Disruption of the growth hormone-Signal transducer and activator of transcription 5-Insulinlike growth factor 1 axis severely aggravates liver fibrosis in a mouse model of cholestasis

Blaas, Leander; Kornfeld, Jan-Wilhelm; Schramek, Daniel; Musteanu, Mónica; Zollner, Gernot; Gumhold, J.; Zijl, Franziska van; Schneller, Doris; Esterbauer, Harald; Egger, Gerda; Mair, Markus; Kenner, Lukas; Mikulits, Wolfgang; Eferl, Robert; Moriggl, Richard; Penninger, Josef; Trauner, Michael; Casanova, Emilio

doi:10.1002/hep.23469

Cited by 50 publications

(52 citation statements)

References 42 publications

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“…The systemic application of IGF-I as recombinant protein or incorporated in a viral vector construct was found to improve liver function in the context of liver cirrhosis in animal models and in patients [11][12][13]. IGF-I might likely exert its antifibrotic effect [14] and/or improve liver function partly by modulating transforming growth factor-beta 1 (TGF-b1) expression/ signaling events [15] and/or by inducing hepatocyte proliferation [16] or survival [17].…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stromal Cells Engineered to Produce IGF-I by Recombinant Adenovirus Ameliorate Liver Fibrosis in Mice

Fiore

BayoJuan²,

GarciaMariana³

et al. 2015

Stem Cells and Development

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Section: Introductionmentioning

confidence: 99%

Mesenchymal Stromal Cells Engineered to Produce IGF-I by Recombinant Adenovirus Ameliorate Liver Fibrosis in Mice

Fiore

BayoJuan²,

GarciaMariana³

et al. 2015

Stem Cells and Development

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“…Alteration of STAT5 signaling is associated with liver conditions such as fatty liver, fibrosis, and hepatocellular carcinoma [6]. Hepatocyte and cholangiocyte deletion of STAT5 in animal studies has revealed early and severe liver fibrosis through a reduced expression of important hepato-protective genes as well as increased numbers of apoptotic hepatocytes [7]. Loss of hepatic GH-STAT5 signaling causes defects in lipid and glucose metabolism leading to steatosis, hyperglycemia, and insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

The Role of Signal Transducer and Activator of Transcription 5 and Transforming Growth Factor-β<sub>1</sub> in Hepatic Fibrosis Induced by Chronic Hepatitis C Virus Infection in Egyptian Patients

2018

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Objective: To investigate the possible role of signal transducer and activator of transcription 5 (STAT5) in the pathogenesis of liver fibrosis in Egyptian patients with chronic hepatitis C (CHC) virus infection and its relation to hepatic stellate cells (HSC). Subjects and Methods: Sixty-five patients (46 males and 19 females) were divided into 4 groups based on the severity of fibrosis as detected by Fibroscan as follows: F1, n = 15; F2, n = 21; F3, n = 13; and F4, n = 16. Twenty age- and gender-matched healthy persons volunteered as controls. The serum levels of STAT5, TGF-β1, α-smooth muscle actin (α-SMA), fasting blood sugar, and fasting insulin, as well as homeostasis model assessment of insulin resistance (HOMA-IR), were determined and compared for all groups. The usefulness of the studied serum biomarkers for predicting liver fibrosis was evaluated using a receiver operating characteristic curve. Results: Serum levels of STAT5 were significantly lower in patients compared to controls (9.69 ± 5.62 vs. 14.73 ± 6.52, p ≤ 0.001); on the contrary, TGF-β1, α-SMA, and HOMA-IR were significantly higher in patients compared to controls (mean: 1,796.04 vs. 1,636.94; 14.94 vs. 8.1; and 7.91 vs. 4.18; p ≤ 0.01 and 0.001, respectively). TGF-β1 and α-SMA showed a progressive increase with advancing severity of hepatic fibrosis (mean TGF-β1: 2,058.4 in F1-F2 and 1,583.8 in F3-F4, p ≤ 0.04; mean α-SMA: 13.59 in F1-F2 and 16.62 in F3-F4, p ≤ 0.05). STAT5 had a significant negative correlation with TGF-β1 (p ≤ 0.001), while no correlation was detected with α-SMA (p ≤ 0.8). Conclusions: STAT5 may play a significant role in hepatic fibrogenesis through the induction of TGF-β1 but not through the activation of hepatic stellate cells.

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“…29 The development of fibrosis and acceleration of hepatocellular carcinoma (HCC) in mice with a liver-specific deletion of STAT5 upon CCl 4 treatment were therefore an unexpected observation. 7,17,18,30 This observation placed STAT5 for the first time into the category of tumor suppressors. In addition to liver, loss of STAT5 in mouse embryonic fibroblasts (MEFs) also led to enhanced cell proliferation.…”

Section: Hepatocellular Carcinoma: Balancing the Cell Cycle Through Smentioning

confidence: 92%

“…18 Excessive STAT3 activation appears to be the common denominator in liver-specific STAT5-and SCOS3-null mice, suggesting that STAT3 is a driver in chemical-induced liver disease observed in these models. This proposal is supported through the use of an independent mouse model based on the hepatoprotective role of the NF-κB venue.…”

Section: Hepatocellular Carcinoma: Balancing the Cell Cycle Through Smentioning

confidence: 99%

“…16 Mouse genetics has shed light onto mechanisms that link loss of GH and STAT5 signaling to NAFLD. Liver-specific loss of GHR 6 or STAT5 7,17 signaling resulted in hepatosteatosis, which in some cases was exacerbated by the introduction of additional genetic 18 or pharmacological 17 lesions. Research on the different Ghr and Stat5 mutant mice helped to define the signaling modules key to GH's contribution in preventing hepatosteatosis.…”

Section: Hepatosteatosismentioning

confidence: 99%

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Context-Specific Growth Hormone Signaling through the Transcription Factor STAT5: Implications for the Etiology of Hepatosteatosis and Hepatocellular Carcinoma

2011

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Growth hormone (GH) controls hepatic physiology to a large extent through the transcription factor signal transducers and activators of transcription (STAT) 5. Here, we focus on lessons learned from the physiology and pathophysiology of mice with disrupted Ghr and Stat5 loci. We discuss that hepatosteatosis and hepatocellular carcinoma observed in the absence of STAT5 can be explained in part through an aberrant activation of STAT1 and STAT3, which in themselves promote cell proliferation and survival. We also argue that STAT5 can be a context-specific tumor suppressor as it negatively regulates cell cycle progression. Lastly, we discuss promiscuity between STAT members that permits a given cytokine receptor to activate different STATs and thereby elicit context-dependent biological responses.

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Disruption of the growth hormone-Signal transducer and activator of transcription 5-Insulinlike growth factor 1 axis severely aggravates liver fibrosis in a mouse model of cholestasis

Cited by 50 publications

References 42 publications

Mesenchymal Stromal Cells Engineered to Produce IGF-I by Recombinant Adenovirus Ameliorate Liver Fibrosis in Mice

Mesenchymal Stromal Cells Engineered to Produce IGF-I by Recombinant Adenovirus Ameliorate Liver Fibrosis in Mice

The Role of Signal Transducer and Activator of Transcription 5 and Transforming Growth Factor-β<sub>1</sub> in Hepatic Fibrosis Induced by Chronic Hepatitis C Virus Infection in Egyptian Patients

Context-Specific Growth Hormone Signaling through the Transcription Factor STAT5: Implications for the Etiology of Hepatosteatosis and Hepatocellular Carcinoma

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