• Source: Pparg coactivator 1 alpha

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein that in humans is encoded by the PPARGC1A gene. PPARGC1A is also known as human accelerated region 20 (HAR20). It may, therefore, have played a key role in differentiating humans from apes.
PGC-1α is the master regulator of mitochondrial biogenesis. PGC-1α is also the primary regulator of liver gluconeogenesis, inducing increased gene expression for gluconeogenesis.




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.
Endurance exercise has been shown to activate the PGC-1α gene in human skeletal muscle. Exercise-induced PGC-1α in skeletal muscle increases autophagy and unfolded protein response.
PGC-1α protein may also be involved in controlling blood pressure, regulating cellular cholesterol homeostasis, and the development of obesity.




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:

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.
Fasting can also increase gluconeogenic gene expression, including hepatic PGC-1α.
It is strongly induced by cold exposure, linking this environmental stimulus to adaptive thermogenesis.
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.
cAMP response element-binding (CREB) proteins, activated by an increase in cAMP following external cellular signals.
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.
SIRT1 binds and activates PGC-1α through deacetylation inducing gluconeogenesis without affecting mitochondrial biogenesis.
PGC-1α has been shown to exert positive feedback circuits on some of its upstream regulators:

PGC-1α increases Akt (PKB) and Phospho-Akt (Ser 473 and Thr 308) levels in muscle.
PGC-1α leads to calcineurin activation.
Akt and calcineurin are both activators of NF-kappa-B (p65). 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. The finding seems to be controversial. Other groups found that PGC-1s inhibit NF-kappa-B activity. 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.




Clinical significance


PPARGC1A has been implicated as a potential therapy for Parkinson's disease conferring protective effects on mitochondrial metabolism.
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.
Massage therapy appears to increase the amount of PGC-1α, which leads to the production of new mitochondria.
PGC-1α and beta has furthermore been implicated in polarization to anti-inflammatory M2 macrophages by interaction with PPAR-γ with upstream activation of STAT6. 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.
PGC-1α has been recently proposed to be responsible for β-aminoisobutyric acid secretion by exercising muscles. 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. This suggests that some of the reported effects of PGC-1α are likely to occur only in the developmental stage.
In the metabolic disorder of combined malonic and methylmalonic aciduria (CMAMMA) due to ACSF3 deficiency, there is a massively increased expression of PGC-1α, which is consistent with upregulated beta oxidation.




Interactions


PPARGC1A has been shown to interact with:

CREB-binding protein
Estrogen-related receptor alpha (ERRα), estrogen-related receptor beta (ERR-β), estrogen-related receptor gamma (ERR-γ).
Farnesoid X receptor
FBXW7
MED1, MED12, MED14, MED17,
NRF1
Peroxisome proliferator-activated receptor gamma
Retinoid X receptor alpha
Thyroid hormone receptor beta
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


MB-3 (drug)
PPARGC1B
Transcription coregulator




References






Further reading






External links


PPARGC1A protein, human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
NURSA C110
FactorBook PGC1A
Overview of all the structural information available in the PDB for UniProt: Q9UBK2 (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.

Kata Kunci Pencarian:

• Pparg coactivator 1 alpha
• Peroxisome proliferator-activated receptor gamma
• PPARGC1B
• Thiazolidinedione
• Forkhead box protein O1
• Nuclear receptor
• EP300
• Peroxisome proliferator-activated receptor
• RELA
• PPRC1