PGC-1 promotes insulin resistance in liver through PPAR-α-dependent induction of TRB-3

Koo, Seung Hoi; Satoh, Hiroaki; Herzig, Stephan; Lee, Chih‐Hao; Hedrick, Susan; Kulkarni, Rohit; Evans, Ronald M.; Olefsky, Jerrold M.; Montminy, Marc

doi:10.1038/nm1044

Cited by 501 publications

(455 citation statements)

References 28 publications

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“…TRIB3 is an inhibitor of the insulin-responsive AKT1 kinase and has been implicated in insulin resistance in several studies using cell lines and animal models [1,2,5,6]. In the present study, we provide initial evidence for an aberrant hepatic expression of TRIB3 in insulin-resistant human study participants.…”

Section: Resultsmentioning

confidence: 52%

“…No associations were observed with PPARA, LXRA (also known as NR1H3), USF2, CHREBP (also known as MLXIPL) and CEBPA transcripts (data not shown). Previous studies in mice showed that Trib3 transcription is increased via coactivation of peroxisome proliferator-activated receptor α (PPARA) by peroxisome proliferator-activated receptor γ coactivator 1 alpha (PPARGC1A, also referred to as PGC-1α) [5]. To determine whether transcription from the human TRIB3 promoter is activated by a similar mechanism, we transiently transfected HepG2 cells with a luciferase reporter construct driven by the human TRIB3 promoter (TRIB3-Prom-Luc).…”

Section: Resultsmentioning

confidence: 99%

“…Trib3 expression was increased in livers of db/db mice, a rodent model of type 2 diabetes [1]. Furthermore hepatic Trib3 gene knock-down enhanced insulin sensitivity, whereas adenovirus-mediated hepatic overexpression of Trib3 promoted hyperglycaemia and glucose intolerance in wild-type mice [5]. In the fasted state, TRIB3 was increased, thereby preventing residual insulin signalling and promoting glucose output by the liver [1].…”

Section: Introductionmentioning

confidence: 99%

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Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans

et al. 2010

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Aims/hypothesis The pseudokinase tribbles homologue 3 (Drosophila) (TRIB3) negatively interferes with insulinmediated phosphorylation and activation of v-akt murine thymoma viral oncogene homologue 1 (AKT1, also known as protein kinase B). Animal studies have shown that Trib3 expression was higher in the fasting state and in animal models of diabetes, promoting hyperglycaemia presumably by increasing glucose production in the liver. Less is known about the role of TRIB3 in insulin resistance in humans, although a gain-of-function mutation associated with abnormalities related to insulin resistance has been described in TRIB3. Methods We determined hepatic mRNA expression of TRIB3 and selected genes encoding enzymes, transcription factors and coactivators involved in glucose homeostasis. We also determined biochemical variables of intermediary metabolism in obese patients with varying degrees of insulin resistance. ResultsIn our study population hepatic TRIB3 mRNA expression was associated with surrogate markers of insulin resistance. TRIB3 expression was significantly increased in a subgroup with high HOMA of insulin resistance (HOMA-IR) compared with a low HOMA-IR group (p=0.0033). TRIB3 transcript levels were correlated with PEPCK (also known as PCK2) mRNA expression (p=0.0014) and mRNA expression of PPARGC1A (p=0.0020), PPARGC1B (p<0.0001), USF1 (p=0.0017), FOXO1 (p=0.0003) and SREBP-1c (also known as SREBF1; p=0.0360). Furthermore ligands of peroxisome proliferator-activated receptor α/retinoid X receptor and overexpression of its coactivator PPARGC1A as well as overexpression of SREBP-1c and its coactivator PPARGC1B increased TRIB3 promoter activity in HepG2 cells. Conclusions/interpretation We have found evidence for a role of aberrant hepatic TRIB3 transcript levels in insulin resistance in obese humans and identified potential transcriptional pathways involved in regulation of TRIB3 gene expression in the liver.

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Section: Resultsmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans

et al. 2010

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“…Contrary to the decrease of PPARGC1A expression in the skeletal muscle of patients with type 2 diabetes, PPARGC1A expression in the liver has been shown to be elevated in animal models of diabetes [8][9][10][11]. Tissue-specific regulation of metabolic pathways through PPARGC1A may take place in the skeletal muscle and liver.…”

mentioning

confidence: 91%

Genes involved in oxidative phosphorylation are coordinately upregulated with fasting hyperglycaemia in livers of patients with type 2 diabetes

et al. 2006

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Aims/hypothesis Mitochondrial oxidative phosphorylation (OXPHOS) plays an important role in the pathophysiology of type 2 diabetes. Genes involved in OXPHOS have been reported to be down-regulated in skeletal muscle from patients with type 2 diabetes; however, hepatic regulation is unknown. Materials and methods We analysed expression of genes involved in OXPHOS from the livers of 14 patients with type 2 diabetes and 14 subjects with NGT using serial analysis of gene expression (SAGE) and DNA chip analysis. We evaluated the correlation between expression levels of genes involved in OXPHOS and the clinical parameters of individuals with type 2 diabetes and NGT. Results Both gene analyses showed that genes involved in OXPHOS were significantly upregulated in the type 2 diabetic liver. In the SAGE analysis, tag count comparisons of mitochondrial transcripts showed that ribosomal RNAs (rRNA) were 3.5-fold over-expressed, and mRNAs were 1.2-fold over-expressed in the type 2 diabetes library. DNA chip analysis revealed that expression of genes involved in OXPHOS, which correlated with several nuclear factors, including estrogen-related receptor-α or peroxisome proliferator-activated receptor-γ, was a predictor of fasting plasma glucose levels, independently of age, BMI, insulin resistance and fasting insulin levels (p=0.04). Surprisingly, genes involved in OXPHOS did not correlate with peroxisome proliferator-activated receptor-γ coactivator-1α or nuclear respiratory factor 1. Conclusions/interpretation Our results indicate that upregulation of genes involved in OXPHOS in the liver, which are regulated by different mechanisms from genes in the skeletal muscle, is associated with fasting hyperglycaemia in patients with type 2 diabetes.

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“…10 TRIB3 has also been shown to interact and inhibit AKT, 11 which has been suggested to suppress insulin signaling. 11,12 In addition, administration of different anticancer agents promotes cancer cell death via TRIB3 upregulation and the subsequent inhibition of Akt. [13][14][15][16][17][18][19] However, the precise molecular basis of the regulation of Akt by TRIB3 and whether loss of this pseudokinase may contribute to cancer initiation and progression remains to be clarified.…”

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confidence: 99%

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

et al. 2014

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Tribbles pseudokinase-3 (TRIB3) has been proposed to act as an inhibitor of AKT although the precise molecular basis of this activity and whether the loss of TRIB3 contributes to cancer initiation and progression remain to be clarified. In this study, by using a wide array of in vitro and in vivo approaches, including a Trib3 knockout mouse, we demonstrate that TRIB3 has a tumorsuppressing role. We also find that the mechanism by which TRIB3 loss enhances tumorigenesis relies on the dysregulation of the phosphorylation of AKT by the mTORC2 complex, which leads to an enhanced phosphorylation of AKT on Ser473 and the subsequent hyperphosphorylation and inactivation of the transcription factor FOXO3. These observations support the notion that loss of TRIB3 is associated with a more aggressive phenotype in various types of tumors by enhancing the activity of the mTORC2/AKT/FOXO axis. Pseudokinases constitute a group of proteins that have a kinase-like domain that lacks at least one of the conserved catalytic residues. 1,2 Different studies have shown that some pseudokinases can exhibit low levels of kinase activity, while others have critical roles as activators of their specific targets. 1,2 Moreover, aberrant regulation of pseudokinases has been implicated in the etiology and progression of a variety of diseases, including cancer. 3 The Tribbles family of pseudokinases was first described in Drosophila as a negative regulator of cell division in early embryogenesis. [4][5][6][7] There are three mammalian Tribbles isoforms (Trib1, Trib2 and Trib3), homologs to the Drosophila tribbles proteins, and they all share a highly conserved central kinase-like domain, which lacks catalytic residues, and a 'tribbles specific' C-terminal domain, which has been proposed to participate in the binding to different Tribbles partners. 8 Tribbles pseudokinase-3 (TRIB3; also named TRB3, NIPK and SKIP3) has been proposed to interact with several proteins, including the transcription factors activating transcription factor 4 (ATF-4) and CHOP 9 as well as with several MAPKs. 10 TRIB3 has also been shown to interact and inhibit AKT, 11 which has been suggested to suppress insulin signaling. 11,12 In addition, administration of different anticancer agents promotes cancer cell death via TRIB3 upregulation and the subsequent inhibition of Akt. [13][14][15][16][17][18][19] However, the precise molecular basis of the regulation of Akt by TRIB3 and whether loss of this pseudokinase may contribute to cancer initiation and progression remains to be clarified.In this study, we investigated the effect of the genetic inactivation of TRIB3 in several cellular and animal models of cancer. Our findings indicate that genetic inhibition of TRIB3 enhances tumorigenesis and that this effect is due -at least primarily -to a selective inactivation of the transcription factor FOXO by the mammalian target of rapamycin complex 2 (mTORC2)/AKT axis. ResultsGenetic inhibition of TRIB3 facilitates oncogene transformation and enhances the tumorigenicity of cancer c...

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PGC-1 promotes insulin resistance in liver through PPAR-α-dependent induction of TRB-3

Cited by 501 publications

References 28 publications

Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans

Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans

Genes involved in oxidative phosphorylation are coordinately upregulated with fasting hyperglycaemia in livers of patients with type 2 diabetes

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

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