Acta Biochimica et Biophysica Sinica Advance Access published February 16, 2011
Acta Biochim Biophys Sin (2011): 1 – 10 | ª The Author 2011. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. DOI: 10.1093/abbs/gmr007.
PGC-1 coactivators in the control of energy metabolism 1Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Nanjing Normal University, Nanjing 210046, China2Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA*Correspondence address. Tel: þ86-25-85891870 (C.L.)/þ1-734-615-3512 (J.L.); Fax: þ86-25-85891870(C.L.)/þ1-734-615-0495 (J.L.);E-mail: [email protected] (C.L.)/[email protected] (J.L.) Chronic disruption of energy balance, where energy in the year 2000 will carry a significant lifetime risk of intake exceeds expenditure, is a major risk factor for the developing type 2 diabetes, and therefore become prone to development of metabolic syndrome. The latter is charac- premature cardiovascular disease, blindness, kidney failure, terized by a constellation of symptoms including obesity, and amputations. A cardinal feature of metabolic syndrome dyslipidemia, insulin resistance, hypertension, and non- is severe obesity, which arises from chronic imbalance alcoholic fatty liver disease. Altered expression of genes between energy intake and energy consumption. As such, involved in glucose and lipid metabolism as well as mito- restoration of the energy balance is a major strategy for the chondrial oxidative phosphorylation has been implicated therapy of metabolic disease including obesity, diabetes, in the pathogenesis of these disorders. The peroxisome hypertension, atherosclerosis, and fatty liver diseases.
proliferator-activated receptor g coactivator-1 (PGC-1) Peroxisome proliferator-activated receptor (PPAR) g family of transcriptional coactivators is emerging as a coactivator-1 (PGC-1) family members are multifunctional hub linking nutritional and hormonal signals and energy transcriptional coregulators that act as ‘molecular switches’ metabolism. PGC-1a and PGC-1b are highly responsive in many metabolic pathways. PGC-1a and PGC-1b have to environmental cues and coordinate metabolic gene pro- been shown to regulate adaptive thermogenesis, mitochon- grams through interaction with transcription factors and drial biogenesis, glucose/fatty-acid metabolism, peripheral chromatin-remodeling proteins. PGC-1a has been impli- circadian clock, fiber-type switching in skeletal muscle, cated in the pathogenic conditions including obesity, and heart development. Their versatile actions are achieved type 2 diabetes, neurodegeneration, and cardiomyopathy, by interacting with different transcription factors in a whereas PGC-1b plays an important role in plasma tissue-specific manner. The potent effects of PGC-1 coacti- lipoprotein homeostasis and serves as a hepatic target for vators in coordinating various metabolic processes under- niacin, a potent hypotriglyceridemic drug. Here, we score their significant role in the control of energy review recent advances in the identification of physiologi- metabolism as well as their potential as targets for pharma- cal and pathophysiological contexts involving PGC-1 coactivators, and also discuss their implications for thera-peutic development.
The PGC-1a gene is located on chromosome 5 in mice(chromosome 4 in humans) and encodes a protein contain- ing 797 (mouse) or 798 (human) amino acids ].
Structural and functional studies have indicated thatPGC-1a has a strong transcriptional activation domain at the N terminus, which interacts with several histone acetyl-transferase (HAT) complexes including 3’-5’-cyclic adeno- The prevalence of contemporary life style, characterized by sine monophosphate (cAMP) response element-binding increased consumption of high-fat, high-fructose food and protein (CREB)-binding protein, p300, and steroid receptor reduced physical activity, has driven a dramatic increase in coactivator-1 ]. These proteins acetylate histones and the incidence of metabolic syndrome. It has been projected remodel chromatin structure into a state that is permissive that, by 2025, one in every three American children born for transcriptional activation. Adjacent to the N-terminal PGC-1 coactivators in the control of energy metabolism domain is a regulatory region that roughly spans 200 energy demand, including the BAT, heart, skeletal muscle, amino acids. Toward the C terminus, PGC-1a recruits the kidney, and brain – In fact, when ectopically thyroid receptor-associated protein/vitamin D receptor- expressed in fat or muscle cells, PGC-1a strongly stimu- interacting protein/mediator complex that facilitates direct lates the program of nuclear and mitochondrial-encoded interaction with the transcription initiation machinery [].
mitochondrial genes as well as organelle biogenesis [].
This region also interacts with the switch/sucrose non- The stimulatory effects of PGC-1a on mitochondrial genes fermentable (SWI/SNF) chromatin-remodeling complex are achieved through its coactivation of nuclear respiratory through its interaction with BAF60a The Ser/Arg-rich factors 1 and 2 (NRF1 and NRF2, respectively) and the domain and an RNA-binding domain toward C terminus estrogen-related receptor a (ERRa) [The induc- have been demonstrated to couple pre-mRNA splicing with tion of NRF1 and NRF2 subsequently leads to the transcription ]. As such, PGC-1a serves as a platform for increased expression of mitochondrial transcription factor the recruitment and assembly of various chromatin- A (mtTFA) [as well as other mitochondrial subunits of remodeling and histone-modifying enzymes to alter local the electron transport chain complex such as b-adenosine- chromatin state. Importantly, the PGC-1a transcriptional triphosphate (ATP) synthase, cytochrome c, and cyto- activator complex is also able to displace repressor pro- chrome oxidase IV []. mtTFA translocates to mito- teins, such as histone deacetylase and small heterodimer chondrial matrix, where it stimulates mitochondrial DNA partner, on its target promoters, providing an alternative replication and mitochondrial gene expression mechanism for gene activation [PGC-1a and PGC-1b As mentioned above, a critical aspect of PGC-1a is share extensive domain similarity and several clusters of that it is highly versatile and has the ability to increase conserved amino acids, such as the LXXLL motif that the transcriptional activity of many nuclear receptor interacts with nuclear receptors and host cell factor 1 inter- families, including members of the estrogen, PPAR, reti- noid X, mineralocorticoid, glucocorticoid (GR), liver X (PGC-1-related coactivator), also contains the activation (LXR), pregnane X, the constitutive androstane, vitamin domain and RNA-binding domain, but overall has more limited homology to PGC-1a and PGC-1b []. The PGC-1 PGC-1a can also bind to unliganded nuclear receptors, family members are conserved in higher vertebrates, as in the case of the orphan hepatic nuclear factor including mammals, birds, and fish. Interestingly, a PGC-1 (HNF) 4a, farnesoid X receptor (FXR), and ERRa, family homologue named Spargel was recently identified suggesting that their conformations are conductive to in Drosophila that could regulate mitochondrial activity ligand-independent mechanisms of gene regulation [].
PGC-1a transcriptional partners are not limited to the Both PGC-1a and PGC-1b robustly regulate mitochon- nuclear receptor superfamily; however, this coactivator drial oxidative metabolism (Fig. ). PGC-1a was initially also associates with a diverse array of other transcription identified as a PPARg-interacting protein from the brown factors, including forkhead/winged helix protein family adipose tissue (BAT) that could regulate adaptive thermo- member FOXO1, as well as a number of zinc-finger pro- genesis in response to cold []. Subsequent studies revealed that the core function of PGC-1a was to stimulate screen ]. The docking interface for these interacting proteins appears to distribute throughout the length of PGC-1a is abundantly expressed in tissues with high PGC-1a. In addition, PGC-1a has three functional Figure 1 The working model of PGC-1 coactivators PGC-1a and PGC-1b regulate diverse metabolic programs through coactivating selective transcriptional factors (TF) associated with regulatory elements of target genes. PGC-1 recruits HAT, SWI/SNF chromatin-remodeling, Sirt1 deacetylase,and mediator complexes to modulate the epigenetic status of chromatin.
PGC-1 coactivators in the control of energy metabolism LXXLL motifs that are responsible for docking nuclear PGC-1a function by repressing its transcription [].
Impaired PGC-1a expression and mitochondrial function proteins enables PGC-1a to regulate various metabolic contributes to neurodegeneration in susceptible neurons processes in a tissue-specific manner.
In addition, PGC-1a plays an important role in theregulation of genes responsible for the detoxification of Tissue-specific metabolic actions of PGC-1 reactive oxygen species (ROS), including copper/zinc superoxide dismutase (SOD1), manganese SOD (SOD2),and glutathione peroxidase 1 ]. In this case, PGC-1a The following section reviews PGC-1 functions in oxi- protects dopaminergic neurons from degeneration caused dative tissues including the brain, heart, brown fat, skeletal by oxidative stress. Taken together, the finding that muscle, liver, and pancreatic islets, based on gain and PGC-1a expression is impaired in the striatum of HD loss-of-function analysis both in cultured cells and in vivo.
patients raises the possibility that molecules activating A summary of tissue-specific PGC-1 functions and the PGC-1a may be therapeutically useful.
phenotype of PGC-1 transgenic mouse models are includedin and respectively.
Heart is an organ with an extremely high and dynamic demand for ATP. Much of this supply comes from fatty-acid b-oxidation, though glucose also serves as fuel several brain areas, predominantly in the striatum, and source. Several studies have demonstrated that PGC-1a is a exhibit behavioral abnormalities including marked hyper- crucial regulator of oxidative metabolism in the heart.
activity and frequent limb clasping Recent studies PGC-1a mRNA levels are strongly induced in the neonatal heart, along with the activation of mitochondrial biogenesis support a crucial role of this factor in neuronal function and the metabolic switch from glycolysis to oxidative and energy balance. Similar brain lesions are observed phosphorylation in cardiac muscle ]. Overexpression of when PGC-1a is selectively ablated in CaMKIIa-positive PGC-1a both in vitro and in vivo powerfully induces mito- neurons, providing direct evidence for its action in chondrial gene expression and biogenesis ]. PGC-1a neurons. Of note, striatal degeneration with hyperactivity expression is reduced in several animal models of cardiac is reminiscent of Huntington’s disease (HD) in humans, dysfunction, which is typically accompanied by a meta- potentially implicating PGC-1a in the selective vulner- bolic switch from fat oxidation to glycolysis []. PGC-1a ability of striatal neurons in HD. To date, the specific null mice exhibit significantly lower cardiac reserve in role of PGC-1a in linking mitochondrial dysfunction to HD pathogenesis has been explored. The mutant hun- Moreover, PGC-1a null mice develop early symptoms of tingtin protein accumulated in HD brain interferes with heart failure, such as activation of the fetal program of Table 1 Tissue-specific functions of PGC-1a and PGC-1b Maintenance of mitochondrial function ROS detoxification Mitochondrial oxidative metabolism [], fatty-acid b-oxidation Mitochondrial OXPHOS mediating the effects of Mitochondrial biogenesis and fat oxidation [Adaptive Brown adipocyte differentiation []; Adaptive Slow-switch muscle fiber [], mitochondrial biogenesis Hepatic fasting response [], homocysteine metabolism [], integration of circadian clock and metabolism [] Suppression of GSIS and membrane depolarization [] PGC-1 coactivators in the control of energy metabolism Table 2 Phenotypes of PGC-1 knockout and transgenic mouse models Hyperactive, cold-sensitive, resistant to diet-induced obesity, lesions in the Reduced muscle performance and exercise capacity, impaired adaptive Impaired glucose tolerance, normal peripheral insulin sensitivity Switch of type II muscle fiber to type IIa and I muscle fibers, resistance to Loss of sarcomeric structure, dilated cardiomyopathy Increased mitochondrial biogenesis, derangements of mitochondrial ultrastructure, Impaired mitochondrial function, reduced body weight and fat mass, increased thermogenesis, blunted chronotropic response to dobutamine in the heart, hepatic steatosis, reduced lipoprotein-associated triglyceride and cholesterol content Decreased activity during the dark cycle, abnormal hypothermia and morbidity, hepatic steatosis, increased serum triglyceride and cholesterol Mitochondrial dysfunction in liver and skeletal muscle, hepatic steatosis, hepatic Increased fatty-acid oxidation, hyperphagia, reduced body weight and adipose tissue, increased exercise capacity, increased IIX fiber content Neonatal lethality, bradycardia, intermittent heart block, reduced cardiac output, reduced growth, a late fetal arrest in mitochondrial biogenesis cardiac gene expression and a significant increase in circu- lating levels of atrial natriuretic peptide, a hallmark of In rodents, BAT is the major organ responsible for adaptive cardiac dysfunction These mice also exhibit lower thermogenesis during cold exposure. In contrast to white treadmill-running capacity and diminished cardiac function adipose tissue, whose primary physiological function is after exercise. However, it should be noted that superphy- energy storage, the main function of BAT is energy dissi- siological expression of PGC-1a in the heart leads to pation, largely in the form of heat. The expression of robust mitochondrial proliferation and myofibrillar displa- PGC-1a is strongly induced in BAT by cold temperature; cement, and dilated cardiomyopathy ensues [As such, PGC-1a is downstream of the b-adrenergic receptor/cAMP therapeutic regulation of PGC-1a in heart failure should pathway and sympathetic nervous system activity ].
aim at restoring PGC-1a function in cardiac muscle within In this case, PGC-1a turns on several key components a therapeutically beneficial window.
involved in the adaptive thermogenic program, including PGC-1b is also abundantly expressed in the heart [].
the stimulation of fuel uptake, mitochondrial fatty-acid Heart function in PGC-1b-deficient mice is largely unaf- b-oxidation, and stimulation of uncoupling protein 1 fected under normal conditions []. However, PGC-1b (UCP1) expression ]. PGC-1a interacts with other ablation reduces mitochondrial content in cardiac muscle nuclear hormone receptors such as PPARa, retinoic acid and blunts the effect of adrenergic stimulation on heart rate receptor, and thyroid receptor to enhance UCP1 expression.
Remarkably, mice with combined deficiency of PGC-1a and PGC-1b (PGC-1ab2/2) die shortly after birth generating heat and uncouples oxidative phosphorylation with small hearts, bradycardia, intermittent heart block, and from ATP production. PGC-1a-deficient mice are unable a markedly reduced cardiac output Cardiac-specific to defend against cold stress due to thermogenic defects ablation of PGC-1b on a PGC-1a-deficient background results in cardiac defects including reduced growth, a late PGC-1b mRNA is induced during white and brown fetal arrest in mitochondrial biogenesis, and persistence of a adipocyte differentiation ]. Interestingly, while the fetal pattern of gene expression These observations expression of PGC-1b is not cold inducible, its deficiency suggest that PGC-1a and PGC-1b collectively are required also impairs adaptive thermogenesis [], suggesting that for the postnatal metabolic and functional maturation of the these two coactivators play non-redundant function in fuel PGC-1 coactivators in the control of energy metabolism RNAi-mediated liver-specific PGC-1a knockdown mice PGC-1a is abundantly expressed in skeletal muscle, par- display the impairment of gluconeogenic gene expression ticularly slow-twitch myofibers, and is rapidly inducible by and hepatic glucose production []. These mice exercise training in rodents and humans – It is develop hypoglycemia and hepatic steatosis upon fasting clear that calcium signaling pathways play important roles In addition, PGC-1a regulates the genes encoding in the induction of PGC-1a through calcineurin and homocysteine synthesis enzymes in the liver and modulates calcium-dependent protein kinases and the subsequent acti- plasma homocysteine levels ]. Forced expression of vation of CREB and myocyte-enhancing factor 2 ].
PGC-1a in vivo leads to elevated plasma homocysteine In addition, p38 mitogen-activated protein kinase ( p38 MAPK) and AMP-dependent kinase (AMPK) are also In mammals, circadian clock regulates major aspects of required for exercise-induced PGC-1a expression ].
energy metabolism, including glucose and lipid homeosta- Interestingly, muscle-specific overexpression muscle cre- sis and mitochondrial respiration. Our recent work revealed atine kinase (MCK) of PGC-1a in mice turns white, glyco- that PGC-1a is a key component of the circadian oscillator lytic skeletal muscles (fast-twitch muscle fibers) into red, that integrates the peripheral clock and energy metabolism PGC-1a stimulates the expression of Bmal1, a core clock gene, in hepatocytes and muscle cells through coacti- vation of the ROR family of orphan nuclear receptors.
slow-twitch myofibers ]. In addition to the regulation of Mice lacking PGC-1a have abnormal diurnal rhythms of mitochondrial function, PGC-1a increases mRNA content activity, body temperature, and metabolic rate. As PGC-1a of enzymes involved in fat metabolism such as fatty-acid expression is regulated by nutritional and hormonal cues, it translocase/CD36, carnitine palmitoyltransferase I, and is likely that it links these signals to the clockwork and medium-chain acyl-coenzyme A dehydrogenase (MCAD) synchronizes tissue metabolism with circadian pacemaker.
in skeletal muscle [Consistent with the molecular PGC-1b expression is increased in response to dietary changes, PGC-1a transgenic muscle has increased fatigue intake of fats and leads hyperlipidemia through activating resistance following electrical stimulation [In contrast, both whole-body and muscle-specific PGC-1a knock out (VLDL) secretion []. Several factors are involved in med- (KO) mice show reduced mRNA and/or protein content of iating the effects of PGC-1b on plasma triglyceride metab- mitochondrial respiratory chain proteins and ATP synthase.
olism, including sterol response element-binding protein They are exercise intolerant and their skeletal muscles are (SREBP), LXR, and Foxa2 Recent studies demon- strated that PGC-1b and its target gene apolipoprotein C3 In primary cultures of rat muscle cells, PGC-1b (ApoC3) are downstream of nicotinic acid, a widely used increases the expression of glucose transporter 4, myosin hypotriglyceridemic drug []. Both acute injection and heavy chain Ib, and other slow-twitch muscle markers chronic feeding of mice with nicotinic acid suppress While PGC-1b also stimulates mitochondrial biogen- PGC-1b and ApoC3 expression in the liver [These esis in skeletal muscle, it appears to drive a program of studies illustrated a new role for PGC-1b in modulating gene expression that is reminiscent of type IIx fibers [].
lipoprotein catabolism and the relevance of this pathway in In addition, the expression of PGC-1b, but not PGC-1a, is therapeutic action of nicotinic acid. Remarkably, systemic decreased along with reduced ERRa activity and MCAD delivery of antisense oligonucleotide targeting PGC-1b expression in skeletal muscle of senescence-accelerated improved systemic metabolic homeostasis in the model of fructose-induced insulin resistance ].
Hepatic PGC-1a expression reaches its peak during early b-Cell dysfunction is cardinal for the development of type postnatal period []. In adults, starvation induces PGC-1a 2 diabetes. PGC-1a is expressed in pancreatic b-cells and expression in the liver through glucagon and GR signaling is elevated in animal models of type 2 diabetes [].
PGC-1a orchestrates a complex program of metabolic Ectopic expression of PGC-1a impairs both early and changes that occur during the transition of a fed to a fasted delayed glucose-stimulated insulin secretion (GSIS) and liver, including gluconeogenesis, fatty-acid b-oxidation, suppresses membrane depolarization without affecting ketogenesis, heme biosynthesis, and bile-acid homeostasis.
baseline insulin secretion. Altered PGC-1a expression is These effects of PGC-1a on fasting adaption are achieved accompanied by increased glucose-6-phosphatase and by coactivating key hepatic transcription factors, such as reduced glucokinase gene expression. Furthermore, UCP2 HNF4a, PPARa, GR, FOXO1, FXR, and LXR []. In may be another effector downstream of PGC-1; UCP2 accordance with these observations, PGC-1a KO mice and PGC-1 coactivators in the control of energy metabolism production, and negatively regulates GSIS Although the mechanism through which PGC-1a is induced in dia-betic animal models is not understood, fatty acids and As PGC-1a regulates multiple aspects of energy metab- incomplete inactivation of FOXO1 may contribute to olism, it is not surprising that PGC-1a has been found to this process. In contrast to animal data, studies in human be dysregulated in several pathological conditions. The type 2 diabetic islets showed that PGC-1a mRNA expression of PGC-1a and its target genes involved in expression is markedly reduced and correlated with the mitochondrial oxidative phosphorylation (OXPHOS) is sig- reduction in insulin secretion in those islets ]. DNA nificantly decreased in the skeletal muscle of patients with methylation of the PGC-1a gene promoter is increased in type 2 diabetes ]. Similar reduction of PGC-1a human diabetic islets. Therefore, the exact function of expression was also observed in the adipose tissue of PGC-1a in pancreatic islets needs further study.
insulin-resistant and morbidly obese individuals [].
The function of PGC-1b in islets is less studied. A Interestingly, thiozolidinedione, an important class of anti- recent study indicated that PGC-1b, in contrast to PGC-1a, diabetic drugs, can enhance the expression of PGC-1a and directly binds to and acts as a coactivator of SREBPs and mitochondrial biogenesis in white adipose tissue [].
Foxa2 involved in pancreas development and function While these observations support a potentially beneficial The authors also showed that PGC-1b suppresses role of PGC-1a in insulin resistance and type 2 diabetes, GSIS via upregulation of UCP2 and granuphilin gene several studies suggested distinct actions of PGC-1a in other tissues. For example, PGC-1a expression is elevatedin the liver of both type 1 and type 2 diabetic mousemodels ]. Furthermore, PGC-1a has been shown to stimulate hepatic glucose production and suppress b-cell Post-translational modifications of PGC-1 energy metabolism and insulin release in mice [].
Paradoxically, transgenic expression of PGC-1a in skeletalmuscle leads to robust mitochondrial biogenesis but also PGC-1a undergoes extensive post-translational modifi- causes insulin resistance, likely the result of imbalance of cations, including acetylation, phosphorylation, methyl- lipid uptake and oxidation [In addition, a common ation, and SUMOylation, in response to nutritional and polymorphism of the PGC-1a gene (Gly482Ser), which hormonal signals. These modifications allow fine-tuning of apparently reduces PGC-1a activity, has been linked to PGC-1a activities in a context-dependent manner. The acetyl transferase general control of amino-acid synthesis In the cardiovascular system, PGC-1a expression is also 5 acetylates PGC-1a at several lysine residues, alters its decreased in hypertrophic heart ]. PGC-1a null mice localization within the nucleus, and inhibits its transcrip- display accelerated cardiac dysfunction and clinical signs tional activity On the contrary, deacetylation of of heart failure In contrast, PPARa ligand-dependent PGC-1a through sirtuin 1 (Sirt1) increases PGC-1a activity transcriptional activity and coactivation by PGC-1a are on gluconeogenic gene transcription in the liver [].
enhanced in the heart by stress including ischemia and PGC-1a is phosphorylated by both p38 MAPK and AMPK hypoxia ]. In peripheral vessel tissues, downregulation in skeletal muscle [], leading to a more stable and of PGC-1a expression was observed in vascular smooth active protein. In contrast, phosphorylation of PGC-1a by muscle cells (VSMCs) treated by oleic acid and high Akt/protein kinase B downstream of the insulin signaling glucose []. Restoration of PGC-1a has beneficial effects cascade in the liver decreased its stability and transcriptional on VSMCs and endothelial cells ]. In this context, activity []. In addition, PGC-1a also undergoes methyl- PGC-1a appears to play an important role in ROS metab- ation at several arginine residues in the C-terminal region olism and defense against oxidative stress. These obser- by protein arginine methyltransferase 1 ]. Finally, vations indicate that PGC-1a is an important factor in the PGC-1a can undergo SUMOylation in conserved lysine regulation of cardiovascular function.
residue 183 and its transcriptional activity is attenuated Abnormalities in mitochondrial function are associated Interestingly, experiments using C2C12 cells have indi- with neurodegenerative disorders including Parkinson’s disease, Alzheimer’s disease, and HD. Levels of PGC-1a PGC-1a for deacetylation by Sirt1 [], suggesting that are reduced in the brain of HD patients due to repression different modifications of PGC-1a likely communicate with of PGC-1a gene expression by mutant huntingtin, leading each other to coordinately regulate its activity. PGC-1b is to mitochondrial defects and increased oxidative stress also acetylated at multiple sites however, the biologi- Expression of PGC-1a partially reverses the toxic cal significance of these events is less well defined.
effects and provides neuroprotection in the HD mutant PGC-1 coactivators in the control of energy metabolism mouse ]. In the peripheral nervous system, PGC-1a has clinical use. For example, coactivators have kinetic benefits been shown to regulate gene expression at the neuromuscu- in controlling biological programs in that they coordinate lar junction and influences expression of acetylcholine different steps in biological programs through the inte- receptors in muscle fibers In addition, elevated gration of the activity of various transcription factors. As PGC-1a levels protect neural cells in culture from cell such, significant biological effects can be achieved by death caused by oxidative-stressor through its induction of quantitatively modulating coactivator function. The diver- sity of post-translational modifications of PGC-1 poten- Energy metabolism in cancer cells differs fundamentally tially allows targeting specific protein – protein interaction from that in its normal counterparts. In general, cancer interface. As discussed above, tissue-specific modulation of cells have high glycolytic activity and prefer glucose as a PGC-1 function is essential for metabolic modulation fuel source, a phenomenon known as the Walburg effect.
without causing deleterious side effects.
The switch from OXPHOS to glycolysis occurs even in thepresence of sufficient oxygen. This aerobic glycolysis has been postulated to enhance cancer cell proliferationand survival. Interestingly, reduced expression of PGC-1a Owing to space limitations, we apologize to those whose has been observed in human breast cancer colon publications related to the discussed issues could not cancer [], liver cancer and ovarian cancer [].
Adenoviral-mediated overexpression of PGC-1a inducesE-cadherin expression while decreasing motility of humanhepatoma HepG2 cells Such manipulation also causes cell apoptosis in human ovarian cancer cells through aPPARg-dependent pathway These findings suggest This work was supported by the grants from the National that PGC-1a is a potentially important regulator of cancer Natural Science Foundation of China (30870928), the cell metabolism and contributes to altered metabolic Research Fund for the Doctoral Program of Higher function in cancer cells. A causal relationship between Education of China (20103207110007), the Fok Ying PGC-1a and cancer development, however, remains to be Tong Education Foundation (121022), the Major Program (09KJA180004) (to C.L.), and the NIH grant (DK077086) The PGC-1 family of transcriptional coactivators has emerged as a regulatory hub within the transcriptional net-works that maintain metabolic homeostasis. The dynamic 1 Puigserver P, Wu Z, Park CW, Graves R, Wright M and Spiegelman BM.
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