Trends in Pharmacological Sciences
ReviewThe biology of PGC-1α and its therapeutic potential
Introduction
Transcriptional changes in gene expression underlie the coordinated regulation of biological programs. These changes are initiated and maintained by the binding of regulatory protein complexes to DNA elements in the enhancer and promoter regions of target genes. Traditionally, DNA-binding transcription factors were thought to be the main regulators of gene expression. However, in recent years, the importance of transcriptional coregulators in the coordination of the expression of genetic programs has been appreciated 1, 2. The family of genes encoding peroxisome proliferator-activated receptor (PPAR) γ coactivator-1 (PGC-1) proteins illustrates how coactivators respond to environmental cues and subsequently regulate biological processes in a tissue-specific and highly coordinated manner 3, 4, 5. All three members of this small family, PGC-1α, PGC-1β and PGC-related coactivator (PRC) are strong promoters of mitochondrial biogenesis and oxidative metabolism 6, 7, 8. In contrast to PRC, which is ubiquitously expressed, PGC-1α and PGC-1β are primarily found in oxidative tissues, including the brain, heart, kidney, muscle, liver, brown adipose tissue (BAT) and pancreas. In these organs, PGC-1α and PGC-1β have both overlapping and clearly distinct functions [9]. Moreover, these two coactivators are differently regulated in development and in response to nutritional and other challenges 8, 10. However, whereas our understanding of the physiological role of PGC-1β remains rudimentary, substantial progress in the study of PGC-1α has been made since its discovery more than a decade ago [11]. This review summarizes recent findings and highlights the potential therapeutic applications of PGC-1α.
Section snippets
PGC-1α regulates tissue-specific gene expression in health and disease
The PGC-1α protein is very versatile and coactivates many transcription factors 3, 4, 5. Binding to different partners enables PGC-1α to regulate distinct biological programs. For example, a combination of coactivation events among PGC-1α, the hepatic nuclear factor 4α (HNF4α) and the forkhead transcription factor Foxo1 determines the rate of fasting-induced hepatic gluconeogenesis 12, 13. In skeletal muscle, myofibrillar genes are controlled by PGC-1α-mediated coactivation of myocyte enhancer
Adipose tissue
In BAT, PGC-1α expression is regulated by cold exposure and β-adrenoceptor agonists [11]. Subsequently, PGC-1α coactivates PPARγ and the thyroid hormone receptor on the uncoupling protein 1 (UCP-1), type 2 deiodinase (DIO2) and other BAT-specific gene promoters [11]. BAT versus white adipose tissue (WAT) selectivity of gene expression is controlled by the distinct assembly of PGC-1α–PR(PRD1-BF1-RIZ1 homologous)-domain-containing protein (Prdm16)–C-terminal binding protein-1 (CtBP1) protein
Liver
The first peak of expression of the gene encoding PGC-1α is observed in the liver at birth [10]. In the adult, fasting and glucagon are the main drivers of hepatic PGC-1α transcription 12, 25. PGC-1α regulates most of the metabolic changes that occur during the transition of a fed to a fasted liver, including gluconeogenesis, fatty-acid β-oxidation, ketogenesis and heme biosynthesis 12, 13, 26, 27. Studies with knockout animals and adenovirally delivered short hairpin RNA constructs revealed a
Brain
In the developing brain, PGC-1α transcription peaks two weeks postnatally in many regions, a period of substantial metabolic changes, mitochondrial biogenesis and synaptic remodeling [33]. The highest PGC-1α concentrations are found in γ-aminobutyric acid (GABA)-positive neurons in the cortex, hippocampus and cerebellum [33]. One of the existing global PGC-1α-knockout lines exhibits increased anxiety [17], whereas a second model shows a profound hyperactivity [16]. Other behavioral changes
Skeletal muscle
In the contracting muscle fiber, the main signaling pathways converge on PGC-1α to increase expression levels and the activity of this coactivator 3, 43, 44. For example, p38 mitogen-activated protein kinase (p38 MAPK) and AMP-dependent kinase (AMPK) are rapidly activated in exercise and subsequently phosphorylate the PGC-1α protein. In addition, PGC-1α transcription is regulated by the motor-neuron-induced rise in intracellular calcium, AMPK, β2-adrenoceptor signaling, nitric oxide and thyroid
Heart
In the heart, PGC-1α transcription is induced at birth and correlates with metabolic maturation and remodeling [58]. As in other tissues, cardiac PGC-1α strongly promotes mitochondrial function and fatty acid β-oxidation [59]. In several mouse models for heart disease accompanied with a substrate switch from fatty acid to glucose utilization, expression of PGC-1α is reduced [60]. At baseline, heart function of PGC-1α-knockout mice seems to be normal 17, 61. However, the cardiac reserve under
Pancreas
In obese mice, in insulin-resistant animal models and in a partial pancreatectomy model for β cell decompensation, the transcriptional rate of the gene encoding PGC-1α in the pancreas is increased over the normally low basal levels [64]. In pancreatic islets, PGC-1α prevents membrane polarization and induces glucose-6-phosphatase and thereby reduces insulin secretion [64]. Notably, a second study of PGC-1α in human pancreatic islets resulted in opposite findings [65]. A common PGC-1α SNP was
Bone and cartilage
Parathyroid-hormone-induced cAMP signaling is a major pathway in osteoclast activation [66]. The gene encoding PGC-1α is a primary target of this signaling cascade and synergistically with Nurr1, a cAMP-induced orphan nuclear receptor, increases the levels of osteopontin and osteocalcin, two key proteins in bone formation [66]. Given the important role of ERRα, one of the strongest interaction partners of PGC-1α, in osteoblasts and osteoclasts [67] and the coactivation of the vitamin D receptor
Problems, pitfalls and opportunities
As a transcriptional coactivator, PGC-1α lacks functional DNA- and ligand-binding domains and therefore is not amenable to direct pharmacological intervention. Strategies to alter the availability of PGC-1α thus have to aim at transcriptional regulation of the gene, modifications of the protein or the interaction with binding partners. Modulation of PGC-1α transcription is hampered by the tight regulation of cellular metabolism. Accordingly, despite different screening efforts 70, 71,
Conclusions
The transcriptional coactivator PGC-1α has a key role in maintaining cellular metabolism. Dysregulation of gene expression and gene polymorphisms of the gene encoding PGC-1α have accordingly been found in a wide variety of different pathological contexts. Furthermore, therapeutic efficacy of PGC-1α modulation has been demonstrated in animal models for different diseases. Thus, pharmacological regulation of PGC-1α expression and activity might be a promising novel approach for the prevention and
Acknowledgements
I thank my colleagues for discussions, ideas and suggestions for writing this manuscript and Christian Gasser for help with the artwork. I apologize for the omission of several important contributions owing to space constraints. Work in my laboratory related to this manuscript has been supported by the Swiss National Science Foundation (SNF PP00A-110746; www.snf.ch), the Muscular Dystrophy Association USA (www.mda.org), the SwissLife ‘Jubiläumsstiftung für Volksgesundheit und medizinische
References (87)
- et al.
Biological control through regulated transcriptional coactivators
Cell
(2004) - et al.
Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation
Mol. Cell
(2007) Metabolic control through the PGC-1 family of transcription coactivators
Cell Metab.
(2005)Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1
Cell
(1999)Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β), a novel PGC-1-related transcription coactivator associated with host cell factor
J. Biol. Chem.
(2002)Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation
Cell Metab.
(2006)PGC-1β in the regulation of hepatic glucose and energy metabolism
J. Biol. Chem.
(2003)A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis
Cell
(1998)Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice
Cell
(2004)Acquirement of brown fat cell features by human white adipocytes
J. Biol. Chem.
(2003)