IGF-1R Contributes to Stress-Induced Hepatocellular Damage in Experimental Cholestasis

Cadoret, Axelle; Rey, Colette; Wendum, Dominique; Elriz, Khaldoun; Tronche, François; Holzenberger, Martin; Housset, Chantal

doi:10.2353/ajpath.2009.081081

Cited by 10 publications

(11 citation statements)

References 61 publications

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“…It is important to note that levels of serum ALP and hepatic PAI1 remained lower in IRS2KO mice at this final time period, suggesting that, although there were no differences in the degree of fibrosis, IRS2 deficiency protects against long-term damage induced by bile accumulation. Taken together, these data have evidenced a delay in the progression towards fibrosis in IRS2KO mice after BDL, in agreement with the work of Cadoret et al (2009) in the IGF1RKO mice. Based on that, we could hypothesize that IRS2 (this study) or IGF1R (Cadoret et al, 2009) deficiency specifically protect against IGF1-mediated HSC activation, as demonstrated here by our in vitro experiments silencing IRS2 in LX2 cells as discussed below.…”

Section: Discussionsupporting

confidence: 91%

Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury

Villar-Lorenzo

Rada

Rey

et al. 2019

Disease Models &Amp; Mechanisms

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Insulin receptor substrate 2 (IRS2) is a key downstream mediator of insulin and insulin-like growth factor 1 (IGF1) signalling pathways and plays a major role in liver metabolism. The aim of this study was to investigate whether IRS2 had an impact on the hepatic fibrotic process associated with cholestatic injury. Bile duct ligation (BDL) was performed in wild-type (WT) and Irs2 -deficient (IRS2KO) female mice. Histological and biochemical analyses, together with fibrogenic and inflammatory responses were evaluated in livers from mice at 3, 7 and 28 days following BDL. We also explored whether activation of human hepatic stellate cells (HSCs) induced by IGF1 was modulated by IRS2. IRS2KO mice displayed reduced disruption of liver histology, such hepatocyte damage and excess deposition of extracellular matrix components, compared with WT mice at 3 and 7 days post-BDL. However, no histological differences between genotypes were found at 28 days post-BDL. The less pro-inflammatory profile of bile acids accumulated in the gallbladder of IRS2KO mice after BDL corresponded with the reduced expression of pro-inflammatory markers in these mice. Stable silencing of IRS2 or inhibition of ERK1/2 reduced the activation of human LX2 cells and also reduced induction of MMP9 upon IGF1 stimulation. Furthermore, hepatic MMP9 expression was strongly induced after BDL in WT mice, but only a slight increase was found in mice lacking IRS2. Our results have unravelled the signalling pathway mediated by IGF1R–IRS2–ERK1/2–MMP9 as a key axis in regulating HSC activation, which might be therapeutically relevant for targeting liver fibrosis.

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Section: Discussionsupporting

confidence: 91%

Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury

Villar-Lorenzo

Rada

Rey

et al. 2019

Disease Models &Amp; Mechanisms

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“…In the acute CCl 4 model, IGF1 did not reduce the initial damage, but caused a more rapid DNA synthesis, resulting in liver regeneration [27]. Depletion of IGF1R reduces ductular and fibrogenic responses and increased cholestasis tolerance in BDL mice [40]. The damage in the Abcb4 −/− mouse is chronic, less severe, and localized to the portal areas [16].…”

Section: Discussionmentioning

confidence: 97%

Insulin-like growth factor 1 enhances bile-duct proliferation and fibrosis in Abcb4−/− mice

Sokolović¹,

Rodríguez‐Ortigosa²,

Bloemendaal³

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Adamant progression of chronic cholangiopathies towards cirrhosis and limited therapeutic options leave a liver transplantation the only effective treatment. Insulin-like growth factor 1 (IGF1) effectively blocks fibrosis in acute models of liver damage in mice, and a phase I clinical trial suggested an improved liver function. IGF1 targets the biliary epithelium, but its potential benefit in chronic cholangiopathies has not been studied. To investigate the possible therapeutic effect of increased IGF1 expression, we crossed Abcb4(-/-) mice (a model for chronic cholangiopathy), with transgenic animals that overexpress IGF1. The effect on disease progression was studied in the resulting IGF1-overexpressing Abcb4(-/-) mice, and compared to that of Abcb4(-/-) littermates. The specificity of this effect was further studied in an acute model of fibrosis. The overexpression of IGF1 in transgenic Abcb4(-/-) mice resulted in stimulation of fibrogenic processes - as shown by increased expression of Tgfß, and collagens 1, 3 and 4, and confirmed by Sirius red staining and hydroxyproline measurements. Excessive extracellular matrix deposition was favored by raise in Timp1 and Timp2, while a reduction of tPA expression indicated lower tissue remodeling. These effects were accompanied by an increase in expression of inflammation markers like Tnfα, and higher presence of infiltrating macrophages. Finally, increased number of Ck19-expressing cells indicated proliferation of biliary epithelium. In contrast to liver fibrosis associated with hepatocellular damage, IGF1 overexpression does not inhibit liver fibrogenesis in chronic cholangiopathy.

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“…Toll-like receptor signaling interferes with the UPR by regulating the ATF4-CHOP pathway and the insulin-like growth factor-1 also regulates ER stress pathways. [56][57][58] Finally, XBP1 mRNA splicing in spleen B cells during plasma cell differentiation is induced by antibody-mediated CD40 activation. 59,60 The regulation of the UPR by extracellular signals may represent a mechanism by which the environment controls cell adaptation to stress.…”

Section: Discussionmentioning

confidence: 99%

A protective role for CD154 in hepatic steatosis in mice

et al. 2010

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Inflammation and lipid metabolism pathways are linked, and deregulation of this interface may be critical in hepatic steatosis. The importance of the dialog between inflammatory signaling pathways and the unfolded protein response (UPR) in metabolism has been underlined. Herein, we studied the role of CD154, a key mediator of inflammation, in hepatic steatosis. To this end, Balb/c mice, wild-type or deficient in CD154 (CD154KO), were fed a diet rich in olive oil. In vitro, the effect of CD154 was studied on primary hepatocyte cultures and hepatocyte-derived cell lines. Results showed that CD154KO mice fed a diet rich in olive oil developed hepatic steatosis associated with reduced apolipoprotein B100 (apoB100) expression and decreased secretion of very low-density lipoproteins. This phenotype correlated with an altered UPR as assessed by reduced X-Box binding protein-1 (XBP1) messenger RNA (mRNA) splicing and reduced phosphorylation of eukaryotic initiation factor 2a. Altered UPR signaling in livers of CD154KO mice was confirmed in tunicamycin (TM) challenge experiments. Treatment of primary hepatocyte cultures and hepatocyte-derived cell lines with soluble CD154 increased XBP1 mRNA splicing in cells subjected to either oleic acid (OA) or TM treatment. Moreover, CD154 reduced the inhibition of apoB100 secretion by HepG2 cells grown in the presence of high concentrations of OA, an effect suppressed by XBP1 mRNA silencing and in HepG2 cells expressing a dominant negative form of inositol requiring ER-to-nucleus signaling protein-1. The control of the UPR by CD154 may represent one of the mechanisms involved in the pathophysiology of hepatic steatosis. Conclusion: Our study identifies CD154 as a new mediator of hepatic steatosis. (HEPATOLOGY 2010;52:1968-1979

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IGF-1R Contributes to Stress-Induced Hepatocellular Damage in Experimental Cholestasis

Cited by 10 publications

References 61 publications

Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury

Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury

Insulin-like growth factor 1 enhances bile-duct proliferation and fibrosis in Abcb4−/− mice

A protective role for CD154 in hepatic steatosis in mice

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