PPARGC1A

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Lua error in Module:Infobox_gene at line 33: attempt to index field 'wikibase' (a nil value). 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 the master regulator of mitochondrial biogenesis.[3][4][5]

Function

PGC-1α is a transcriptional coactivator that regulates the genes involved in energy metabolism. It is the master regulator of mitochondrial biogenesis.[3][4][5] 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.[6] This protein may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.[7]

Regulation

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.[8]
  3. It is induced by endurance exercise[6] 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.[9]
  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 PI3K 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.[10]
  2. PGC-1α leads to calcineurin activation.[11]

Akt and calcineurin are both activators of NF kappa B (p65).[12][13] Through their activation PGC-1α seems to activate NF kappa B. Increased activity of NF kappa B in muscle has recently been demonstrated following induction of PGC-1α.[14] The finding seems to be controversial. Other groups found that PGC-1s inhibit NF kappa B activity.[15] 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.[16]

Moreover, brain-specific isoforms of PGC-1alpha have recently been identified which are likely to play a role in other neurodegenerative disorders such as Huntington's disease and Amyotrophic lateral sclerosis.[17][18]

Massage therapy appears to increase the amount of PGC-1α which leads to the production of new mitochondria.[19][20][21]

PGC-1α and beta has furthermore been implicated in M2 macrophage polarization by interaction with PPARγ[22] with upstream activation of STAT6.[23] 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.[24]

PGC-1α has been recently proposed to be responsible for β-aminoisobutyric acid secretion by exercising muscles.[25] The effect of β-aminoisobutyric acid in white fat includes the activation of thermogenic genes that prompt the browning of white adipose tissue and the consequent increase of background metabolism. Hence, the β-aminoisobutyric acid could act as a messenger molecule of PGC-1α and explain the effects of PGC-1α increase in other tissues such as white fat.

Interactions

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

References

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Further reading

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External links

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

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  17. ↑ Soyal SM, Felder TK, Auer S, Hahne P, Oberkofler H, Witting A, Paulmichl M, Landwehrmeyer GB, Weydt P, Patsch W. A greatly extended PPARGC1A genomic locus encodes several new brain specific isoforms and influences Huntington Disease age-of-onset. Hum Mol Genet. 2012;21:3461-3473.
  18. ↑ Eschbach J*, Schwalenstöcker B*, Soyal S*, Bayer Wiesner D, Akimoto C, Nilsson A-C, Birve A, Meyer T, Dupuis is a-L, Danzer K, Andersen PM, Witting A, Ludolph AC, Patsch W, Weydt P. PGC-1 male-specific disease modifier of human and experimental amyotrophic lateral sclerosis. Hum Mol Genet 2013;22:3477-3484.
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  25. ↑ http://www.cell.com/cell-metabolism/retrieve/pii/S155041311300497X
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