Peroxisome proliferator-activated receptor alpha

Peroxisome proliferator-activated receptor alpha (PPAR-alpha), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a is_associated_with::nuclear receptor protein that in humans is encoded by the PPARA is_associated_with::gene. Together with is_associated_with::Peroxisome proliferator-activated receptor delta and is_associated_with::Peroxisome proliferator-activated receptor gamma, PPAR-alpha is part of the subfamily of is_associated_with::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.

Function
PPAR-alpha is a transcription factor and 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 is_associated_with::ketogenesis, 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 binding and activation, and peroxisomal and mitochondrial fatty acid β-oxidation. PPAR-alpha is primarily activated through ligand binding. Synthetic ligands include the is_associated_with::fibrate drugs, which are used to treat is_associated_with::hyperlipidemia, and a diverse set of insecticides, herbicides, plasticizers, and organic solvents collectively referred to as peroxisome proliferators. Endogenous ligands include fatty acids such as is_associated_with::arachidonic acid as well as other is_associated_with::polyunsaturated fatty acids and various fatty acid-derived compounds such as certain members of the is_associated_with::15-Hydroxyicosatetraenoic acid family of arachidonic acid metabolites, e.g. 15(S)-HETE, 15(R)-HETE, and 15(S)-HpETE

Tissue distribution
Expression of PPAR-alpha is highest in tissues that oxidize is_associated_with::fatty acids at a rapid rate. In rodents, highest mRNA 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.

Knock-out studies
Studies using mice lacking functional PPAR-alpha indicate that PPAR-alpha 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 is_associated_with::ketone bodies, is_associated_with::hypoglycemia, and is_associated_with::fatty liver.

Pharmacology
PPAR-alpha serves as cellular receptor for is_associated_with::fibrates, a class of drugs used in the treatment of dyslipidemia. Fibrates effectively lower serum is_associated_with::triglycerides 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, in contrast to is_associated_with::statins. PPAR-alpha agonists may carry therapeutic value for the treatment of is_associated_with::Non-alcoholic fatty liver disease. PPAR-alpha may also be a site of action of certain is_associated_with::anticonvulsants

Target genes
PPAR-alpha 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 is_associated_with::PDK4, is_associated_with::ACOX1, 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. The maps, constructed for mouse liver and human liver, put PPAR-alpha at the center of a regulatory hub impacting fatty acid uptake and intracellular binding, mitochondrial β-oxidation and peroxisomal fatty acid oxidation, is_associated_with::ketogenesis, triglyceride turnover, is_associated_with::gluconeogenesis, and is_associated_with::bile synthesis/secretion.

Interactions
Peroxisome proliferator-activated receptor alpha has been shown to interact with:
 * AIP,
 * is_associated_with::EP300
 * HSP90AA1,
 * NCOA1, and
 * NCOR1.