PGC-1α: a potent transcriptional cofactor involved in the pathogenesis of type 2 diabetes

Soyal, Selma M.; Krempler, Franz; Oberkofler, Hannes; Patsch, Wolfgang

doi:10.1007/s00125-006-0268-6

Cited by 131 publications

(82 citation statements)

References 114 publications

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“…In the present study, PMQ increased mRNA expression of Ppara and its target genes, including Aco, Mcad and Cpt1b, in C2C12 myotubes. PPAR gamma, coactivator 1α (PGC-1α) is involved in numerous biological responses related to energy homeostasis, thermal regulation and glucose metabolism [42]. Although PGC-1α was originally identified as a transcriptional coactivator of the nuclear receptor PPARγ, it is now known that PGC-1α coactivates PPARα in the transcriptional control of mitochondrial fatty acid oxidation [43].…”

Section: Discussionmentioning

confidence: 99%

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

Shen

Han

et al. 2012

Diabetologia

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Aims/hypothesis Pentamethylquercetin (PMQ) has recently been shown to have glucose-lowering properties. Here, we aimed to characterise the effectiveness and underlying mechanisms of PMQ for ameliorating metabolic disorders in vivo and vitro. Methods We generated a mouse model of obesity by neonatal administration of monosodium glutamate (MSG) and used it to assess the properties of PMQ as a treatment for metabolic disorders. We also investigated the possible underlying mechanisms of PMQ in the prevention of metabolic disorders. Results Compared with normal mice, MSG mice had metabolic disorders, including central obesity, hyperinsulinaemia, insulin resistance, hyperglycaemia, hyperlipidaemia, decreased phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), and downregulated levels of GLUT4 in gastrocnemius muscles. In MSG mice, PMQ treatment (5, 10, 20 mg/kg daily) reduced body weight gain, waist circumference, adipose tissue mass, serum glucose, triacylglycerol and total cholesterol, while improving insulin resistance, activating AMPK and increasing ACC phosphorylation and GLUT4 abundance. In C2C12 myotubes, PMQ (10 μmol/l) increased glucose consumption by ∼65%. PMQ treatment (1-10 μmol/l) also activated AMPK, increased ACC phosphorylation and GLUT4 abundance, and upregulated the expression of some key genes involved in fatty acid oxidation. Conclusions/interpretation These findings suggest that PMQ can ameliorate metabolic disorders at least in part via stimulation of AMPK activity.

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Section: Discussionmentioning

confidence: 99%

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

Shen

Han

et al. 2012

Diabetologia

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“…A taxonomic comparison indicated that all main interacting domains of PGC-1␣ are highly conserved across recently diverged mammalian species (16). Although exon 1L is located in an evolutionarily conserved region, L-PGC-1␣ transcript homologues were not detected in livers of several mammals.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Novel Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α) Isoform in Human Liver

Felder

Soyal

Oberkofler

et al. 2011

Journal of Biological Chemistry

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Peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1␣) is a transcriptional coactivator that contributes to the regulation of numerous transcriptional programs including the hepatic response to fasting. Mechanisms at transcriptional and post-transcriptional levels allow PGC-1␣ to support distinct biological pathways. Here we describe a novel human liver-specific PGC-1␣ transcript that results from alternative promoter usage and is induced by FOXO1 as well as glucocorticoids and cAMP-response element-binding protein signaling but is not present in other mammals. Hepatic tissue levels of novel and wild-type transcripts were similar but were only moderately associated (p < 0.003). Novel mRNA levels were associated with a polymorphism located in its promoter region, whereas wildtype transcript levels were not. Furthermore, hepatic PCK1 mRNA levels exhibited stronger associations with the novel than with the wild-type transcript levels. Except for a deletion of 127 amino acids at the N terminus, the protein, termed L-PGC-1␣, is identical to PGC-1␣. L-PGC-1␣ was localized in the nucleus and showed coactivation properties that overlap with those of PGC-1␣. Collectively, our data support a role of L-PGC-1␣ in gluconeogenesis, but functional differences predicted from the altered structure suggest that L-PGC-1␣ may have arisen to adapt PGC-1␣ to more complex metabolic pathways in humans. PGC-1␣2 (PPARGC1A) influences transcription in an exceptional variety of biological pathways including adaptive thermogenesis (1), mitochondrial biogenesis (2), skeletal muscle fiber determination and neuromuscular junction formation (3, 4), angiogenesis (5, 6), hepatic gluconeogenesis (7-9), fatty acid ␤-oxidation (10), regulation of clock genes (11), and protection of neural cells from reactive oxygen species (12, 13). Recent reviews describe the numerous functions of this fascinating protein (14 -17).Several levels of regulation have been implicated to explain the diverse roles of PGC-1␣ and its interactions with distinct transcription factors. For some pathways, expression levels of PGC-1␣ and transcription factors coactivated by PGC-1␣ are crucial (18). In addition, various signaling pathways target PGC-1␣ at the post-translational level. Such modifications detailed recently (19) alter the stability of PGC-1␣ and/or direct interactions with specific factors, thereby enhancing distinct transcriptional programs.Alternative splicing and/or transcription initiation, resulting in gain or deletion of interacting domains or signaling targets, represents another mode of regulation (15). Several PGC-1␣ isoforms have been reported in animal models (20,21). A short PGC-1␣ isoform was shown to be coexpressed with wild-type PGC-1␣ in mouse tissues and in human heart (22). The alternatively spliced mRNA is translated into a truncated protein, termed NT-PGC-1␣, that retains the N-terminal transactivation and nuclear receptor interaction domains and is functionally active.Knowledge about PGC-1␣ expression and regulation in human tissu...

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“…PGC-1␣ is now known to be a key player in the maintenance of glucose, lipid, and energy homeostasis and has been implicated in pathogenic conditions such as obesity, diabetes, neurodegeneration, and cardiomyopathy (13). The PGC-1␣/HNF4␣ partnership has been demonstrated as being particularly important in various metabolic pathways, including mitochondrial biogenesis, gluconeogenesis and insulin secretion, and onset of diabetes (17)(18)(19)(20).…”

Section: Hepatocyte Nuclear Factor 4␣ (Hnf4␣)mentioning

confidence: 99%

Multiple Binding Modes between HNF4α and the LXXLL Motifs of PGC-1α Lead to Full Activation

Rha

Shoelson

et al. 2009

Journal of Biological Chemistry

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Hepatocyte nuclear factor 4␣ (HNF4␣) is a novel nuclear receptor that participates in a hierarchical network of transcription factors regulating the development and physiology of such vital organs as the liver, pancreas, and kidney. Among the various transcriptional coregulators with which HNF4␣ interacts, peroxisome proliferation-activated receptor ␥ (PPAR␥) coactivator 1␣ (PGC-1␣) represents a novel coactivator whose activation is unusually robust and whose binding mode appears to be distinct from that of canonical coactivators such as NCoA/SRC/ p160 family members. To elucidate the potentially unique molecular mechanism of PGC-1␣ recruitment, we have determined the crystal structure of HNF4␣ in complex with a fragment of PGC-1␣ containing all three of its LXXLL motifs. Despite the presence of all three LXXLL motifs available for interactions, only one is bound at the canonical binding site, with no additional contacts observed between the two proteins. However, a close inspection of the electron density map indicates that the bound LXXLL motif is not a selected one but an averaged structure of more than one LXXLL motif. Further biochemical and functional studies show that the individual LXXLL motifs can bind but drive only minimal transactivation. Only when more than one LXXLL motif is involved can significant transcriptional activity be measured, and full activation requires all three LXXLL motifs. These findings led us to propose a model wherein each LXXLL motif has an additive effect, and the multiple binding modes by HNF4␣ toward the LXXLL motifs of PGC-1␣ could account for the apparent robust activation by providing a flexible mechanism for combinatorial recruitment of additional coactivators and mediators.

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PGC-1α: a potent transcriptional cofactor involved in the pathogenesis of type 2 diabetes

Cited by 131 publications

References 114 publications

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

Characterization of Novel Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α) Isoform in Human Liver

Multiple Binding Modes between HNF4α and the LXXLL Motifs of PGC-1α Lead to Full Activation

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