PPARGC1A

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.^[6][7][8] 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) ^{[citation needed]}. 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.^[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]

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.^[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 (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.^[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]

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 Huntington's disease and 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 M2 macrophages by interaction with PPAR-γ^[34] with upstream activation of STAT6.^[35] 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.^[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.

PPARGC1A has been shown to interact with:

• CREB-binding protein^[40]
• Estrogen-related receptor alpha (ERRα),^[41] estrogen-related receptor beta (ERR-β), estrogen-related receptor gamma (ERR-γ).
• Farnesoid X receptor^[42]
• FBXW7^[43]
• MED1,^[44] MED12,^[44] MED14,^[44] MED17,^[44]
• NRF1^[45]
• Peroxisome proliferator-activated receptor gamma^[40][44]
• Retinoid X receptor alpha^[46]
• Thyroid hormone receptor beta^[47]

ERRα and PGC-1α are coactivators of both glucokinase (GK) and SIRT3, binding to an ERRE element in the GK and SIRT3 promoters.^{[citation needed]}

• MB-3 (drug)
• PPARGC1B
• Transcription coregulator

• 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.