TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes

Nakagawa, Yoshimi; Shimano, Hitoshi; Yoshikawa, Tomohiro; Ide, Tomohiro; Tamura, Muneaki; Furusawa, Mika; Yamamoto, Takashi; Inoue, Noriyuki; Matsuzaka, Takashi; Takahashi, Akimitsu; Hasty, Alyssa H.; Suzuki, Hiroaki; Sone, Hirohito; Toyoshima, Hideo; Yahagi, Naoya; Yamada, Nobuhiro

doi:10.1038/nm1334

Cited by 169 publications

(129 citation statements)

References 36 publications

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“…Therefore, we focused on revealing regulatory mechanisms of the IRS2 promoter. Nakagawa et al (2006) who worked with a truncated IRS2 promoter in HepG2 cells described a sequence in the promoter that is located closer to the translation start codon compared to our findings. FOXO1 and TFE3 are able to bind in this region resulting in promoter activation (Nakagawa et al 2006).…”

Section: Discussionsupporting

confidence: 65%

“…In the present study we were able to verify this region as important for IRS2 transcription. However, Nakagawa et al (2006) used a smaller part of the promoter that was shorter than K611 bp referring to the translation start site, explaining why Nakagawa et al have missed the region described in the present study. By investigating larger promoter fragments, we were able to identify another region in the IRS2 promoter responsible for an even higher activation of IRS2 transcription than that achieved by TFE3.…”

Section: Discussionmentioning

confidence: 78%

“…In the same promoter region TFE3 was found to be an important transcription factor that activates IRS2 promoter activity. TFE3 binds an E-box that overlaps in sequence with the SREBP-1 binding site and sits beside the FOXO3 binding site (Nakagawa et al 2006), whereas TFE3 activates the promoter synergistically with FKH transcription factor O1 (FOXO1).…”

Section: Introductionmentioning

confidence: 99%

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Identification of a region in the human IRS2 promoter essential for stress induced transcription depending on SP1, NFI binding and ERK activation in HepG2 cells

Udelhoven¹,

Leeser²,

Freude³

et al. 2009

Journal of Molecular Endocrinology

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Recent studies have discovered changes in the insulin-/IGF1 signaling affecting glucose metabolism and the molecular pathogenesis of human hepatocellular cancer. Insulin/IGF1 receptor mediates its intracellular effects by recruitment of one out of the four different insulin receptor substrates (IRS). To investigate mechanisms of IRS2 expression, we analyzed transcriptional regulation of IRS2 in human HepG2 cells. We identified a region 688 bp upstream of the translation start codon responsible for w90% of basal human IRS2 promoter activity in HepG2 cells, and confirmed binding of specificity protein 1 (also called Sp1 transcription factor, SP1) and nuclear factor 1 (NFI) in this region. Mutation of both SP1 and NFI binding sites or inhibition of extracellular signal regulated kinase (ERK) suppressed IRS2 promoter activity almost completely, revealing a major role of MAP kinases (MAPK) for IRS2 transcription. Activating this cascade with oxidative stress increased IRS2 promoter activity and endogenous IRS2 expression substantially. IRS2 promoter activity rose even more after additional inhibition of p38MAPK indicating an inhibitory effect of p38MAPK on ERK mediated IRS2 transcription. Activation of the MAPK pathway using interleukin 1, beta (IL1B) increased IRS2 promoter activity similar to oxidative stress. In contrast IL1B decreases and inhibition of the MAPK pathway increases IRS1 promoter activity revealing opposed effects of IL1B and ERK on the expression of different IRS proteins. In conclusion we discovered a specific region (K688 to K611 bp) in the IRS2 promoter essential for basal promoter activity and oxidative stress induced transcription depending on ERK activation and SP1 and NFI binding in human hepatocytes.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

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Identification of a region in the human IRS2 promoter essential for stress induced transcription depending on SP1, NFI binding and ERK activation in HepG2 cells

Udelhoven¹,

Leeser²,

Freude³

et al. 2009

Journal of Molecular Endocrinology

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“…Furthermore, the up-regulation of SREBP-1c-regulated lipogenesis contributes to the development of insulin resistance via the down-regulation of IRS-2 in the liver. 39,40 Indeed, in our study, the induction of lipoprotein lipase and SREBP-1c and the repression of IRS-2 were detected in the livers of mice fed the Ath diet (Fig. 7).…”

Section: Discussionsupporting

confidence: 57%

Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet

et al. 2007

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Recently, nonalcoholic steatohepatitis (NASH) was found to be correlated with cardiovascular disease events independently of the metabolic syndrome. The aim of this study was to investigate whether an atherogenic (Ath) diet induces the pathology of steatohepatitis necessary for the diagnosis of human NASH and how cholesterol and triglyceride alter the hepatic gene expression profiles responsible for oxidative stress. We

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“…Previous studies in rodents indicated that systemic infusion of recombinant adenovirus resulted in a preferential targeting of the transgene to the liver [31]. We then evaluated the metabolic and functional effects of SPHK1 on livers of diabetic mice.…”

Section: Resultsmentioning

confidence: 99%

Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice

Chen²,

Wang³

et al. 2007

Diabetologia

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Aims/hypothesis The aim of this study was to determine the potential role of sphingosine kinase 1 (SPHK1), a key sphingolipid metabolic enzyme, in glucose metabolism and homeostasis. Methods SMMC-7721 hepatoma cells and C2C12 myotube cells were used to explore the role of SPHK1 in glucose uptake in vitro. KK/Ay type 2 diabetic mice, which were transfected with adenovirus harbouring the human SPHK1 gene by i.v. injection, were used to investigate the glucoselowering effects of SPHK1 in vivo.Results The basal glucose uptake and the insulin-stimulated glucose uptake in both 7721 cells and C2C12 cells were markedly enhanced when SPHK1 was overexpressed by adenovirus-mediated gene transfer, whereas they were substantially reduced when the expression of SPHK1 was inhibited or the activity of SPHK1 was blocked. Insulin could activate SPHK1 of both cell lines in a dosedependent manner. SPHK1 gene delivery significantly reduced the blood glucose level of KK/Ay diabetic mice, but had no effect on that of normal animals. It also attenuated elevated levels of plasma insulin, NEFA, triacylglycerol, cholesterol and LDL, significantly ameliorated hyperglycaemia-induced injury of liver, heart and kidney, and enhanced phosphorylation of insulin-signalling kinases such as Akt and glycogen synthase kinase 3β in livers of the diabetic animals. Conclusions/interpretation SPHK1 is involved in insulin signalling and plays an important role in the regulation of glucose and fat metabolism; adenovirus-mediated SPHK1 gene transfer might provide a novel strategy in the treatment of type 2 diabetes mellitus.

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TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes

Cited by 169 publications

References 36 publications

Identification of a region in the human IRS2 promoter essential for stress induced transcription depending on SP1, NFI binding and ERK activation in HepG2 cells

Identification of a region in the human IRS2 promoter essential for stress induced transcription depending on SP1, NFI binding and ERK activation in HepG2 cells

Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet

Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice

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