peroxisome proliferator-activated receptor alpha; PPAR-alpha; nuclear receptor subfamily 1 group C member 1 (PPARA, NR1C1, PPAR)

Function

• activated by fatty acids & peroxisome proliferators
• binds to DNA as heterodimer with RXR
• physiologic roles:
  • lipid metabolism
    • inhibition of adipocyte differentiation
    • upregulation of enzymes that regulate lipolysis & fatty acid oxidation in adipocytes
  • down-regulation of inflammation
• forms heterodimers with retinoic acid receptor-X (RXR); the PPAR-alpha/RXR heterodimer binds to the PPRE enhancer element.
• activated PPAR-alpha/RXR:
  • inhibits:
    • AP1 via binding to jun
    • NF-kappa B via binding to p65
  • may compete other nuclear receptors for RXRE enhancer elements (improper fit may bind without activation)
  • induces peroxisome proliferation
  • induces beta-oxidation of fatty acids
• endogenous ligands (activators)
  • saturated fatty acids
    • palmitic acid [16:0] (3+)
    • stearic acid [18:0] (3+)
  • monounsaturated fatty acids
    • palmitoleic acid [16:1] (3+)
    • oleic acid [18:1] (3+)
    • elaidic acid [20:1] (2+)
  • polyunsaturated fatty acids
    • linoleic acid [18:2, n-6] (3+)
    • alpha-linolenic acid [18:3, n-3] (3+)
    • gamma-linolenic acid [18:3, n-6] (3+)
    • dihomo-gamma-linolenic acid [20:3, n-6] (3+)
    • arachidonic acid [20:4, n-6] (3+)
    • eicosapentaenoic acid [22:5, n-3] (3+)
    • docosahexaenoic acid [22:6, n-3] (2+)
  • eicosanoids
    • PGA1 (+)
    • PGA2 (+)
    • PGD1 (2+)
    • PGD2 (2+)
    • PGJ2 (+)
    • 15-deoxy-delta 12,14-PGJ2 (+)
    • 8(S)-HETE (3+)
    • 8-HEPE (2+)
    • LTB4 (+/-)
• coactivators include:
  • PPAR-binding protein
  • steroid coactivator-1 (SRC-1) (may be insignificant)
• corepressors include:
  • RXR-interacting protein 13 (nuclear receptor corepressor)
  • SMRT/TRAC c ) RIP140
• other interactions:
  • dUTPase prevents PPAR-RXR heterodimerization
  • HMG CoA synthase
    • not strictly coactivator but increases activity of PPAR-alpha
  • c-jun inhibits activation of PPAR-alpha/RXR (reciprocal inhibition)

* uncertain as to identity of these proteins

Expression

• liver, intestine (4+)
• kidney (2+)
• spleen (1+)

Pathology

• PPAR-alpha essential for hepatocarcinogenicity of peroxisome proliferators (mechanism unknown)

Pharmacology

Exogenous agonists: (peroxisome proliferators)

• hypolipidemic drugs
  • WY-14-643 (3+)
  • clofibrate (2+)
  • ciprofibrate (2+)
  • gemfibrozil (2+)
  • nafenopin (2+)
  • GW2331 (3+)
  • bezafibrate (1+)
• non-steroidal anti-inflammatory drugs (NSAIDs)
  • indomethacin (1+)
  • ibuprofen (1+)
  • fenoprofen (2+)
• other
  • monoethylhexyl phthalate (3+)
  • trichloroacetic acid (1+)
  • eicosatetraynoic acid (ETYA) (3+)
  • LTB4 antagonists
    • MK-571 (2+)
    • LY-171883 (2+)

More general terms

• peroxisome proliferator-activated receptor (PPAR)

Additional terms

• hydroxymethylglutaryl [HMG] CoA synthase
• peroxisome proliferator response element (PPRE)
• retinoid X receptor (RXR)

Database

• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:5465
• OMIM: https://mirror.omim.org/entry/170998
• UniProt: http://www.uniprot.org/uniprot/Q07869.html