PPAR-α is primarily activated through ligand binding. Endogenous ligands include fatty acids such as
arachidonic acid as well as other
polyunsaturated fatty acids 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 metabolite. Synthetic ligands include the
fibrate drugs, which are used to treat
hyperlipidemia, and a diverse set of insecticides, herbicides, plasticizers, and organic solvents collectively referred to as peroxisome proliferators.
Function
PPAR-α is a
transcription factor regulated by
free fatty acids, and is a major regulator of lipid metabolism in the liver.[7] PPAR-alpha is activated under conditions of energy deprivation and is necessary for the process of
ketogenesis, a key adaptive response to prolonged fasting.[8][9] 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 and
mitochondrial fatty acid
β-oxidation.[10] Activation of fatty acid oxidation is facilitated by increased expression of
CPT1 (which brings long-chain lipids into mitochondria) by PPAR-α.[11] PPAR-α also inhibits
glycolysis, while promoting liver
gluconeogenesis and
glycogen synthesis.[7]
Expression of PPAR-α is highest in tissues that oxidize
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.[12] 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.[13] Mice lacking PPAR-alpha also have an impaired response to fasting, characterized by major metabolic perturbations including low plasma levels of
ketone bodies,
hypoglycemia, and
fatty liver.[8]
Pharmacology
PPAR-α is the pharmaceutical target of
fibrates, a class of drugs used in the treatment of dyslipidemia. Fibrates effectively lower serum
triglycerides and raises serum
HDL-cholesterol levels.[14] 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
statins. PPAR-α, agonists may carry therapeutic value for the treatment of
non-alcoholic fatty liver disease. PPAR-alpha may also be a site of action of certain
anticonvulsants.[15][16]
An endogenous compound, 7(S)-Hydroxydocosahexaenoic Acid (7(S)-HDHA/
"7-HDoHE". PubChem.
National Center for Biotechnology Information.), which is a
Docosanoid 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.[17]
Previous evidence for the compound's function was speculative based on the structure and study of the chemical synthesis.[18]
Both high sugar and low protein diets elevate the circulating liver hormone
FGF21 in humans by means of PPAR-α, although this effect can be accompanied by FGF21-resistance.[19]
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.[10] Classical target genes of PPAR-alpha include
PDK4,
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. These 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,
ketogenesis, triglyceride turnover,
gluconeogenesis, and
bile synthesis/secretion.
^Citraro R, Russo E, Scicchitano F, van Rijn CM, Cosco D, Avagliano C, Russo R, D'Agostino G, Petrosino S, Guida F, Gatta L, van Luijtelaar G, Maione S, Di Marzo V, Calignano A, De Sarro G (2013). "Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-α receptor activation in a genetic model of absence epilepsy". Neuropharmacology. 69: 115–26.
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^Zhang M, Sayyad AA, Dhesi A, Orellana A (November 2020). "Enantioselective Synthesis of 7(S)-Hydroxydocosahexaenoic Acid, a Possible Endogenous Ligand for PPARα". J Org Chem. 85 (21): 13621–13629.
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10.1021/acs.joc.0c01770.
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van Raalte DH, Li M, Pritchard PH, Wasan KM (2005). "Peroxisome proliferator-activated receptor (PPAR)-alpha: a pharmacological target with a promising future". Pharm. Res. 21 (9): 1531–8.
doi:
10.1023/B:PHAM.0000041444.06122.8d.
PMID15497675.
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Mukherjee R, Jow L, Noonan D, McDonnell DP (1995). "Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators". J. Steroid Biochem. Mol. Biol. 51 (3–4): 157–66.
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