Liver-specific and proliferation-induced deoxyribonuclease I hypersensitive sites in the mouse insulin-like growth factor binding protein-1 gene

Crissey

Molecular and Cellular Biology

et al. 2001

Self Cite

123

116

Following hepatic injury or stress, gluconeogenic and acute-phase response genes are rapidly upregulated to restore metabolic homeostasis and limit tissue damage. Regulation of the liver-restricted insulin-like growth factor binding protein 1 (IGFBP-1) gene is dramatically altered by changes in the metabolic state and hepatectomy, and thus it provided an appropriate reporter to assess the transcriptional milieu in the liver during repair and regeneration. The cytokine interleukin-6 (IL-6) is required for liver regeneration and repair, and it transcriptionally upregulates a vast array of genes during liver growth by unknown mechanisms. The liver, which plays an important role in maintaining metabolic and synthetic homeostasis, constitutes a conditional renewal system in which parenchymal cells normally in G 0 may be induced to proliferate following toxic damage, hepatitis, and surgical resection that culminates in the rapid restoration of hepatic parenchyma (35). To maintain glucose balance following the acute loss of liver mass posthepatectomy, phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), and other genes involved in gluconeogenesis are rapidly upregulated in the regenerating liver (14, 37, 54, 55). However, the molecular mechanism by which the liver maintains metabolic homeostasis despite the acute loss of twothirds of hepatic tissue or after injury is not known.Liver regeneration, a hyperplastic response, involves the proliferation of the mature functioning cells composing the intact organ (35,54,55). Of the known cytokines released after liver injury or hepatectomy, interleukin-6 (IL-6) has been shown to be required for normal liver regeneration and repair (8,24). In IL6 Ϫ/Ϫ mice, a highly significant reduction in hepatocyte DNA synthesis, increased liver necrosis, discrete G 1 -phase abnormalities including absence of STAT3 activation, reduction in AP-1 activation, and selective abnormalities in gene expression are observed posthepatectomy and after carbon tetrachloride injury, all of which are corrected by injection with IL-6.Among those genes whose expression is abnormal in IL-6 Ϫ/Ϫ livers after partial hepatectomy are those encoding proteins involved in cell cycle progression such as AP-1 factors, c-Myc, and cyclin D1. However, a number of other genes with less clear connection to cell growth show blunted induction in the absence of IL-6, including the insulin-like growth factor binding protein 1 (IGFBP-1) gene. The mechanism by which IL-6 activates such a vast array of genes is unknown. We chose to study IGFBP-1 because of its proposed role in both hepatic growth and metabolism.IGFBP-1 is an immediate-early gene induced at the transcriptional level in the remnant liver following partial hepatectomy (26,38,50). It is distinct in that its plasma level is dynamically regulated by changes in the metabolic state and after hepatic injury. Of the known upregulators of IGFBP-1 transcription, only IL-6 and phorbol esters have been demonstrated to overcome the strong inhibition of IGFB...

Section: Ilsupporting

confidence: 60%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Interleukin-6-Induced STAT3 and AP-1 Amplify Hepatocyte Nuclear Factor 1-Mediated Transactivation of Hepatic Genes, an Adaptive Response to Liver Injury

Crissey

Molecular and Cellular Biology

et al. 2001

Self Cite

123

116

Journal of Biological Chemistry

“…In the present study, we characterized the elements in the promoter of human P4H␣(I). We found that the E-box-like sequence (CACGGG), which has been shown to bind upstream stimulatory factors (USF) (25)(26)(27), in the position of bp Ϫ135 is vital for P4H␣(I) transcription. Upstream stimulatory factor (USF1/USF2) appears to be the transcription factor that controls the basal P4H␣(I) expression.…”

mentioning

confidence: 99%

Human Prolyl-4-hydroxylase α(I) Transcription Is Mediated by Upstream Stimulatory Factors

Chen

Shen

Wang

et al. 2006

Prolyl-4-hydroxylase ␣(I) (P4H␣(I)) is the rate-limiting subunit for P4H enzyme activity, which is essential for procollagen hydroxylation and secretion. In the current study, we have characterized the human P4H␣(I) promoter for transcription factors and DNA elements regulating P4H␣(I) expression. Using a progressive deletion cloning approach, we have constructed pGL3-P4H␣(I) recombinant plasmids. We have identified a positive regulatory region at the positions of bp ؊184 to ؊97 responsible for ϳ80% of the P4H␣(I) promoter efficiency. Three E-boxes were located within this region, and the E-box at position bp ؊135 explains most of the regulatory capacity. Upstream stimulatory factors (USF1/USF2) were shown to bind on the E-box using chromatin immunoprecipitation assay. Suppression of USF1 and/or USF2 using specific short interference RNA resulted in a significant reduction in P4H␣(I) promoter activity, and overexpressed USF1 or USF2 increased P4H␣(I) promoter activity significantly. Although transforming growth factor ␤1 increased the USF1/USF2-E-box binding and P4H␣(I) promoter activity, this up-regulatory effect can be largely prevented by USF1/ USF2-specific short interference RNA. On the other hand, cigarette smoking extracts, which have been shown to suppress P4H␣(I) expression, inhibited the binding between the USF1/USF2 and E-box, resulting in a reduced P4H␣(I) promoter activity. Furthermore, the E-box on the P4H␣(I) promoter appeared to indiscriminately bind with either USF1 or USF2, with a similar outcome on the promoter efficiency. In conclusion, our study shows that USF1/ USF2 plays a critical role in basal P4H␣(I) expression, and both positive (transforming growth factor ␤1) and negative (cigarette smoking extract) regulators appear to influence the USF-E-box interaction and affect P4H␣(I) expression.

Deficiency of G-protein-coupled bile acid receptor Gpbar1 (TGR5) enhances chemically induced liver carcinogenesis

Chen

Forman

et al. 2013

Hepatology

Gpbar1 (TGR5), a membrane-bound bile acid receptor, is well known for its roles in regulation of energy homeostasis and glucose metabolism. We recently reported that TGR5 activation inhibits nuclear factor κB (NF-κB)-mediated inflammation. Here we show that TGR5 deficiency enhances chemically-induced liver carcinogenesis, and that TGR5 is a negative regulator of signal transducer and activator of transcription 3 (STAT3) signaling. Mice lacking TGR5 were much more susceptible to diethylnitrosamine (DEN)-induced acute liver injury and liver carcinogenesis than wild-type (WT) mice. Consistent with the increasing incidence of liver cancer in TGR5−/− mice, hepatocyte death, compensatory proliferation, and gene expression of certain inflammatory cytokines and matrix metalloproteinases were more sensitive to DEN induction in the absence of TGR5 signaling. In vitro, TGR5 activation greatly inhibited proliferation and migration of human liver cancer cells. We then found that TGR5 activation strongly suppressed STAT3 signaling in vitro and in vivo. Furthermore, we revealed that TGR5 antagonizes STAT3 pathway through suppressing STAT3 phosphorylation, its transcription activity and DNA binding activity, which suggests that TGR5 antagonizes liver tumorigenesis at least in part by inhibiting STAT3 signaling. Conclusion These findings identify TGR5 as a novel liver tumor suppressor that may serve as an attractive therapeutic tool for human liver cancer.