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Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha
Available structures
PDB Ortholog search: RCSB
RNA expression pattern

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein that in humans is encoded by the PPARGC1A gene.[1]

PPARGC1A is also known as human accelerated region 20 (HAR20). It may, therefore, have played a key role in differentiating humans from apes.[2]


PGC-1α is a transcriptional coactivator that regulates the genes involved in energy metabolism. PGC-1α is a regulator of mitochondrial biogenesis and function.[3] This protein interacts with the nuclear receptor PPAR-γ, which permits the interaction of this protein with multiple transcription factors. This protein can interact with, and regulate the activities of, cAMP response element-binding protein (CREB) and nuclear respiratory factors (NRFs). It provides a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis, and is a major factor that regulates muscle fiber type determination. Endurance exercise has been shown to activate the PGC-1α gene in human skeletal muscle.[4] This protein may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.[5]


PGC-1α is thought to be a master integrator of external signals. It is known to be activated by a host of factors, including:

  1. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), both formed endogenously in the cell as by-products of metabolism but upregulated during times of cellular stress.
  2. It is strongly induced by cold exposure, linking this environmental stimulus to adaptive thermogenesis.[6]
  3. It is induced by endurance exercise[4] and recent research has shown that PGC-1α determines lactate metabolism, thus preventing high lactate levels in endurance athletes and making lactate as an energy source more efficient.[7]
  4. cAMP response element-binding (CREB) proteins, activated by an increase in cAMP following external cellular signals.
  5. Protein kinase B / Akt is thought to downregulate PGC-1α, but upregulate its downstream effectors, NRF1 and NRF2. Akt itself is activated by PIP3, often upregulated by IP3K after G-protein signals. The Akt family is also known to activate pro-survival signals as well as metabolic activation.
  6. SIRT1 binds and activates PGC-1α through deacetylation.

PGC-1α has recently been shown to exert positive feedback circuits on some of its upstream regulators:

  1. PGC-1α increases Akt (PKB) and Phospho-Akt (Ser 473 and Thr 308) levels in muscle.[8]
  2. PGC-1α leads to calcineurin activation.[9]

Akt and calcineurin are both activators of NF kappa B (p65).[10][11] Through their activation PGC-1α seems to acivate NF kappa B. Increased activity of NF kappa B in muscle has recently been demonstrated following induction of PGC-1α.[12] The finding seems to be controversial. Other groups found that PGC-1s inhibit NF kappa B activity.[13] The effect was demonstrated for PGC-1 alpha and beta.

Clinical significance

Recently PPARGC1A has been implicated as a potential therapy for Parkinson's Disease conferring protective effects on mitochondrial metabolism.[14]

Massage therapy appears to increase the amount of PGC-1α which leads to the production of new mitochondria.[15][16][17]

PGC-1α and beta has furthermore been implicated in M2 macrophage polarization by interaction with PPARγ[18] with upstream activation of STAT6.[19] An independent study confirmed the effect of PGC-1 on polarisation of macrophages towards M2 via STAT6/PPAR gamma and furthermore demonstrated that PGC-1 inhibits proinflammatory cytokine production.[20]


PPARGC1A has been shown to interact with:

ERRalpha and PGC-1α are coactivators of both Glucokinase (GK) and SIRT3, binding to an ERRE elements in the GK and SIRT3 promoters.

See also


Further reading

External links

  • Medical Subject Headings (MeSH)
  • C110

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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