Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a
nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...
protein functioning as a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
that in humans is encoded by the ''PPARA''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Together with
peroxisome proliferator-activated receptor delta
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.
This gene encodes a member of the peroxisome pr ...
and
peroxisome proliferator-activated receptor gamma
Peroxisome proliferator- activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone reverse insulin resistance
receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor functioning as a tran ...
, PPAR-alpha is part of the subfamily of
peroxisome proliferator-activated receptor
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 regu ...
s. 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
hepatocarcinogen
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
s that causes proliferation of
peroxisome
A peroxisome () is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen pero ...
s.
Expression
PPAR-α is primarily activated through ligand binding. Endogenous ligands include fatty acids such as
arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
as well as other
polyunsaturated fatty acids
Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic proper ...
and various fatty acid-derived compounds such as certain members of the
15-hydroxyeicosatetraenoic acid family of arachidonic acid metabolites, e.g. 15(''S'')-HETE, 15(R)-HETE, and 15(S)-HpETE and
13-hydroxyoctadecadienoic acid, a
linoleic acid
Linoleic acid (LA) is an organic compound with the formula COOH(CH2)7CH=CHCH2CH=CH(CH2)4CH3. Both alkene groups are cis-trans isomerism, ''cis''. It is a fatty acid sometimes denoted 18:2 (n-6) or 18:2 ''cis''-9,12. A linoleate is a salt (chem ...
metabolite. Synthetic ligands include the
fibrate
In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid (phenoxyisobutyric acid). They are used for a range of metabolic disorders, mainly hypercholesterolemia (high cholesterol), ...
drugs, which are used to treat
hyperlipidemia
Hyperlipidemia is abnormally elevated levels of any or all lipids (fats, cholesterol, or triglycerides) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also used as an umbre ...
, and a diverse set of insecticides, herbicides, plasticizers, and organic solvents collectively referred to as peroxisome proliferators.
Function
![Human hepatocyte PPARalpha transcriptome](https://upload.wikimedia.org/wikipedia/commons/e/e4/Human_hepatocyte_PPARalpha_transcriptome.png)
PPAR-α is a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
regulated by
free fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
s, and is a major regulator of lipid metabolism in the liver.
PPAR-alpha is activated under conditions of energy deprivation and is necessary for the process of
ketogenesis
Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, unde ...
, a key adaptive response to prolonged fasting.
Activation of PPAR-alpha promotes uptake, utilization, and catabolism of fatty acids by upregulation of genes involved in fatty acid transport, fatty acid binding and activation, and
peroxisomal
A peroxisome () is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen per ...
and
mitochondrial
A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
fatty acid
β-oxidation
In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycle, ...
.
Activation of fatty acid oxidation is facilitated by increased expression of
CPR1 (which brings long-chain lipids into mitochondria) by PPAR-α.
PPAR-α also inhibits
glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
, while promoting liver
gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrat ...
and
glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body.
Glycogen functions as one o ...
synthesis.
In
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s, PPAR-α inhibits the uptake of
glycated low-density lipoprotein
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
(LDL cholesterol), inhibits
foam cell
Foam cells, also called lipid-laden macrophages, are a type of cell that contain cholesterol. These can form a plaque that can lead to atherosclerosis and trigger heart attacks and stroke.
Foam cells are fat-laden cells with a M2 macrophage-like ...
(
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
) formation, and inhibits pro-inflammatory
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s.
Tissue distribution
Expression of PPAR-α is highest in tissues that oxidize
fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...
s at a rapid rate. In rodents, highest
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
expression levels of PPAR-alpha are found in liver and brown adipose tissue, followed by heart and kidney.
Lower PPAR-alpha expression levels are found in small and large intestine, skeletal muscle and adrenal gland. Human PPAR-alpha seems to be expressed more equally among various tissues, with high expression in liver, intestine, heart, and kidney.
Knockout studies
Studies using mice lacking functional PPAR-alpha indicate that PPAR-α is essential for induction of peroxisome proliferation by a diverse set of synthetic compounds referred to as peroxisome proliferators.
Mice lacking PPAR-alpha also have an impaired response to fasting, characterized by major metabolic perturbations including low plasma levels of
ketone bodies
Ketone bodies are water-soluble molecules that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA (acetyl- ...
,
hypoglycemia
Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...
, and
fatty liver
Fatty liver disease (FLD), also known as hepatic steatosis, is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. Complicat ...
.
Pharmacology
PPAR-α is the pharmaceutical target of
fibrate
In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid (phenoxyisobutyric acid). They are used for a range of metabolic disorders, mainly hypercholesterolemia (high cholesterol), ...
s, a class of drugs used in the treatment of dyslipidemia. Fibrates effectively lower serum
triglyceride
A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride'').
Triglycerides are the main constituents of body fat in humans and other vertebrates, as w ...
s and raises serum
HDL-cholesterol levels.
Although clinical benefits of fibrate treatment have been observed, the overall results are mixed and have led to reservations about the broad application of fibrates for the treatment of
coronary heart disease
Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...
, in contrast to
statin
Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs.
Low- ...
s. PPAR-α, agonists may carry therapeutic value for the treatment of
non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic ...
. PPAR-alpha may also be a site of action of certain
anticonvulsant
Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...
s.
An endogenous compound, 7(S)-Hydroxydocosahexaenoic Acid (7(S)-HDHA/), which is a
Docosanoid
In biochemistry, docosanoids are signaling molecules made by the metabolism of twenty-two-carbon fatty acids (EFAs), especially the omega-3 fatty acid, Docosahexaenoic acid (DHA) (i.e. 4''Z'',7''Z'',10''Z'',13''Z'',16''Z'',19''Z''-docosahexaenoic a ...
derivative of the omega-3 fatty acid DHA was isolated as an endogenous high affinity ligand for PPAR-alpha in the rat and mouse brain. The 7(S) enantiomer bound with micromolar affity to PPAR alpha with 10 fold higher affinity compared to the (R) enantiomer and could trigger dendritic activation.
Previous evidence for the compound's function was speculative based on the structure and study of the chemical synthesis.
Both high sugar and low protein diets elevate the circulating liver hormone
FGF21
Fibroblast growth factor 21 is a liver-secreted peptide hormone that in humans is encoded by the ''FGF21'' gene. Together with FGF19 (FGF15 in rodents) and FGF23, this protein is a member of the endocrine subgroup within the fibroblast growth fa ...
in humans by means of PPAR-α, although this effect can be accompanied by FGF21-resistance.
Target genes
PPAR-α governs biological processes by altering the expression of a large number of target genes. Accordingly, the functional role of PPAR-alpha is directly related to the biological function of its target genes. Gene expression profiling studies have indicated that PPAR-alpha target genes number in the hundreds.
Classical target genes of PPAR-alpha include
PDK4
Pyruvate dehydrogenase lipoamide kinase isozyme 4, mitochondrial is an enzyme that in humans is encoded by the ''PDK4'' gene. It codes for an isozyme of pyruvate dehydrogenase kinase.
This gene is a member of the PDK/BCKDK protein kinase family a ...
,
ACOX1
Peroxisomal acyl-coenzyme A oxidase 1 is an enzyme that in humans is encoded by the ''ACOX1'' gene.
The protein encoded by this gene is the first enzyme of the fatty acid beta-oxidation pathway, which catalyzes the desaturation of acyl-CoAs to 2- ...
, and
CPT1. Low and high throughput gene expression analysis have allowed the creation of comprehensive maps illustrating the role of PPAR-alpha as master regulator of lipid metabolism via regulation of numerous genes involved in various aspects of lipid metabolism. These maps, constructed for
mouse liver and
human liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it is ...
, put PPAR-alpha at the center of a regulatory hub impacting fatty acid uptake and intracellular binding, mitochondrial
β-oxidation
In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycle, ...
and peroxisomal fatty acid oxidation,
ketogenesis
Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, unde ...
, triglyceride turnover,
gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrat ...
, and
bile
Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile ...
synthesis/secretion.
Interactions
PPAR-α has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
AIP,
*
EP300
Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the ''EP300'' gene. It functions as histone ace ...
[
* ]HSP90AA1
Heat shock protein HSP 90-alpha is a protein that in humans is encoded by the ''HSP90AA1'' gene.
Function
The gene, HSP90AA1, encodes the human stress-inducible 90-kDa heat shock protein alpha (Hsp90A). Complemented by the constitutively expr ...
,[
* ]NCOA1
The nuclear receptor coactivator 1 (''NCOA1'') is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA1 is recruited to DNA promotion sites by ...
, and
* NCOR1
The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 (TRAC-1) is a protein that in humans is encoded by the ''NCOR1'' gene.
NCOR1 is a transcriptional coregulatory protein which c ...
.
*Palmitoylethanolamide
Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, and lipid modulator PEA has been studied in ''in vitro'' and ''in vivo'' systems using exogenously added or dosed compound; there is evidence that it binds to a nuclear receptor, thr ...
(PEA)
*Oleoylethanolamide
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.
O ...
(OEA)
*Anandamide
Anandamide (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid rec ...
(AEA)
* 7( S)-Hydroxydocosahexaenoic Acid (7-HDoHE)
See also
* Peroxisome proliferator-activated receptor
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 regu ...
* Fibrate
In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid (phenoxyisobutyric acid). They are used for a range of metabolic disorders, mainly hypercholesterolemia (high cholesterol), ...
*Endocannabinoid system
The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors (CBRs), and cannabinoid receptor proteins that are expressed t ...
References
Further reading
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{{PPAR modulators
Intracellular receptors
Transcription factors