PPARGC1A

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PGC-1α
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PPARGC1A
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000109819

ENSMUSG00000029167

UniProt

Q9UBK2

O70343

RefSeq (mRNA)

NM_013261
NM_001330751
NM_001330752
NM_001330753

NM_008904

RefSeq (protein)
Location (UCSC)n/aChr 5: 51.61 – 51.73 Mb
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein that in humans is encoded by the PPARGC1A gene.[4] PPARGC1A is also known as human accelerated region 20 (HAR20). It may, therefore, have played a key role in differentiating humans from apes.[5]

PGC-1α is the

master regulator of mitochondrial biogenesis.[6][7][8] PGC-1α is also the primary regulator of liver gluconeogenesis, inducing increased gene expression for gluconeogenesis.[9]

Function

PGC-1α is a gene that contains two promoters, and has 4 alternative splicings. PGC-1α is a transcriptional

muscle fiber types.[10]

Endurance exercise has been shown to activate the PGC-1α gene in human skeletal muscle.[11] Exercise-induced PGC-1α in skeletal muscle increases autophagy[12][13] and unfolded protein response.[14]

PGC-1α protein may also be involved in controlling blood pressure, regulating cellular cholesterol homeostasis, and the development of obesity.[15]

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. upregulated
    during times of cellular stress.
  2. Fasting can also increase gluconeogenic gene expression, including hepatic PGC-1α.[16][17]
  3. It is strongly induced by cold exposure, linking this environmental stimulus to adaptive thermogenesis.[18]
  4. It is induced by endurance exercise[11] 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.[19]
  5. cAMP response element-binding (CREB) proteins, activated by an increase in cAMP following external cellular signals.
  6. Protein kinase B (
    PI3K after G protein
    signals. The Akt family is also known to activate pro-survival signals as well as metabolic activation.
  7. deacetylation inducing gluconeogenesis without affecting mitochondrial biogenesis.[20]

PGC-1α has 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.[21]
  2. PGC-1α leads to calcineurin activation.[22]

Akt and calcineurin are both activators of

NF-kappa-B (p65).[23][24] 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.[25] The finding seems to be controversial. Other groups found that PGC-1s inhibit NF-kappa-B activity.[26]
The effect was demonstrated for PGC-1 alpha and beta.

PGC-1α has also been shown to drive NAD biosynthesis to play a large role in renal protection in acute kidney injury.[27]

Clinical significance

Recently PPARGC1A has been implicated as a potential therapy for Parkinson's disease conferring protective effects on mitochondrial metabolism.[28]

Moreover, brain-specific isoforms of PGC-1alpha have recently been identified which are likely to play a role in other neurodegenerative disorders such as

amyotrophic lateral sclerosis.[29][30]

Massage therapy appears to increase the amount of PGC-1α, which leads to the production of new mitochondria.[31][32][33]

PGC-1α and beta has furthermore been implicated in polarization to anti-inflammatory

proinflammatory cytokine production.[36]

PGC-1α has been recently proposed to be responsible for β-aminoisobutyric acid secretion by exercising muscles.[37] 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.

PGC-1α increases BNP expression by coactivating ERRα and / or AP1. Subsequently, BNP induces a chemokine cocktail in muscle fibers and activates macrophages in a local paracrine manner, which can then contribute to enhancing the repair and regeneration potential of trained muscles.

Most studies reporting effects of PGC-1α on physiological functions have used mouse models in which the PGC-1α gene is either knocked out or overexpressed from conception. However, some of the proposed effects of PGC-1α have been questioned by studies using inducible knockout technology to remove the PGC-1α gene only in adult mice. For example, two independent studies have shown that adult expression of PGC-1α is not required for improved mitochondrial function after exercise training.[38][39] This suggests that some of the reported effects of PGC-1α are likely to occur only in the developmental stage.

Interactions

PPARGC1A has been shown to

interact
with:

ERRα and PGC-1α are coactivators of both

SIRT3, binding to an ERRE element in the GK and SIRT3 promoters.[citation needed
]

See also

References

  1. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029167 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. PMID 10585775
    .
  5. S2CID 18107797
    .
  6. ^
    PMID 24606795
    . Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass [3]. ... This work reviews different strategies to enhance mitochondrial bioenergetics in order to ameliorate the neurodegenerative process, with an emphasis on clinical trials reports that indicate their potential. Among them creatine, Coenzyme Q10 and mitochondrial targeted antioxidants/peptides are reported to have the most remarkable effects in clinical trials.
  7. ^
    PMID 24606801
    . Mitochondrial biogenesis (MB) is the essential mechanism by which cells control the number of mitochondria.
  8. ^
    PMID 26443844
    .
  9. PMID 32518153
    .
  10. S2CID 4415526
    .
  11. ^
    PMID 12563009
    .
  12. PMID 25673772
    .
  13. PMID 26869683
    .
  14. PMID 21284983
    .
  15. ^ "Entrez Gene: PPARGC1A peroxisome proliferator-activated receptor gamma, coactivator 1 alpha".
  16. PMID 16271533.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  17. S2CID 11184579
    .
  18. S2CID 835984
    .
  19. PMID 23650363
    .
  20. S2CID 4380393
    .
  21. PMID 22143799
    .
  22. PMID 21918181
    .
  23. PMID 15653325
    .
  24. S2CID 7184948
    .
  25. PMID 22384185
    .
  26. PMID 20404331
    .
  27. PMID 26982719
    .
  28. PMID 20926834
    .
  29. PMID 22589246
    .
  30. PMID 23669350
    .
  31. S2CID 2610669
    .
  32. ^ Brown E (2012-02-01). "Study works out kinks in understanding of massage". Los Angeles Times.
  33. ^ "Videos | The Buck Institute for Research on Aging". Buckinstitute.org. Retrieved 2013-10-11.
  34. PMID 20723894
    .
  35. PMID 22448168
    .
  36. PMID 16814729
    .
  37. PMID 24411942
    .
  38. PMID 27780821
    .
  39. S2CID 195786475
    .
  40. ^
    PMID 10558993
    .
  41. PMID 15087503
    .
  42. PMID 14729567
    .
  43. PMID 18198341
    .
  44. ^
    PMID 14636573
    .
  45. S2CID 16143809
    .
  46. PMID 11714715
    .
  47. PMID 11751919
    .

Further reading

External links

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

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