Hepatocyte Growth Factor Family Negatively Regulates Hepatic Gluconeogenesis via Induction of Orphan Nuclear Receptor Small Heterodimer Partner in Primary Hepatocytes

Chanda, Dipanjan; Li, Tiangang; Song, Kwang Hoon; Kim, Yong‐Hoon; Sim, Jeonggu; Lee, Chul‐Ho; Chiang, John Y.L.; Choi, Hueng‐Sik

doi:10.1074/jbc.m109.022244

Cited by 51 publications

(74 citation statements)

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“…USFs are known to be engaged in several processes related to maintaining lipid and glucose homeostasis (43)(44)(45)(46). Thus, the role of USFs in the generation of the Th17 immune response is of potential interest for further understanding the proposed relationship between metabolic disorders and inflammation (47).…”

Section: Discussionmentioning

confidence: 99%

Upstream Stimulating Factors Regulate the Expression of RORγT in Human Lymphocytes

Ratajewski

Walczak‐Drzewiecka

Sałkowska

et al. 2012

The Journal of Immunology

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Retinoic acid-related orphan receptor γT (RORγT) is the orphan nuclear receptor that regulates the development of Th17 cells and the expression of IL-17. The differentiation of Th17 cells is associated with the upregulation of RORγT mRNA, and the mechanisms regulating that process in human cells are not well understood. We investigated the transcriptional regulation of RORγT in a human lymphocytic cell line and Th17 differentiated from naive CD4+ cells from human peripheral blood. A series of experiments, including 5′ deletion and in situ mutagenesis analysis of the human RORγT promoter, chromatin immunoprecipitation, and overexpression of selected transcription factors, revealed that the transcription factors upstream stimulatory factor 1 (USF-1) and USF-2 are indispensable for the transcription of RORγT in human lymphocytes. There was also upregulation of USF-1 and USF-2 during the differentiation of Th17 cells from naive CD4+ cells. In this article, we report the first analysis, to our knowledge, of the human RORγT promoter and demonstrate the role of the USF-1 and USF-2 transcription factors in regulating the expression of RORγT in human lymphocytes. Thus, USFs are important for the molecular mechanisms of Th17 differentiation, and possible changes in the expression of USFs might be of interest for inflammatory conditions with a Th17 component. Furthermore, these observations suggest a possible link between metabolic disorders in which the role of glucose-induced USF expression has already been established and autoimmune diseases in which the upregulation of RORγT is frequently detected.

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Section: Discussionmentioning

confidence: 99%

Upstream Stimulating Factors Regulate the Expression of RORγT in Human Lymphocytes

Ratajewski

Walczak‐Drzewiecka

Sałkowska

et al. 2012

The Journal of Immunology

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“…Our previous studies have demonstrated that AMPK elevated SHP gene expression via USF-1 (upstream stimulatory factor) (29). AMPK-mediated FIGURE 7.…”

Section: Discussionmentioning

confidence: 99%

“…The pGL3basic-G6Pase (Ϫ1227/ϩ57) and PEPCK (Ϫ2.0 kb) promoter constructs were previously described (29). 8ϫ CREluc constructs were constructed by inserting into the pGL2-promoter vector between BglII sites.…”

Section: Methodsmentioning

confidence: 99%

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AMPK-dependent Repression of Hepatic Gluconeogenesis via Disruption of CREB·CRTC2 Complex by Orphan Nuclear Receptor Small Heterodimer Partner

Lee

Seo

Song

et al. 2010

Journal of Biological Chemistry

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142

104

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Orphan nuclear receptor small heterodimer partner (SHP) plays a key role in transcriptional repression of gluconeogenic enzyme gene expression. Here, we show that SHP inhibited protein kinase A-mediated transcriptional activity of cAMP-response element-binding protein (CREB), a major regulator of glucose metabolism, to modulate hepatic gluconeogenic gene expression. Deletion analysis of phosphoenolpyruvate carboxykinase (PEPCK) promoter demonstrated that SHP inhibited forskolin-mediated induction of PEPCK gene transcription via inhibition of CREB transcriptional activity. In vivo imaging demonstrated that SHP inhibited CREB-regulated transcription coactivator 2 (CRTC2)-mediated cAMP-response elementdriven promoter activity. Furthermore, overexpression of SHP using adenovirus SHP decreased CRTC2-dependent elevations in blood glucose levels and PEPCK or glucose-6-phosphatase (G6Pase) expression in mice. SHP and CREB physically interacted and were co-localized in vivo. Importantly, SHP inhibited both wild type CRTC2 and S171A (constitutively active form of CRTC2) coactivator activity and disrupted CRTC2 recruitment on the PEPCK gene promoter. In addition, metformin or overexpression of a constitutively active form of AMPK (Ad-CA-AMPK) inhibited S171A-mediated PEPCK and G6Pase gene expression, and hepatic glucose production and knockdown of SHP partially relieved the metformin-and Ad-CA-AMPK-mediated repression of hepatic gluconeogenic enzyme gene expression in primary rat hepatocytes. In conclusion, our results suggest that a delayed effect of metformin-mediated induction of SHP gene expression inhibits CREB-dependent hepatic gluconeogenesis.Glucose homeostasis is regulated by the opposing actions of insulin and glucagon (1-3), and glucose production in the liver is controlled primarily by gluconeogenesis (4). The regulation of hepatic gluconeogenesis involves the transcriptional regulation of key metabolic enzymes, including PEPCK 6 and G6Pase. The gluconeogenic program is largely regulated at the level of transcription and the process is coordinated by CREB via its direct binding to the cAMP-response element (CRE) site on the promoter of PEPCK, G6Pase, or PGC-1␣ (PPAR␥ coactivator-1␣) (5).Metformin has been shown to activate AMP-activated protein kinase (AMPK) via an LKB1-dependent mechanism (6). AMPK is a serine/threonine kinase that functions as an intracellular energy sensor and has been implicated in the modulation of glucose and fatty acid metabolism (7). AMPK is activated by physiological stimuli, including exercise, muscle contraction, and hormones, such as adiponectin and leptin, as well as by physiological stresses, glucose deprivation, hypoxia, oxidative stress, and osmotic shock conditions (8, 9). In the liver, activation of AMPK suppresses hepatic gluconeogenesis acutely by direct phosphorylation of its substrates, including CREB-binding protein (CBP) (10), CRTC2 (11), and GSK3␤ (glycogen synthase kinase 3␤) (12). Recent studies also suggest that AMPK induces SHP gene expression and inhibits hepatic g...

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“…7 Moreover, the authors provide data indicating that TLR signaling induces endogenous SHP expression in an AMPKdependent manner, consistent with previous findings that show that AMPK contributes to the induction of shp expression by various extracellular stimuli. 8,9 TLRdependent activation of AMPK requires intracellular Ca 21 influx, whereas other extracellular stimuli might trigger AMPK activation in a Ca 21 -independent manner. AMPK activation mediates SHP expression via transcription factor upstream stimulatory factor-1.…”

mentioning

confidence: 99%

SHP limits TLR signaling, an inducible transcriptional corepressor

Zhang¹,

Shen²

2011

Cell Mol Immunol

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Hepatocyte Growth Factor Family Negatively Regulates Hepatic Gluconeogenesis via Induction of Orphan Nuclear Receptor Small Heterodimer Partner in Primary Hepatocytes

Cited by 51 publications

References 40 publications

Upstream Stimulating Factors Regulate the Expression of RORγT in Human Lymphocytes

Upstream Stimulating Factors Regulate the Expression of RORγT in Human Lymphocytes

AMPK-dependent Repression of Hepatic Gluconeogenesis via Disruption of CREB·CRTC2 Complex by Orphan Nuclear Receptor Small Heterodimer Partner

SHP limits TLR signaling, an inducible transcriptional corepressor

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