World Library  
Flag as Inappropriate
Email this Article
 

Ppargc1a

Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha
1XB7
Available structures
PDB Ortholog search: RCSB
Identifiers
PPARGC1A Gene
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]

Function

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]

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.[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]

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

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.

This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and USA.gov, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for USA.gov and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
 
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
 
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.
 



Copyright © World Library Foundation. All rights reserved. eBooks from Hawaii eBook Library are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.