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.^[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]

PPARGC1A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1XB7, 3B1M, 3CS8, 3D24, 3U9Q, 3V9T, 3V9V, 4QJR, 4QK4
Identifiers
Aliases	PPARGC1A, LEM6, PGC-1(alpha), PGC-1v, PGC1, PGC1A, PPARGC1, PGC-1alpha, PPARG coactivator 1 alpha, PGC-1α
External IDs	OMIM: 604517; MGI: 1342774; HomoloGene: 7485; GeneCards: PPARGC1A; OMA:PPARGC1A - orthologs
Gene location (Mouse) Chr. Chromosome 5 (mouse)[1] Band 5|5 C1 Start 51,611,592 bp[1] End 51,725,068 bp[1]
RNA expression pattern Bgee Human Mouse (ortholog) n/a Top expressed in atrioventricular valve retinal pigment epithelium lateral geniculate nucleus deep cerebellar nuclei medial vestibular nucleus dorsal tegmental nucleus substantia nigra ciliary body pontine nuclei barrel cortex BioGPS More reference expression data
Gene ontology Molecular function promoter-specific chromatin binding transcription factor binding chromatin binding protein binding nuclear receptor binding nucleic acid binding DNA binding sequence-specific DNA binding transcription coactivator activity alpha-tubulin binding transcription coregulator activity androgen receptor binding nuclear receptor coactivator activity RNA binding chromatin DNA binding ubiquitin protein ligase binding signaling receptor binding estrogen receptor binding peroxisome proliferator activated receptor binding Cellular component cytoplasm cytosol cytosolic ribosome nucleus RNA polymerase II, core complex apical dendrite soma PML body nucleoplasm intracellular membrane-bounded organelle Biological process negative regulation of neuron apoptotic process response to dietary excess negative regulation of glycolytic process response to fructose cellular response to interleukin-6 rhythmic process cellular response to resveratrol response to thyroid hormone cellular response to fructose stimulus cellular response to ionomycin adaptive thermogenesis response to ischemia circadian rhythm fatty acid oxidation response to metformin cellular response to caffeine response to electrical stimulus involved in regulation of muscle adaptation temperature homeostasis cellular response to hypoxia cellular response to glucose stimulus positive regulation of fatty acid oxidation cellular response to transforming growth factor beta stimulus positive regulation of progesterone biosynthetic process regulation of transcription, DNA-templated cellular response to follicle-stimulating hormone stimulus androgen metabolic process response to reactive oxygen species positive regulation of mitochondrial DNA metabolic process digestion response to leucine response to norepinephrine response to epinephrine transcription, DNA-templated negative regulation of mitochondrial fission positive regulation of transcription, DNA-templated positive regulation of glomerular visceral epithelial cell apoptotic process response to nutrient levels RNA splicing skeletal muscle atrophy cellular respiration negative regulation of signaling receptor activity positive regulation of gluconeogenesis transcription initiation from RNA polymerase II promoter cellular response to potassium ion negative regulation of neuron death negative regulation of protein phosphorylation positive regulation of cellular respiration mRNA processing protein stabilization mitochondrion organization positive regulation of DNA-binding transcription factor activity response to electrical stimulus circadian regulation of gene expression cerebellum development positive regulation of ATP biosynthetic process regulation of NMDA receptor activity galactose metabolic process positive regulation of muscle tissue development regulation of circadian rhythm flavone metabolic process adipose tissue development respiratory electron transport chain positive regulation of cellular metabolic process response to muscle activity cellular response to nitrite positive regulation of smooth muscle cell proliferation gluconeogenesis androgen receptor signaling pathway negative regulation of smooth muscle cell proliferation response to hypoxia response to organic cyclic compound cellular glucose homeostasis cellular response to tumor necrosis factor cellular response to estradiol stimulus human ageing negative regulation of smooth muscle cell migration response to activity positive regulation of histone acetylation cellular response to fatty acid autophagy of mitochondrion cellular response to thyroid hormone stimulus response to methionine response to starvation response to cold cellular response to oxidative stress forebrain development cellular response to lipopolysaccharide positive regulation of transcription by RNA polymerase II positive regulation of mitochondrion organization brown fat cell differentiation protein-containing complex assembly energy homeostasis positive regulation of gene expression positive regulation of cold-induced thermogenesis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10891 19017 Ensembl ENSG00000109819 ENSMUSG00000029167 UniProt Q9UBK2 O70343 RefSeq (mRNA) NM_013261 NM_001330751 NM_001330752 NM_001330753 NM_008904 RefSeq (protein) NP_001317680 NP_001317681 NP_001317682 NP_037393 NP_001341754 NP_001341755 NP_001341756 NP_001341757 NP_032930 NP_001389916 NP_001389917 NP_001389918 NP_001389919 NP_001389920 Location (UCSC) n/a Chr 5: 51.61 – 51.73 Mb PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

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 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]

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.^[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]

Clinical significance

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.

Interactions

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]}

See also

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

References

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Further reading

• Hasstedt SJ, Ren QF, Teng K, Elbein SC (February 2001). "Effect of the peroxisome proliferator-activated receptor-gamma 2 pro(12)ala variant on obesity, glucose homeostasis, and blood pressure in members of familial type 2 diabetic kindreds". J. Clin. Endocrinol. Metab. 86 (2): 536–41. doi:10.1210/jcem.86.2.7205. PMID 11158005.
• Andersson U, Scarpulla RC (June 2001). "Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells". Mol. Cell. Biol. 21 (11): 3738–49. doi:10.1128/MCB.21.11.3738-3749.2001. PMC 87014. PMID 11340167.
• Ek J, Andersen G, Urhammer SA, Gaede PH, Drivsholm T, Borch-Johnsen K, Hansen T, Pedersen O (December 2001). "Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus". Diabetologia. 44 (12): 2220–6. doi:10.1007/s001250100032. PMID 11793024.
• Oberkofler H, Esterbauer H, Linnemayr V, Strosberg AD, Krempler F, Patsch W (May 2002). "Peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1 recruitment regulates PPAR subtype specificity". J. Biol. Chem. 277 (19): 16750–7. doi:10.1074/jbc.M200475200. PMID 11875072.
• Esterbauer H, Oberkofler H, Linnemayr V, Iglseder B, Hedegger M, Wolfsgruber P, Paulweber B, Fastner G, Krempler F, Patsch W (April 2002). "Peroxisome proliferator-activated receptor-gamma coactivator-1 gene locus: associations with obesity indices in middle-aged women". Diabetes. 51 (4): 1281–6. doi:10.2337/diabetes.51.4.1281. PMID 11916956.
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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.