Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice

Takemura, Takayo; Yoshida, Yasuhiko; Kiso, Shinichi; Kizu, Takashi; Furuta, Kunimaro; Ezaki, Hisao; Hamano, Mina; Egawa, Mayumi; Chatani, Norihiro; Kamada, Y.; Imai, Yumiko; Higashiyama, Shigeki; Iwamoto, Ryo; Mekada, Eisuke; Takehara, Tetsuo

doi:10.1016/j.bbrc.2013.05.097

Cited by 36 publications

(35 citation statements)

References 28 publications

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“…Mouse liver samples or cells were homogenized or scraped off in RIPA buffer containing 50 mM Tris (pH 7.5), 150 mM NaCl, 1 mM EDTA, 0.1% sodium deoxycholate, 0.1% SDS, 1% Nonidet P-40, phosphatase inhibitor mixture, and complete protease inhibitor mixture (Roche Applied Science, Basel, Switzerland). Western blot analysis was performed as described previously (40). The following antibodies were used for immunodetection: anti-phospho-Met (Tyr 1234 ), anti-Met, anti-phospho-ERK1/2 (Thr 202 /Tyr 204 ), anti-ERK1/2, anti-phospho-Gab1 (Tyr 627 ), and anti-Gab1, purchased from Cell Signaling Technology (Danvers, MA), and anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH), purchased from Trevigen (Gaithersburg, MD).…”

Section: Methodsmentioning

confidence: 99%

“…During the progression of liver fibrosis, various growth factors are involved in liver fibrogenesis and fibrolysis (14,28,37,40,43,44). To date, several studies have demonstrated protective roles of hepatocyte growth factor (HGF) against liver fibrogenesis (43,44).…”

mentioning

confidence: 99%

“…To date, several studies have demonstrated protective roles of hepatocyte growth factor (HGF) against liver fibrogenesis (43,44). In contrast to HGF, the effects of epidermal growth factor (EGF) family members on liver fibrosis have been shown to differ from one another in a mouse model of liver fibrosis (14,28,40). We and others recently showed that deletion of heparin-binding EGF enhances liver fibrosis (14,40).…”

mentioning

confidence: 99%

“…In contrast to HGF, the effects of epidermal growth factor (EGF) family members on liver fibrosis have been shown to differ from one another in a mouse model of liver fibrosis (14,28,40). We and others recently showed that deletion of heparin-binding EGF enhances liver fibrosis (14,40). In contrast, deletion of amphiregulin, another member of the EGF family, has been reported to improve hepatic fibrogenesis (28).…”

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confidence: 99%

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Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice

Kizu

Yoshida

Furuta

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Grb2-associated binder 1 (Gab1) adaptor protein amplifies signals downstream of a broad range of growth factors/receptor tyrosine kinases. Although these signals are implicated in liver fibrogenesis, the role of Gab1 remains unclear. To elucidate the role of Gab1, liver fibrosis was examined in hepatocyte-specific Gab1-conditional knockout (Gab1CKO) mice upon bile duct ligation (BDL). Gab1CKO mice developed exacerbated liver fibrosis with activation of hepatic myofibroblasts after BDL compared with control mice. The antifibrotic role of hepatocyte Gab1 was further confirmed by another well-established mouse model of liver fibrosis using chronic injections of carbon tetrachloride. After BDL, Gab1CKO mice also displayed exacerbated liver injury, decreased hepatocyte proliferation, and enhanced liver inflammation. Furthermore, cDNA microarray analysis was used to investigate the potential molecular mechanisms of the Gab1-mediated signal in liver fibrosis, and the fibrosis-promoting factor chemokine (C-C motif) ligand 5 ( Ccl5) was identified as upregulated in the livers of Gab1CKO mice following BDL. Interestingly, in vitro studies using primary hepatocytes isolated from control and Gab1CKO mice revealed that the loss of Gab1 resulted in increased hepatocyte CCL5 synthesis upon lipopolysaccharide stimulation. Finally, pharmacological antagonism of CCL5 reduced BDL-induced liver fibrosis in Gab1CKO mice. In conclusion, our results demonstrate that hepatocyte Gab1 is required for liver fibrosis and that hepatocyte CCL5 could be an important contributor to this process. Thus, we present a novel antifibrotic function of hepatocyte Gab1 in liver fibrogenesis.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice

Kizu

Yoshida

Furuta

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…They promote proliferation of hepatocytes after liver challenge as reported in many rodent models. [97][98][99][100][101][102] EGFR is expressed in both the parenchymal and nonparenchymal liver cells, and several studies have reported that amphiregulin enhances liver fibrosis through its mitogenic effect on HSCs. 102,103 These effects, protecting hepatocytes as well as profibrotic HSCs, could account for the fact that ADAM17 hepatocyte-deficient mice do not develop exaggerated fibrosis after intoxication with CCl 4 (our observation, unpublished).…”

Section: Regulator Of Growth Factor Signaling In the Livermentioning

confidence: 99%

Metalloproteinases in liver fibrosis: current insights

Zbodakova¹,

Chalupský²,

Turečková³

et al. 2017

MNM

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Liver fibrosis is defined by excessive deposition of extracellular matrix. The fibrotic conditions result from the imbalance between synthesis and deposition of fibrous tissues and decomposition of these matrix proteins. This process can be reversed as a regular part of the healing process after hepatic damage or can become chronic. When the protein matrix synthesis predominates and the decomposition is suppressed, fibrosis will progress into irreversible cirrhosis or steatosis. Among the molecular players involved in fibrotic liver diseases, metalloproteinases of matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase (ADAM) families are critical in the development of liver fibrosis and its resolution. Previously, MMPs were recognized as extracellular matrix degrading enzymes. Currently, they are also known as mediators in a variety of processes related to immunity and tissue repair. In this article, we have reviewed the models of liver fibrosis and findings on MMPs and ADAMs in hepatic fibrosis conditions.

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Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen‐induced liver injury in mice

et al. 2016

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Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure. In APAP-induced acute liver failure, hepatocyte death and subsequent liver regeneration determines the prognosis of patients, making it necessary to identify suitable therapeutic targets based on detailed molecular mechanisms. Grb2-associated binder 1 (Gab1) adaptor protein plays a crucial role in transmitting signals from growth factor and cytokine receptors to downstream effectors. In this study, we hypothesized that Gab1 is involved in APAP-induced acute liver failure. Hepatocyte-specific Gab1 conditional knockout (Gab1CKO) and control mice were treated with 250 mg/kg of APAP. After APAP treatment, Gab1CKO mice had significantly higher mortality and elevated serum alanine aminotransferase levels compared to control mice. Gab1CKO mice had increased hepatocyte death and increased serum levels of high mobility group box 1, a marker of hepatocyte necrosis. In addition, Gab1CKO mice had reduced hepatocyte proliferation. The enhanced hepatotoxicity in Gab1CKO mice was associated with increased activation of stress-related c-Jun N-terminal kinase (JNK) and reduced activation of extracellular signal-regulated kinase and AKT. Furthermore, Gab1CKO mice showed enhanced mitochondrial translocation of JNK accompanied by an increase in the release of mitochondrial enzymes into the cytosol, which is indicative of increased mitochondrial dysfunction and subsequent nuclear DNA fragmentation. Finally, in vitro experiments showed that Gab1-deficient hepatocytes were more susceptible to APAP-induced mitochondrial dysfunction and cell death, suggesting that hepatocyte Gab1 is a direct target of APAP-induced hepatotoxicity. Conclusion: Hepatocyte Gab1 plays a critical role in controlling the balance between hepatocyte death and compensatory hepatocyte proliferation during APAP-induced liver injury.

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Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice

Cited by 36 publications

References 28 publications

Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice

Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice

Metalloproteinases in liver fibrosis: current insights

Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen‐induced liver injury in mice

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