PGC-1 coactivators: inducible regulators of energy metabolism in health and disease

Abstract

Members of the PPARγ coactivator-1 (PGC-1) family of transcriptional coactivators serve as inducible coregulators of nuclear receptors in the control of cellular energy metabolic pathways. This Review focuses on the biologic and physiologic functions of the PGC-1 coactivators, with particular emphasis on striated muscle, liver, and other organ systems relevant to common diseases such as diabetes and heart failure.Members of the nuclear receptor (NR) superfamily relay physiologic and nutritional cues to critical gene regulatory responses. The molecular links between external stimuli, cellular signaling events, and NR-mediated transcriptional control are currently being unraveled. New information emerging over the past decade has demonstrated that NRs receive regulatory input through multiple mechanisms including levels of endogenous ligand, availability of heterodimeric NR partners, and posttranslational modifications. Activating signals trigger the recruitment of coactivator complexes onto the NR platform, leading to enzymatic modification of chromatin, increased access of the RNA polymerase II machinery to RNA, and activation of target gene transcription (Figure 1). Availability of certain coactivator proteins also serves critical regulatory functions linking physiologic stimuli to NR activity. Perhaps the best example of this latter mechanism involves the PPARγ coactivator-1 (PGC-1) family of transcriptional coactivators. PGC-1 coactivators serve as inducible NR "boosters" to equip the organism to meet the energy demands of diverse physiologic and dietary conditions. This Review will focus on the role of this interesting coactivator family in the control of organ-specific biologic responses to the physiologic and pathophysiologic milieu. Emphasis will be given to tissue-specific regulatory features relevant to heart failure and diabetes.The PGC-1 family: inducible transcriptional coactivators orchestrating control of cellular energy metabolism The transcriptional coactivator PGC-1α was identified through its functional interaction with the nuclear receptor PPARγ in brown adipose tissue (BAT), a mitochondria-rich tissue specialized for thermogenesis (1). Thereafter, 2 related coactivators, PGC-1β (also termed PERC) and PGC-1-related coactivator (PRC), were discovered ( Figure 1) (2-4). PGC-1α and PGC-1β are preferentially expressed in tissues with high oxidative capacity, such as heart, slow-twitch skeletal muscle, and BAT, where they serve critical roles in the regulation of mitochondrial functional capacity and cellular energy metabolism (1, 3, 5-7). Less is known about the expression patterns and biologic roles of PRC (2, 8).PGC-1 coactivator docking to specific transcription factors provides a platform for the recruitment of regulatory protein complexes that exert powerful effects on gene transcription ( Figure 1). The amino-terminal region of PGC-1 coactivators interacts with proteins containing histone acetyltransferase (HAT) activity, including CREB-binding protein/p300 and steroid receptor coactivator-...

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Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

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Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: Impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter

“…Studies in humans and rodents have demonstrated that altered PPARGC1A signaling leads to insulin resistance, as recently reviewed. 21 Moreover, PPARGC1A is highly inducible in the liver and heart in response to physiological conditions that demand increased mitochondrial energy production. 21 PPARGC1A interacts with TFAM, which is required for the replication and maintenance of mtDNA.…”

“…21 Moreover, PPARGC1A is highly inducible in the liver and heart in response to physiological conditions that demand increased mitochondrial energy production. 21 PPARGC1A interacts with TFAM, which is required for the replication and maintenance of mtDNA. 22 Therefore, to determine whether the status of liver DNA methylation of these two genes was associated with peripheral insulin resistance, we measured the level of DNA methylation of three putative methylation target sites (CpG) in the promoters of PPARGC1A (located at positions relative to TSS: À513, À519, and À615) and Tfam (located at positions relative to TSS: À433, À442, and À499).…”