Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice

Lafdil, Fouad; Chobert, Marie-Noële; Deveaux, Vanessa; Zafrani, Elie‐Serge; Mavier, Philippe; Nakano, Toru; Laperche, Yannick; Brouillet, Arthur

doi:10.1016/j.jhep.2009.02.030

Cited by 45 publications

(51 citation statements)

References 37 publications

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“…The livers were removed from animals under anesthesia and processed as previously described. 29 Blood samples were collected to measure serum alanine aminotransferase (ALT) activity by using an Advia 1650 automate (Bayer Diasys). Animal manipulations were performed according to the recommendations of the French ethical committee and under the supervision of authorized investigators.…”

Section: Materials and Methods Animals And Experimental Designmentioning

confidence: 99%

“…Immunohistochemistry was carried out on paraffin-embedded or 5 mm-thick frozen sections, as previously described. 29 Primary antibodies were mouse monoclonal anti-cytokeratin 19 (CK19) (1:150, Novocastra Laboratories), anti-aSMA (1:1000; Sigma-Aldrich), anti-desmin (1:200; DakoCytomotion), anti-CD68 (1:150; Serotec) and rabbit polyclonal anticollagen 1 (1:200; Serotec) or anti-TGFb (1:50; Santa Cruz). Fluorescent labeling of CK19 and CD68 was achieved on 6 mm frozen sections using secondary goat anti-mouse IgG Alexa fluor 488 and 555, respectively (1:1000), after incubation with the Image-iTtFX signal enhancer to reduce the background (Invitrogen).…”

Section: Caspase-3 Activitymentioning

confidence: 99%

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Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats

Chobert

Couchie

Fourcot

et al. 2012

Laboratory Investigation

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Section: Materials and Methods Animals And Experimental Designmentioning

confidence: 99%

Section: Caspase-3 Activitymentioning

confidence: 99%

Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats

Chobert

Couchie

Fourcot

et al. 2012

Laboratory Investigation

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“…In liver pathologies, a hepatoprotective role for Gas6 has been reported in ischemia/reperfusion-induced damage [14], and in the wound healing response to liver injury [15,16]. In normal liver, Gas6 is mainly expressed in Kupffer cells, while Axl is found in macrophages and in quiescent HSC [17].…”

Section: Introductionmentioning

confidence: 99%

Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

Bárcena

Stefanović

Tutusaus

et al. 2015

Journal of Hepatology

126

152

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Background & Aims Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Axl, a receptor tyrosine kinase, and its ligand Gas6 are involved in cell differentiation, immune response and carcinogenesis. Methods HSCs were obtained from wild type and Axl−/− mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR. Experimental fibrosis was studied in CCl4-treated wild type and Axl−/− mice, and in combination with Axl inhibitor. Gas6 and Axl serum levels were measured in alcoholic liver disease (ALD) and hepatitis C virus (HCV) patients. Results In primary mouse HSCs, Gas6 and Axl levels paralleled HSC activation. rGas6 phosphorylated Axl and AKT prior to HSC phenotypic changes, while Axl siRNA silencing reduced HSC activation. Moreover, BGB324 blocked Axl/AKT phosphorylation and diminished HSC activation. In addition, Axl KO mice displayed decreased HSC activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. Similarly, BGB324 reduced collagen deposition and CCl4-induced liver fibrosis in mice. Importantly, Gas6 and Axl serum levels increased in ALD and HCV patients, inversely correlating with liver functionality. Conclusions: The Gas6/Axl axis is required for full HSC activation. Gas6 and Axl serum levels increase in parallel to chronic liver disease progression. Axl targeting may be a therapeutic strategy for liver fibrosis management.

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“…It is secreted by endothelial cells and has been reported to have mitogenic and anti-apoptotic effects on several cell types, such as NIH 3T3 fibroblasts, cardiac fibroblasts and hepatic cells [18][19][20] and to play a role in liver regeneration [21]. Gas6 mRNA is present in the pancreas [22] and synthesised by alpha cells of the islets of Langerhans [23].…”

Section: Introductionmentioning

confidence: 99%

Growth arrest specific protein (GAS) 6: a role in the regulation of proliferation and functional capacity of the perinatal rat beta cell

et al. 2013

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Aims/hypothesis Maternal low-protein (LP) diet during gestation results in a reduced beta cell mass in the offspring at birth and this may hamper the ability to adapt to high-energy food and sedentary lifestyle later in life. To investigate the biology behind the LP-offspring phenotype, this study aimed to identify differentially expressed genes in the pancreas and their potential role in the fetal programming. Methods Wistar rats were given either an LP diet or normalchow (NC) diet during gestation and differentially expressed genes in the offspring around the time of birth were identified using RNA microarray and quantitative PCR. The role of a differentially expressed gene, growth arrest specific protein 6 (GAS6), was evaluated in vitro using neonatal rat islets.Results The mRNA level of Gas6, known to be mitogenic in other tissues, was reduced in LP offspring. The mRNA content of Mafa was increased in LP offspring suggesting an early maturation of beta cells. When applied in vitro, GAS6 increased proliferation of neonatal pancreatic beta cells, while reducing glucose-stimulated insulin secretion without changing the total insulin content of the islets. In addition, GAS6 decreased the mRNA content of Mafa. Conclusions/interpretation We propose a role for GAS6 in the regulation of pancreatic beta cells in the critical period around the time of birth. Our results support the hypothesis that the reduced beta cell mass seen in LP offspring is caused by a change in the intra-uterine environment that favours premature maturation of the beta cells.Keywords Fetal programming . Growth arrest specific protein 6 (GAS6) . Pancreatic beta cells

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Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice

Cited by 45 publications

References 37 publications

Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats

Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats

Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

Growth arrest specific protein (GAS) 6: a role in the regulation of proliferation and functional capacity of the perinatal rat beta cell

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