PGC-1a

Co-activator of PPAR-gamma

PGC-1α is a co-activator of the nuclear receptor PPARγ, and it is highly expressed when energy requirements are high. PGC-1α is not expressed in tissues such as myocardium, skeletal muscle, nervous system, liver, kidney, and adipose tissue, and mainly regulates the synthesis of mitochondrial proteins (including respiratory chain complex subunits) by activating the nuclear transcription factor NRF1. (R6)

Regulation (from Wikipedia)

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.

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

Source: Wikipedia

Mitochondrial biogenesis

The mitochondrial biogenesis “master regulator” PGC-1α is reduced in aged mouse knee cartilages. PGC-1α acts by inducing transcription of nuclear respiratory factors (e.g. NRF1 and NRF2), thereby increasing expression of mitochondrial transcription factor A (TFAM), as well as other nuclear-encoded mitochondria respiratory chain complex subunits.

Induced TFAM translocates to the mitochondrion, where it stimulates mitochondrial biogenesis as manifested by stimulation of mitochondrial DNA replication and mitochondrial gene expression (R2)

AMPK + SIRT1

AMPK phosphorylates and then SIRT1 deacetylates PGC1a to make it active, and the process is NAD-dependent:

PGC-1α activity is modulated by phosphorylation and NAD+-dependent deacetylation via the functionally interactive metabolic biosensors AMP-activated protein kinase (AMPK) and sirtuin-1 (SIRT1), respectively (23,24).

AMPK phosphorylates PGC-1α protein, which triggers SIRT1-mediated deacetylation and activation of PGC-1α (23,24).

Activation of AMPK also stimulates SIRT1 activation by increasing the intracellular concentration of NAD+ (23,24).

In chondrocytes, activation of AMPK suppresses NF-κB activation, oxidative stress and multiple inflammatory and pro-catabolic responses (19,25,26). Importantly, PGC-1α is required for AMPK to suppress oxidative stress and pro-catabolic responses in chondrocytes (21). (R2)

Glucose homeostasis

A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1alpha at specific lysine residues in an NAD(+)-dependent manner.

SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1alpha, but does not regulate the effects of PGC-1alpha on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate.

Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1alpha. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan. (R7)

Chronic exercise

Thus, changes in muscle plasticity induced by chronic exercise, for example fiber-type switching towards the more oxidative and high endurance type IIa and type I fibers, correlate with an increased basal expression of PGC-1α.

Furthermore, higher levels of PGC-1α are found in oxidative fibers compared to glycolytic fibers, even in a rested state. (R3)

Methionine cycle

In this study, we found that the expression of key enzymes involved in Hcy metabolism is induced in the liver in response to fasting.

This induction coincides with increased expression of peroxisome proliferator-activated receptor- coactivator (PGC)-1, a transcriptional coactivator that regulates hepatic gluconeogenesis and mitochondrial function.

PGC-1 stimulates the expression of genes involved in Hcy metabolism in cultured primary hepatocytes as well as in the liver. (R5)

PGC-1α is a master regulator of lipid metabolism and fatty acid oxidation. It is regulated by methylation and acetylation. The deacetylation of the PGC-1α protein leads to its activation and is known to coactivate PPAR-α to enhance the expression of fatty acid oxidation genes, antioxidant enzymes, and mitochondrial biogenesis.

Methyl-deficient diets decrease the expression of SIRT1 and subsequent activation of PGC-1α through imbalanced acetylation and methylation of the latter dysregulating energy metabolism.

The impaired expression and/or activity of methionine synthase in fibroblasts from patients with mutations in MTR and/or other inherited disorders of vitamin B12 metabolism also result in decreased protein expression of SIRT1, which plays a key role in the underlying pathological mechanisms of these disorders (R15)

Impaired fat oxidation

subjects with a family history of type 2 diabetes had an impaired ability to increase fatty acid oxidation in response to the high-fat meal.

This was related to impaired activation of genes involved in lipid metabolism, including those for peroxisome proliferator-activated receptor coactivator-1alpha (PGC1alpha) and fatty acid translocase (FAT)/CD36.

Of interest, adiponectin receptor-1 expression decreased 23% after the high-fat meal in both groups, but it was not changed after the high-carbohydrate meal.

In conclusion, an impaired ability to increase fatty acid oxidation precedes the development of insulin resistance in genetically susceptible individuals. PGC1alpha and FAT/CD36 are likely candidates in mediating this response. (R8)

It seems that PGC-1a expression response is not only reduced relatively to the control, but it actually goes downwards, while it’s increased in the control group:

In our study in response to a physiological fat bolus, we observed that PGC1α expression tended toward an increase in response to a high-fat meal in control subjects, but relatives of individuals with type 2 diabetes tended to decrease PGC1α expression.

Similarly, we observed that FAT/CD36 expression tended to increase in control subjects after the high-fat meal, but it was reduced in the group with the strong genetic predisposition to type 2 diabetes. (R8)

Fasting Response

Mice deficient in PGC-1fail to activate adaptive responses following various environmental and physiological stresses.

In particular, hepatic fasting response is impaired in PGC-1 null mice and in hepatocytes isolated from these mice, suggesting that this factor serves as a nodal point in the regulation of energy metabolism in the liver. (R5)

As expected, PGC-1mRNA expression is increased by approximately fourfold in the liver after overnight fasting, and it returns to the fed levels following refeeding. (R5)

Fasting increases expression of MAT1A, AHCY and BHMT. However MAT2A, CBS, MTR and MTRR remain unchanged:

The mRNA levels of Mat1a, Ahcy, and Bhmt are also significantly elevated in response to starvation… In contrast, the expression of Mat2a, Cbs, Mtr, and Mtrr remains unchanged under these conditions… As expected, the concentration of methionine is lower in the liver in response to fasting. On the contrary, plasma total Hcy level is significantly increased by starvation. (R5)

This seems like the right half of the methionine cycle is up-regulated, but not the left side and not the transsulfuration pathway, and since BHMT depends on TMG, recycling of Met doesn’t happen efficiently.

Whereas AdoMet and AdoHcy levels remain similar in transduced livers, hepatic methionine concentrations are decreased by 41% in response to PGC-1a. (R5)

Coordination of fasting response

The adaptation of the liver to fasting is mediated by several transcription factors, including cAMP-responsive element-binding protein (CREB), hepatocyte nuclear factor 4 α (HNF4α), forkhead box protein O1 (FOXO1), nuclear respiratory factor 1 (NRF1), and peroxisome proliferator-activated receptor α (PPARα), which activate specific but overlapping sets of target genes. CREB, HNF4α, and FOXO1 are particularly important for the induction of gluconeogenesis, whereas PPARα is important for induction of genes involved in mitochondrial and peroxisomal β-oxidation and ketogenesis. (R9).

Heme synthesis

PGC1a regulates 5-aminolevulinate synthase (ALAS-1), but not the other enzymes in the heme synthesis pathway:

We show that the rate-limiting enzyme in hepatic heme biosynthesis, 5-aminolevulinate synthase (ALAS-1), is regulated by the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Elevation of PGC-1α in mice via adenoviral vectors increases the levels of heme precursors in vivo as observed in acute attacks. The induction of ALAS-1 by fasting is lost in liver-specific PGC-1α knockout animals, as is the ability of porphyrogenic drugs to dysregulate heme biosynthesis. These data show that PGC-1α links nutritional status to heme biosynthesis and acute hepatic porphyria. (R12)

In contrast to ALAS-1, none of the other seven genes of the heme biosynthetic pathway were induced by PGC-1α in rat liver (R12)

Involvement of Nrf1

In the ALAS-1 promoter, two binding sites for the nuclear respiratory factor-1 (NRF-1) have been identified. NRF-1 is a transcription factor that increases expression of nuclear-encoded mitochondrial genes and is known to be potently coactivated by PGC-1α. Thus, NRF-1 is a potential binding partner by which PGC-1α controls ALAS-1 expression. (R12)

Nrf2 is both a target and an upstream

PGC1a increased expression of Nrf2. But Nrf2 also increases expression of PGC1a:

3.5. Nrf2 Regulates PGC1α at the Transcriptional Level in SKOV3 Cells

The PGC1α promoter contains a conserved ARE sequence that can be bound by Nrf2, so we also determined whether Nrf2 directly binds to the PGC1α promoter after proteasome inhibition in SKOV3 cells. … We analyzed the PGC1α promoter sequence using the JASPAR database and predicted three potential Nrf2-binding fragments. … These data provide evidence that Nrf2 regulates PGC1α expression at the transcriptional level in SKOV3 cells. (R14)

S6K1

Resveratrol

PGC-1α can be activated by deacetylation reactions catalyzed by SIRT1. Resveratrol is currently known as a potent activator of SIRT1.

We found that high-glucose stimulation results in time-dependent decreases in the expression of SIRT1, PGC-1α, and its downstream genes NRF1 and mitochondrial transcription factor A (TFAM) for mouse podocytes, and increases ROS levels in cells and mitochondria. … Resveratrol can reduce the oxidative damage and apoptosis of podocytes induced by high-glucose stimulation via SIRT1/PGC-1α-mediated mitochondrial protection. (R6)

Coenzyme Q10

Mitochondrial and nuclear membranes were isolated from the LAD region. Nuclear-bound PGC1α levels were > 200-fold higher with administration of four weeks of CoQ10 treatment (p = 0.016).

Conclusions Four weeks of dietary CoQ10 in HM pigs enhances active, nuclear-bound PGC1α and increases the expression of ETC proteins within mitochondria of HM tissue. (R10)

HM here stands for “hibernating myocardium”.

Creatine

Our results indicate that damage to mitochondria is crucial in the differentiation imbalance caused by oxidative stress and that the Cr-prevention of these injuries is invariably associated with the recovery of the normal myogenic capacity. We also found that Cr activates AMPK and induces an upregulation of PGC-1-α expression, two events which are likely to contribute to the protection of mitochondrial quality and function. (R13)

Saffron

Nevertheless, saffron significantly increased PGC1-α gene expression in AD rats (P = 0.001). The interaction of ET and saffron was significant in increasing PGC1-α gene expression in AD rats (P = 0.001). (R15)

Sulfite

Sulfite decreases level of PGC1a in the nucleus:

The effects of sulfite and bezafibrate (30 mg/kg/day) on the nuclear content of PGC-1α, the major regulator of mitochondrial biogenesis, were also evaluated once sulfite reduced mitochondrial mass and bezafibrate prevented this effect. It can be observed in Fig. 7 that sulfite decreased the nuclear PGC-1α immunocontent and that bezafibrate totally prevented this alteration. (R16)

Role of PGC-1α in Schizophrenia. Low Nrf1

Nrf1 is a co-activator of PGC1a. It’s suggested that reduction of Nrf1 leads to diminished activation of the target genes of PGC1a:

While control subjects with high PGC-1α expression exhibited high PV and Nefh expression, schizophrenia subjects with high PGC-1α expression did not, suggesting dissociation between PGC-1α expression and these targets in schizophrenia.

Unbiased analyses of the promoter regions for PGC-1α-dependent transcripts revealed enrichment of binding sites for the PGC-1α-interacting transcription factor nuclear respiratory factor 1 (NRF-1).

NRF-1 mRNA expression was reduced in schizophrenia, and its transcript levels predicted that of PGC-1α-dependent targets in schizophrenia. Interestingly, the positive correlation between PGC-1α and PV, Syt2, or Cplx1 expression was lost in schizophrenia patients with low NRF-1 expression, suggesting that NRF-1 is a critical predictor of these genes in disease.

These data suggest that schizophrenia involves a disruption in PGC-1α and/or NRF-1-associated transcriptional programs in the cortex and that approaches to enhance the activity of PGC-1α or transcriptional regulators like NRF-1 should be considered with the goal of restoring normal gene programs and improving cortical function. (R1)

Co-activator of RXR

PGC1a was found to be a co-activator of RXR:

In a transient transfection assay, PGC-1 augments ligand-stimulated RXR transcription. Furthermore, PGC-1 efficiently enhances the RXR element-driven reporter gene transcription by all three RXR isoforms.

An immunoprecipitation assay reveals that PGC-1 and RXRalpha interact in vivo. In addition, a glutathione S-transferase pull-down assay showed that this interaction requires the presence of the LXXLL motif of PGC-1.

We demonstrate further, in a mammalian two-hybrid assay, that this physical interaction also requires the presence of the AF-2 region of RXR to interact with the LXXLL motif of PGC-1, which is consistent with our protein-protein interaction results. A time-resolved fluorescence assay shows that a peptide within the NR box of PGC-1 is efficiently recruited by a ligand-bound RXRalpha in vitro.

Finally, PGC-1 and TIF2 synergistically enhance ligand-activated RXRalpha transcriptional activity. Taken together, these results indicate that PGC-1 is a bona fide coactivator for RXRalpha. (R11)