Peroxisome proliferator-activated receptor alpha
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| Location (UCSC) | Chr 22: 46.15 – 46.24 Mb | Chr 15: 85.62 – 85.69 Mb | |||||||
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Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the PPARA gene.[5] 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.[6]
Expression
PPAR-α is primarily activated through ligand binding. Endogenous ligands include fatty acids such as
Function
PPAR-α is a
In macrophages, PPAR-α inhibits the uptake of glycated low-density lipoprotein (LDL cholesterol), inhibits foam cell (atherosclerosis) formation, and inhibits pro-inflammatory cytokines.[11]
Tissue distribution
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.
Pharmacology
PPAR-α is the pharmaceutical target of
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
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.
Interactions
PPAR-α has been shown to
- AIP,[20]
- EP300[21][22]
- HSP90AA1,[20]
- NCOA1,[21][23] and
- NCOR1.[22]
- Palmitoylethanolamide (PEA)
- Oleoylethanolamide (OEA)
- Anandamide (AEA)
- 7( S)-Hydroxydocosahexaenoic Acid (7-HDoHE)[17]
- PFAS[24]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000186951 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022383 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 7684926.
- S2CID 4306126.
- ^ PMID 20936117.
- ^ PMID 10359558.
- PMID 27983603.
- ^ PMID 24944896.
- ^ S2CID 26425698.
- PMID 8536636.
- PMID 7539101.
- S2CID 23332777.
- PMID 23724059.
- S2CID 27701532.
- ^ PMID 35857636.
- S2CID 221825661.
- PMID 33758421.
- ^ PMID 12482853.
- ^ PMID 9407140.
- ^ PMID 10336495.
- PMID 9626662.
- PMID 22107727.
Further reading
- Rakhshandehroo M, Hooiveld G, Müller M, Kersten S (2009). "Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human". PLOS ONE. 4 (8): e6796. PMID 19710929.
- Berger J, Moller DE (2002). "The mechanisms of action of PPARs". Annu. Rev. Med. 53: 409–35. PMID 11818483.
- Kuenzli S, Saurat JH (2003). "Peroxisome proliferator-activated receptors in cutaneous biology". Br. J. Dermatol. 149 (2): 229–36. S2CID 644071.
- Mandard S, Müller M, Kersten S (2004). "Peroxisome proliferator-activated receptor alpha target genes". Cell. Mol. Life Sci. 61 (4): 393–416. S2CID 39380100.
- 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. S2CID 24728859.
- Lefebvre P, Chinetti G, Fruchart JC, Staels B (2006). "Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis". J. Clin. Invest. 116 (3): 571–80. PMID 16511589.
- 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. S2CID 28301985.
- Miyata KS, McCaw SE, Patel HV, Rachubinski RA, Capone JP (1996). "The orphan nuclear hormone receptor LXR alpha interacts with the peroxisome proliferator-activated receptor and inhibits peroxisome proliferator signaling". J. Biol. Chem. 271 (16): 9189–92. PMID 8621574.
- Chu R, Lin Y, Rao MS, Reddy JK (1996). "Cloning and identification of rat deoxyuridine triphosphatase as an inhibitor of peroxisome proliferator-activated receptor alpha". J. Biol. Chem. 271 (44): 27670–6. PMID 8910358.
- Tugwood JD, Aldridge TC, Lambe KG, Macdonald N, Woodyatt NJ (1997). "Peroxisome proliferator-activated receptors: structures and function". Ann. N. Y. Acad. Sci. 804: 252–65. S2CID 84519126.
- Li H, Gomes PJ, Chen JD (1997). "RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2". Proc. Natl. Acad. Sci. U.S.A. 94 (16): 8479–84. PMID 9238002.
- Dowell P, Ishmael JE, Avram D, Peterson VJ, Nevrivy DJ, Leid M (1998). "p300 functions as a coactivator for the peroxisome proliferator-activated receptor alpha". J. Biol. Chem. 272 (52): 33435–43. PMID 9407140.
- Inoue I, Shino K, Noji S, Awata T, Katayama S (1998). "Expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary cultures of human vascular endothelial cells". Biochem. Biophys. Res. Commun. 246 (2): 370–4. PMID 9610365.
- Treuter E, Albrektsen T, Johansson L, Leers J, Gustafsson JA (1998). "A regulatory role for RIP140 in nuclear receptor activation". Mol. Endocrinol. 12 (6): 864–81. PMID 9626662.
- Rubino D, Driggers P, Arbit D, Kemp L, Miller B, Coso O, Pagliai K, Gray K, Gutkind S, Segars J (1998). "Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action". Oncogene. 16 (19): 2513–26. PMID 9627117.
- Yuan CX, Ito M, Fondell JD, Fu ZY, Roeder RG (1998). "The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion". Proc. Natl. Acad. Sci. U.S.A. 95 (14): 7939–44. PMID 9653119.
- Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, Fruchart JC, Chapman J, Najib J, Staels B (1998). "Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages". J. Biol. Chem. 273 (40): 25573–80. PMID 9748221.
- Costet P, Legendre C, Moré J, Edgar A, Galtier P, Pineau T (1998). "Peroxisome proliferator-activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis". J. Biol. Chem. 273 (45): 29577–85. PMID 9792666.
- Masuda N, Yasumo H, Furusawa T, Tsukamoto T, Sadano H, Osumi T (1998). "Nuclear receptor binding factor-1 (NRBF-1), a protein interacting with a wide spectrum of nuclear hormone receptors". Gene. 221 (2): 225–33. PMID 9795230.
- Rakhshandehroo M, Sanderson LM, Matilainen M, Stienstra R, Carlberg C, de Groot PJ, Müller M, Kersten S (2007). "Comprehensive analysis of PPARalpha-dependent regulation of hepatic lipid metabolism by expression profiling". PPAR Res. 2007: 1–13. PMID 18288265.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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