosphate dehydrogenase (GPD1). PPARγ also functions in macrophage lipid metabolism by inducing the expression of the macrophage scavenger receptor, FAT/CD36. The PPARγ target genes listed in the following Table do not constitute a complete list, but are intended to represent many of the genes discussed in other pages of this site.

PPARγ Target Genes in Adipogenesis, Lipid, and Glucose Homeostasis

Adipocyte Differentiation
Gene Name Function / Comments
FABP4 fatty acid binding protein 4, adipocyte, adipocyte fatty acid binding protein P2 (aP2); regulator of toxic lipid-induced ER stress; is secreted from adipocytes and influences hepatic glucose homeostasis
UCP1 uncoupling protein 1; major determinant of brown adipocytes (BAT), involved in adaptive thermogenesis by acting as an uncoupler of mitochondrial oxidative phosphorylation
PLIN1 perilipin 1; hormonally-regulated protein on the surface of fat droplets; phosphorylated by PKA and then directs PKA-activated hormone-sensitive lipase (HSL) to diacylglycerides in the droplets
Gene Name Function / Comments
ADPN adiponectin; also known as adipoQ for adipocyte, C1q and collagen-domain containing protein
Gene Name Function / Comments
ACACA acetyl-CoA carboxylase 1 (ACC1); acetyl-CoA carboxylase-α (alpha); major rate-limiting enzyme of fatty acid synthesis
ELOVL4 elongation of very long-chain fatty acids-like 4; required for the synthesis of very long chain saturated fatty acids; also required for very long chain polyunsaturated fatty acid synthesis that are unique to retina, sperm, and brain
LXRA liver X receptor α (alpha)
ME1 malic enzyme 1; involved in the pathway by which acetyl-CoA is transported out of the mitochondria as citrate, converts cytosolic malate to pyruvate while also generating NADPH
SCD1 stearoyl-CoA desaturase 1, (delta) Δ9-desaturase
Gene Name Function / Comments
ACAT1 acetyl-CoA acetyltransferase; acetoacetyl-CoA thiolase, mitochondrial; catalyzes the last step of ketone body breakdown (ketolysis); also involved in the catabolism of isoleucine
Lipid Binding & Transport / Lipoproteins
Gene Name Function / Comments
APOA2 apolipoprotein A-II; primary apoprotein of HDL; activates hepatic lipase
APOE apolipoprotein E; important for recognition of lipoprotein particles by the LDL  receptor; essential for metabolism of triglyceride-rich lipoproteins
CD36 leukocyte differentiation antigen 36; also known as fatty acid translocase, FAT; is a lipoprotein scavenger receptor as well as a membrane fatty acid transporter
LDLR LDL receptor
LIPC hepatic lipase, hepatic triglyceride lipase (HTGL); synthesized by heptocytes and bound to hepatic endothelial surfaces via heparin sulfate proteoglycans (HSPGs); catalyzes hydrolysis of fatty acids at the sn1 position of phospholipids and of mono-, di-, and triacylglycerides associated with a variety of lipoproteins
LRP1 LDL receptor-related protein 1
LPL lipoprotein lipase, bound to vascular endothelial cell surfaces; predominantly expressed in cardiac and skeletal muscle and adipose tissue; catalyzes hydrolysis of fatty acids at the sn1 and sn2 position of phospholipids and of mono-, di-, and triacylglycerides associated with a variety of lipoproteins
OLR1 oxidized LDL (oxLDL) receptor; also identified as the endothelial oxLDL receptor: LOX-1
FATP1 fatty acid transport protein 1; very long-chain acyl-CoA synthetase family member 4 (ACSVL4); solute carrier family 27, member 2 (SLC27A1); integral membrane protein involved in uptake of long-chain and very long-chain fatty acids along simultaneous with CoA activation
FATP2 fatty acid transport protein 2; very long-chain acyl-CoA synthetase (VLACS); solute carrier family 27, member 2 (SLC27A2); integral membrane protein involved in uptake of long-chain and very long-chain fatty acids along simultaneous with CoA activation
Glucose Homeostasis
Gene Name Function / Comments
G6PC glucose-6-phosphatase, catalytic
GPD1 glycerol-3-phosphate dehydrogenase 1, cytosolic; enzyme of glycerol-phosphate shuttle used to transfer cytosolic NADH into the mitochondria; also involved in the synthesis of triglycerides in adipose tissue
GCK glucokinase
PEPCK phosphoenolpyuvate carboxykinase
PDK4 pyruvate dehydrogenase kinase 4; expressed in all tissue but with highest levels cardiac and skeletal muscles

In addition to the role of PPARγ in the regulation of the expression of numerous genes that are involved in lipid and glucose homeostasis the receptor also plays a role in anti-inflammatory and anti-cancer pathways. The effects of PPARγ on lipid and glucose metabolism is via direct activation of target genes. However, the ability of PPARγ to effect anti-inflammatory responses is due not only to the activation of anti-inflammatory gene but also to ligand-dependent trans-repression by which PPARγ inhibits the activity of pro-inflammatory transcription factors such as nuclear factor κB (NFκB). Additional pro-inflammatory genes whose expression is inhibited by PPARγ-mediated trans-repression include activator protein-1 (AP-1), signal transducers and activators of transcription 1 (STAT-1), and nuclear factor of activated T cells (NFAT). PPARγ exerts a significant anti-inflammatory effect at the level of macrophage-mediated pro-inflammatory responses. PPARγ inhibits recruitment of macrophages to sites of inflammation via repressing the transcription of monocyte chemoattractant protein-1 (MCP-1) as well as the receptor for MCP-1, CC chemokine receptor 2 (CCR2). Stimulated macrophages release numerous pro-inflammatory molecules and PPARγ activation has been shown to inhibit the production of many of them. The secretion of the inflammatory cytokines, TNF-α, IL-1β, IL-6, and IL-12, by macrophages is inhibited by PPARγ activation. PPARγ also represses the production of nitric oxide (NO) via inhibition of expression of iNOS.

PPARγ is expressed in several other inflammatory cells including dendritic cells (DC) which are master antigen presenting cells (APCs), naive and activated T cells, and B cells. In DCs activation of PPARγ inhibits the production of the pro-inflammatory cytokine, IL-12 as well as the chemokines CXCL10 and CCL5 that are involved in the recruitment of T helper cells (Th1 cells). Activation of PPARγ reduces the ability of DCs to be stimulated by Toll-like receptor (TLR) agonists resulting in a reduced capacity of the DCs to stimulate T cell proliferation. DCs in which PPARγ has been activated induce T cell anergy coupled with impaired expression of both Th1 and Th2 cytokines and a failure of secondary clonal expansion when the T cells are re-stimulated. Activation of PPARγ also increases the formation of and suppressive functions of regulatory T cells (Tregs). Expression of PPARγ is also seen in B cells where the effects of its activation lead to anti-proliferative responses. PPARγ activation also induces cytotoxic effects in both normal and malignant B cells.

Given the critical importance of PPARγ in normal lipid and glucose metabolism as well as in the regulation of inflammatory responses it is not surprising that metabolic disorders have been identified that are due to mutations in the PPARG gene. The most prevalent PPARγ gene variant is a polymorphism that results in the substitution of a proline for an alanine at codon 12 (P12A) in the unique N-terminal region of PPARγ2. The allelic frequency of this polymorphism has been shown to range between 2% and 23% in various ethnic populations. There is a modest (1.25-fold) but highly significant correlation with the presence of the P12A allele and the risk for development of type 2 diabetes. Disruption in metabolism has also been associated with mutations that affect ligand binding to PPARγ. These loss-of-function mutations in the LBD of PPARγ can exert dominant-negative effects due to an increase in the affinity of the receptor for co-repressors or due to an attenuated ability to recruit co-activators. Patients that harbor these PPARγ LBD mutations manifest with severe insulin resistance and type 2 diabetes, early atherosclerosis, early hypertension, dyslipidemia and polycystic ovaries in female patients. This constellation of phenotypes, as a result of loss of ligand binding to PPARγ, is referred to as PPARγ ligand resistance syndrome (PLRS).

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PPARδ is expressed in most tissues and is involved in the promotion of mitochondrial fatty acid oxidation, energy consumption, and thermogenesis. Although expression of PPARδ is near ubiquitous it still plays an important tissue and cellular context-specific role in adipose tissue mass, skin inflammatory responses, wound healing, and neural cell myelination. Studies in mice and humans has revealed that PPARδ is a key metabolic regulator and has the potential to be a therapeutic target in the treatment of the metabolic syndrome. Current pharmacologic targeting of PPARδ is aimed at increasing HDL levels in humans since experiments in animals have shown that increased PPARδ levels result in increased HDL and reduced levels of serum triglycerides. Given its relationship to the steroid/thyroid hormone superfamily of nuclear receptors the PPARδ gene is also identified as NR1C2.

The human PPARδ gene (symbol = PPARD) is located on chromosome 6p21.2–p21.2 spanning 10.7kb and composed of 8 exons encoding a 441 amino acid protein. Similar to PPARα and PPARγ, the PPARδ protein contains a DBD, a LBD, and two activation function domains identified as AF-1 and AF-2.

Unlike PPARα and PPARγ for which synthetic pharmacologically relevant ligands have been developed, no PPARδ agonists are currently in clinical use. However, several synthetic ligands have been identified and are being tested for use in treating dyslipidemias. For example the PPARδ-specific ligand GW501516 has been shown to increase circulating HDL levels and decrease triglyceride and insulin levels in healthy volunteers. Natural ligands for PPARδ include 14– to 18–carbon fatty acids, 16– to 20–carbon PUFAs, triglycerides, prostacyclin (PGI2), prostaglandin A1 (PGA1), and retinoic acid.

Activation of PPARδ in WAT and BAT, skeletal muscle, and cardiac muscle exerts a broad range of effects on cell growth, glucose homeostasis, lipid metabolism, and inflammatory responses. In BAT activation of PPARδ results in increased expression of genes involved in fatty acid oxidation such as ACOX1, CPT-1, very long-chain acyl-CoA dehydrogenase (VLCAD), and long-chain acyl-CoA dehydrogenase (LCAD). PPARδ also activates genes involved in triglyceride metabolism such as hormone sensitive lipase (HSL) and genes that uncouple oxidative phosphorylation resulting in thermogenesis (uncoupling protein 1, UCP1). UCP1 is also activated by PPARδ in WAT. PPARδ is also involved in lipoprotein metabolism via activation of the ABCA1 transporter that functions in reverse cholesterol transport as well as inhibition of the gene encoding the intestinal cholesterol absorption protein Niemann-Pick C1-like-1 (NPC1L1). Of clinical significance is the fact that PPARδ ligands have been shown to reduce triglyceride accumulation in BAT and liver and enhances fatty acid oxidation in genetically obese mice. In models of high-fat diet-induced obesity PPARδ ligands result in retarded weight gain indicating that clinical use of PPARδ activators could be beneficial as anti-obesity agents.

In skeletal muscle PPARδ is involved in fatty acid transport and oxidation, mitochondrial respiration and thermogenesis, and oxidative metabolism. Expression of PPARδ in skeletal muscle is some 10- and 50-fold higher than PPARα and PPARγ, respectively. Expression of PPARδ is found preferentially in oxidative relative to glycolytic myofibers. Activation of PPARδ in skeletal muscle results in increased expression of CPT-1, HMG-CoA synthase 2 (HMGCS2), succinate dehydrogenase (SDH), citrate synthase, cytochrome oxidase II, cytochrome oxidase IV, uncoupling protein 2 (UCP2), ACOX1, VLCAD, LCAD, and MCAD. Fasting results in increased expression of PPARδ indicating that the receptor mediates the fasting-dependent rise in skeletal muscle fatty acid oxidation.

PPARδ also plays an important role in the regulation of macrophage-mediated inflammatory processes and as such exerts an anti-atherogenic function. Unlike the roles of PPARα and PPARγ in the regulation of macrophage cholesterol and lipoprotein metabolism, there is no clear indication that PPARδ is likewise involved. However, experiments with PPARδ knock-out mice have shown that loss of this receptor is correlated to reduced levels of the inflammatory mediators monocyte chemoattractant protein-1 (MCP-1), IL-1β, and matrix metalloprotein-9 (MMP-9). In addition, it was shown that the inflammatory suppressor protein B cell lymphoma-6 (BCL-6) forms a complex with PPARδ and that it is released from PPARδ upon ligand binding. Thus, activation of PPARδ results in the release and activation of an important anti-inflammatory mediator. When synthetic PPARδ ligands are used in experimental animals a significant decrease in the expression of vascular wall inflammatory mediators is observed. These include MCP-1, IL-1β, TNF-α, interferon-γ (IFN-γ), and the adhesion molecules vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Other proinflammatory proteins are found at reduced levels in the serum following PPARδ activation including MCP-1, IL-12, TNF receptor-1 (TNF-R1), and RANTES (regulated upon activation, normal T cell expressed and secreted). These animal studies indicate that there is potential for the use of synthetic PPARδ ligands to reduce the inflammatory events associated with atherosclerosis.

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Last modified: January 11, 2017