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

Furuta, Kunimaro; Yoshida, Yasuhiko; Ogura, Satoshi; Kurahashi, T.; Kizu, Takashi; Maeda, Shinichiro; Egawa, Mayumi; Chatani, Norihiro; Nishida, Keigo; Nakaoka, Yoshikazu; Kiso, Shinichi; Kamada, Y.; Takehara, Tetsuo

doi:10.1002/hep.28410

Cited by 23 publications

(23 citation statements)

References 51 publications

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“…In the present study, our data showed that STAT3/Erk signaling transductions were activated, as evidenced by increased p-STAT3 and p-Erk1/2 expression. Consistent with previous reports 37 - 38 , our work also suggested that the mitogenic signaling transduction of Erk was also induced in control and liposN groups in APAP-induced acute liver injury. Meanwhile mTOR signaling transduction was activated in total liver extracts by liposIA as evidenced by increased p-mTOR (S2448), upstream protein p-Akt as well as two substrates p-p70s6K (S371) and p-4EBP1-pT45.…”

Section: Discussionsupporting

confidence: 93%

Tethering Interleukin-22 to Apolipoprotein A-I Ameliorates Mice from Acetaminophen-induced Liver Injury

Chen¹,

Zhang²,

Fan³

et al. 2017

Theranostics

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Increasing evidence indicates that interleukin-22 (IL-22) holds tremendous potential as a protective agent in preventing liver injury, but its pleiotropic effects and pathogenic role in carcinogenesis, rheumatoid arthritis and psoriasis restrict its systemic application. Here, we first developed a nanoparticle (liposIA) as a liver-targeted agent through IL-22 tethered to apolipoprotein A-I (ApoA-I) in a gene therapy vector. LiposIA was prepared using thin film dispersion method and the complexes exhibited desirable nanoparticle size, fine polydisperse index, highly efficient transfection, and excellent serum and storage stability. Biodistribution and hepatic STAT3 phosphorylation studies revealed that IL-22 tethered to ApoA-I led to highly efficient liver targeting. More importantly, our studies showed that a single-dose of liposIA was able to protect mice against acetaminophen-induced liver injury and did not initiate inflammatory response or systemic toxicity in vivo. During this process, activated STAT3/Erk and Akt/mTOR signaling transductions were observed, as well as inhibition of reactive oxygen species (ROS) generation, which prevented mitochondrial dysfunction. These studies demonstrated that IL-22 tethered to apolipoprotein A-I could target and ameliorate acetaminophen-induced acute liver injury, which highlighted that a targeted strategy for IL-22 delivery might have broad utility for the protection of hepatocellular damage.

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Section: Discussionsupporting

confidence: 93%

Tethering Interleukin-22 to Apolipoprotein A-I Ameliorates Mice from Acetaminophen-induced Liver Injury

Chen¹,

Zhang²,

Fan³

et al. 2017

Theranostics

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“…Although at 6 h post APAP administration p-JNK levels were not affected by Fibapo these were significantly reduced by 10 h ( Figure 2c ). Concomitantly, increased activation of extracellular signal-regulated kinase 1/2 (ERK1/2), considered part of the compensatory pro-regenerative signaling triggered by APAP toxicity, 39 , 43 was observed in Fibapo-treated mice ( Figure 2d ). Expression of Bcl-xL , an inhibitor of mitochondrial-dependent cell death involved in hepatoprotection from APAP-induced injury, 14 , 42 was enhanced upon Fibapo treatment ( Figure 2e ).…”

Section: Resultsmentioning

confidence: 99%

Engineered fibroblast growth factor 19 protects from acetaminophen-induced liver injury and stimulates aged liver regeneration in mice

et al. 2017

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The liver displays a remarkable regenerative capacity triggered upon tissue injury or resection. However, liver regeneration can be overwhelmed by excessive parenchymal destruction or diminished by pre-existing conditions hampering repair. Fibroblast growth factor 19 (FGF19, rodent FGF15) is an enterokine that regulates liver bile acid and lipid metabolism, and stimulates hepatocellular protein synthesis and proliferation. FGF19/15 is also important for liver regeneration after partial hepatectomy (PH). Therefore recombinant FGF19 would be an ideal molecule to stimulate liver regeneration, but its applicability may be curtailed by its short half-life. We developed a chimaeric molecule termed Fibapo in which FGF19 is covalently coupled to apolipoprotein A-I. Fibapo retains FGF19 biological activities but has significantly increased half-life and hepatotropism. Here we evaluated the pro-regenerative activity of Fibapo in two clinically relevant models where liver regeneration may be impaired: acetaminophen (APAP) poisoning, and PH in aged mice. The only approved therapy for APAP intoxication is N-acetylcysteine (NAC) and no drugs are available to stimulate liver regeneration. We demonstrate that Fibapo reduced liver injury and boosted regeneration in APAP-intoxicated mice. Fibapo improved survival of APAP-poisoned mice when given at later time points, when NAC is ineffective. Mechanistically, Fibapo accelerated recovery of hepatic glutathione levels, potentiated cell growth-related pathways and increased functional liver mass. When Fibapo was administered to old mice prior to PH, liver regeneration was markedly increased. The exacerbated injury developing in these mice upon PH was attenuated, and the hepatic biosynthetic capacity was enhanced. Fibapo reversed metabolic and molecular alterations that impede regeneration in aged livers. It reduced liver steatosis and downregulated p21 and hepatocyte nuclear factor 4 α (Hnf4α) levels, whereas it stimulated Foxm1b gene expression. Together our findings indicate that FGF19 variants retaining the metabolic and growth-promoting effects of this enterokine may be valuable for the stimulation of liver regeneration.

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“…Gab1β expression also increased LIFR-mediated Erk and Akt phosphorylation, directly implicating the adaptor as a transducer of LIFR signals. PI3K/Akt signalling has been shown to be involved in Gab1-mediated cell survival, and in ESCs, activation of this pathway has been reported to promote cell growth, survival and self-renewal ( Cherif et al, 2015 ; Fan et al, 2016 ; Fukumoto et al, 2009 ; Furuta et al, 2016 ; Hishida et al, 2015 ; Holgado-Madruga and Wong, 2003 ; Holgado-Madruga et al, 1997 ; Jirmanova et al, 2002 ; Paling et al, 2004 ; Sun et al, 2014 ; Watanabe et al, 2006 ). By contrast, Erk activation is normally associated with ESC differentiation, and inhibition of Mek-Erk signalling promotes ESC self-renewal ( Burdon et al, 1999 ; Ying et al, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

LIF-dependent survival of embryonic stem cells is regulated by a novel palmitoylated Gab1 signalling protein

Sutherland

Ruhe

Gattegno-Ho

et al. 2018

Journal of Cell Science

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The cytokine leukaemia inhibitory factor (LIF) promotes self-renewal of mouse embryonic stem cells (ESCs) through activation of the transcription factor Stat3. However, the contribution of other ancillary pathways stimulated by LIF in ESCs, such as the MAPK and PI3K pathways, is less well understood. We show here that naive-type mouse ESCs express high levels of a novel effector of the MAPK and PI3K pathways. This effector is an isoform of the Gab1 (Grb2-associated binder protein 1) adaptor protein that lacks the N-terminal pleckstrin homology (PH) membrane-binding domain. Although not essential for rapid unrestricted growth of ESCs under optimal conditions, the novel Gab1 variant (Gab1β) is required for LIF-mediated cell survival under conditions of limited nutrient availability. This enhanced survival is absolutely dependent upon a latent palmitoylation site that targets Gab1β directly to ESC membranes. These results show that constitutive association of Gab1 with membranes through a novel mechanism promotes LIF-dependent survival of murine ESCs in nutrient-poor 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

Cited by 23 publications

References 51 publications

Tethering Interleukin-22 to Apolipoprotein A-I Ameliorates Mice from Acetaminophen-induced Liver Injury

Tethering Interleukin-22 to Apolipoprotein A-I Ameliorates Mice from Acetaminophen-induced Liver Injury

Engineered fibroblast growth factor 19 protects from acetaminophen-induced liver injury and stimulates aged liver regeneration in mice

LIF-dependent survival of embryonic stem cells is regulated by a novel palmitoylated Gab1 signalling protein

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