PGC-1 coactivators in the control of energy metabolism

Abstract

Chronic disruption of energy balance, where energy intake exceeds expenditure, is a major risk factor for the development of metabolic syndrome. The latter is characterized by a constellation of symptoms including obesity, dyslipidemia, insulin resistance, hypertension, and nonalcoholic fatty liver disease. Altered expression of genes involved in glucose and lipid metabolism as well as mitochondrial oxidative phosphorylation has been implicated in the pathogenesis of these disorders. The peroxisome proliferator-activated receptor g coactivator-1 (PGC-1) family of transcriptional coactivators is emerging as a hub linking nutritional and hormonal signals and energy metabolism. PGC-1a and PGC-1b are highly responsive to environmental cues and coordinate metabolic gene programs through interaction with transcription factors and chromatin-remodeling proteins. PGC-1a has been implicated in the pathogenic conditions including obesity, type 2 diabetes, neurodegeneration, and cardiomyopathy, whereas PGC-1b plays an important role in plasma lipoprotein homeostasis and serves as a hepatic target for niacin, a potent hypotriglyceridemic drug. Here, we review recent advances in the identification of physiological and pathophysiological contexts involving PGC-1 coactivators, and also discuss their implications for therapeutic development.

Peroxisome Proliferator-activated Receptor γ Coactivator 1β (PGC-1β) Protein Attenuates Vascular Lesion Formation by Inhibition of Chromatin Loading of Minichromosome Maintenance Complex in Smooth Muscle Cells

“…The PGC-1 family of transcriptional coactivators consists of three members, PGC-1␣, PGC-1␤, and PGC-1-related coactivator (PRC) (15)(16)(17). The first member of the PGC-1 family was identified as a peroxisome proliferator-activated receptor ␥ (PPAR␥)-interacting protein and named PGC-1␣ (18).…”

Activation of AMPK attenuates LPS-induced acute lung injury by upregulation of PGC1α and SOD1

“…PGC-1α has been identified to be a central regulator of energy metabolism, and is expressed at high levels in tissues with high metabolic rates (19). A previous study suggests that PGC-1α is required for the induction of numerous ROS-detoxifying enzymes, including SOD1, SOD2 and glutathione peroxidase 1, and cells lacking PGC-1α have an increased sensitivity to oxidative stress (14).…”

Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1α

“…Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a key metabolic transcriptional coactivator protein that associates with numerous transcription factors and increases their ability to induce expression of their cognate target genes (1,2). A key attribute of PGC-1α is its ability to enhance oxidative metabolism and mitochondrial biogenesis (3).…”

“…PGC-1α also can induce tissue-specific programs such as hepatic gluconeogenesis (4), thermogenesis in brown adipose tissue (BAT) (5), and fiber-type switching in skeletal muscle (6). PGC-1α is induced by a variety of physiological stimuli in the tissues where it acts, including exercise in muscle, cold in BAT, and fasting or diabetes in the liver (1,2). Mechanistically, PGC-1α induces gene expression via a strong transcriptional activation domain at its N terminus.…”