PPARGC1A explained

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] PGC-1α is also the primary regulator of liver gluconeogenesis, inducing increased gene expression for gluconeogenesis.[6]

Function

PGC-1α is a gene that contains two promoters, and has 4 alternative splicings. PGC-1α is a transcriptional coactivator that regulates the genes involved in energy metabolism. It is the master regulator of mitochondrial biogenesis. 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 activity of, cAMP response element-binding protein (CREB) and nuclear respiratory factors (NRFs) . PGC-1α provides a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis, and is a major factor causing slow-twitch rather than fast-twitch muscle fiber types.[7]

Endurance exercise has been shown to activate the PGC-1α gene in human skeletal muscle.[8] Exercise-induced PGC-1α in skeletal muscle increases autophagy[9] [10] and unfolded protein response.[11]

PGC-1α protein may also be involved in controlling blood pressure, regulating cellular cholesterol homeostasis, and the development of obesity.[12]

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 and reactive nitrogen species, both formed endogenously in the cell as by-products of metabolism but upregulated during times of cellular stress.
  2. Fasting can also increase gluconeogenic gene expression, including hepatic PGC-1α.[13] [14]
  3. It is strongly induced by cold exposure, linking this environmental stimulus to adaptive thermogenesis.[15]
  4. It is induced by endurance exercise 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.[16]
  5. cAMP response element-binding (CREB) proteins, activated by an increase in cAMP following external cellular signals.
  6. 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.
  7. SIRT1 binds and activates PGC-1α through deacetylation inducing gluconeogenesis without affecting mitochondrial biogenesis.[17]

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.[18]
  2. PGC-1α leads to calcineurin activation.[19]

Akt and calcineurin are both activators of NF-kappa-B (p65).[20] [21] 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.[22] The finding seems to be controversial. Other groups found that PGC-1s inhibit NF-kappa-B activity.[23] 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.[24]

Clinical significance

Recently PPARGC1A has been implicated as a potential therapy for Parkinson's disease conferring protective effects on mitochondrial metabolism.[25]

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.[26] [27]

Massage therapy appears to increase the amount of PGC-1α, which leads to the production of new mitochondria.[28] [29] [30]

PGC-1α and beta has furthermore been implicated in polarization to anti-inflammatory M2 macrophages by interaction with PPAR-γ[31] with upstream activation of STAT6.[32] 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.[33]

PGC-1α has been recently proposed to be responsible for β-aminoisobutyric acid secretion by exercising muscles.[34] 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.[35] [36] 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 glucokinase (GK) and SIRT3, binding to an ERRE element in the GK and SIRT3 promoters.

See also

Further reading

Notes and References

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  2. Pollard KS, Salama SR, Lambert N, Lambot MA, Coppens S, Pedersen JS, Katzman S, King B, Onodera C, Siepel A, Kern AD, Dehay C, Igel H, Ares M, Vanderhaeghen P, Haussler D . An RNA gene expressed during cortical development evolved rapidly in humans . Nature . 443 . 7108 . 167–72 . September 2006 . 16915236 . 10.1038/nature05113 . 2006Natur.443..167P . 18107797 .
  3. Valero T . 2014 . Mitochondrial biogenesis: pharmacological approaches . . 20 . 35 . 5507–9 . 10.2174/138161282035140911142118 . 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. . free . 10454/13341.
  4. Sanchis-Gomar F, García-Giménez JL, Gómez-Cabrera MC, Pallardó FV . Mitochondrial biogenesis in health and disease. Molecular and therapeutic approaches . Curr. Pharm. Des. . 20 . 35 . 5619–5633 . 2014 . 24606801 . 10.2174/1381612820666140306095106. Mitochondrial biogenesis (MB) is the essential mechanism by which cells control the number of mitochondria. .
  5. Dorn GW, Vega RB, Kelly DP . 2015 . Mitochondrial biogenesis and dynamics in the developing and diseased heart . . 29 . 19 . 1981–91 . 10.1101/gad.269894.115 . 4604339 . 26443844.
  6. Klein MA, Denu JM . Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators . . 295 . 32 . 11021–11041 . 2020 . 10.1074/jbc.REV120.011438. 7415977 . 32518153. free .
  7. Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM . Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres . . 418 . 6899 . 797–801 . 2002 . 10.1038/nature00904 . 12181572 . 2002Natur.418..797L . 4415526 .
  8. Pilegaard H, Saltin B, Neufer PD . February 2003 . Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle . . 546 . Pt 3 . 851–8 . 10.1113/jphysiol.2002.034850 . 2342594 . 12563009.
  9. Vainshtein A, Tryon LD, Pauly M, Hood DA . Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle . . 308 . 9 . C710-719 . 2015 . 10.1152/ajpcell.00380.2014. 25673772 . 4420796 .
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  11. Wu J, Ruas JL, Estall JL, Rasbach KA, Choi JH, Ye L, Boström P, Tyra HM, Crawford RW, Campbell KP, Rutkowski DT, Kaufman RJ, Spiegelman BM . The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex . . 13 . 2 . 160–169 . 2011 . 10.1016/j.cmet.2011.01.003 . 3057411 . 21284983 .
  12. Web site: Entrez Gene: PPARGC1A peroxisome proliferator-activated receptor gamma, coactivator 1 alpha.
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  16. Summermatter S, Santos G, Pérez-Schindler J, Handschin C . May 2013 . Skeletal muscle PGC-1α controls whole-body lactate homeostasis through estrogen-related receptor α-dependent activation of LDH B and repression of LDH A . . 110 . 21 . 8738–43 . 2013PNAS..110.8738S . 10.1073/pnas.1212976110 . 3666691 . 23650363 . free.
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