Activation of focal adhesion kinase and JNK contributes to the extracellular matrix and cAMP-GEF mediated survival from bile acid induced apoptosis in rat hepatocytes

Usechak, Paul; Gates, Anna; Webster, Cynthia R. L.

doi:10.1016/j.jhep.2008.04.015

Cited by 11 publications

(5 citation statements)

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“…BDL-induced liver damage in cFLIP Ϫ/Ϫ mice involves a prolonged activation of JNK related to inhibition of NF-B, p65, and p38. JNK activation has been implicated in the cytotoxic effects of bile salts promoting apoptotic and necrotic cell death (15,20,55). In the current study, bile duct-ligated mice exhibited a significantly increased phosphorylation of the p46 and p54 isoforms of JNK at day 2, which was enhanced in cFLIP Ϫ/Ϫ mice and maintained up to day 7, while wild-type mice showed decreasing JNK activation at day 7 (Fig.…”

Section: Bdl-induced Acute Liver Injury In Vivo and Bile Acid-inducedsupporting

confidence: 50%

Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation

Gehrke

Nagel

Straub

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in hepatocytes promoted acute cholestatic liver injury early after BDL, which was characterized by a rapid release of proinflammatory and chemotactic cytokines (TNF, IL-6, IL-1β, CCL2, CXCL1, and CXCL2), an increased presence of CD68 macrophages and an influx of neutrophils in the liver, and resulting apoptotic and necrotic hepatocyte cell death. Mechanistically, liver injury in cFLIP mice was aggravated by reactive oxygen species, and sustained activation of the JNK signaling pathway. In parallel, cytoprotective NF-κB p65, A20, and the MAPK p38 were inhibited. Increased injury in cFLIP mice was accompanied by activation of hepatic stellate cells and profibrogenic regulators. The antagonistic caspase 8-homolog cFLIP is a critical regulator of acute, cholestatic liver injury. NEW & NOTEWORTHY The current paper explores the role of a classical modulator of hepatocellular apoptosis in early, cholestatic liver injury. These include activation of NF-κB and MAPK signaling, production of inflammatory cytokines, and recruitment of neutrophils in response to cholestasis. Because these signaling pathways are currently exploited in clinical trials for the treatment of nonalcoholic steatohepatitis and cirrhosis, the current data will help in the development of novel pharmacological options in these indications.

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Section: Bdl-induced Acute Liver Injury In Vivo and Bile Acid-inducedsupporting

confidence: 50%

Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation

Gehrke

Nagel

Straub

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In rat hepatocytes, cAMP-mediated protection against bile acid-induced apoptosis is PKA independent. Further supporting this shielding effect, the EPAC specific agonist 007 protects rat hepatocytes against bile acid-, Fas ligand-, and TNF-␣-induced apoptosis by Src/PI3K-dependent activation of Akt (209,338) or focal adhesion kinase and dephosphorylation of the proapoptotic JNK (1052). Subsequent studies reveal that glycogen synthase kinase 3␤ (GSK3␤), downstream of PI3K/Akt, is responsible for EPAC-mediated protection of hepatocyte from bile acidinduced apoptosis.…”

Section: Epac Proteins and Hepatic Functionsmentioning

confidence: 90%

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Robichaux

Cheng

2018

Physiological Reviews

162

226

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This review focuses on one family of the known cAMP receptors, the exchange proteins directly activated by cAMP (EPACs), also known as the cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs). Although EPAC proteins are fairly new additions to the growing list of cAMP effectors, and relatively "young" in the cAMP discovery timeline, the significance of an EPAC presence in different cell systems is extraordinary. The study of EPACs has considerably expanded the diversity and adaptive nature of cAMP signaling associated with numerous physiological and pathophysiological responses. This review comprehensively covers EPAC protein functions at the molecular, cellular, physiological, and pathophysiological levels; and in turn, the applications of employing EPAC-based biosensors as detection tools for dissecting cAMP signaling and the implications for targeting EPAC proteins for therapeutic development are also discussed.

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“…We interpret this to indicate that AKT signaling in hepatocytes may be preferentially activated by 5‐HT secreting SI NEN metastases. In our studies, pAKT/AKT activity was completely reversed by SB269970, suggesting that AKT signaling is predominantly a 5‐HT 7 receptor‐mediated effect via the PKA‐independent cAMP‐GEF/Rap pathway . A partial but not complete response was evident with Ketanserin/PRX‐08066, suggesting either antagonism at the 5‐HT 7 receptor level or an effect via 5‐HT 2 receptors.…”

Section: Discussionmentioning

confidence: 99%

Serotonin and the 5‐HT7 receptor: The link between hepatocytes, IGF‐1 and small intestinal neuroendocrine tumors

et al. 2013

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Platelet-derived serotonin (5-HT) is involved in liver regeneration. The liver is also the metastatic site for malignant enterochromaffin (EC) cell "carcinoid" (neuroendocrine) neoplasms, the principal cellular source of 5-HT. We hypothesized that 5-HT produced by metastatic EC cells played a role in the hepatic tumor-microenvironment principally via 5-HT 7 receptor-mediated activation of hepatocyte IGF-1 synthesis and secretion. Using isolated rat hepatocytes, we evaluated 5-HT 7 receptor expression (using PCR, sequencing and western blot). ELISA, cell transfection and western blots delineated 5-HT-mediated signaling pathways (pCREB, AKT and ERK). IGF-1 synthesis ⁄ secretion was evaluated using QPCR and ELISA. IGF-1 was tested on small intestinal neuroendocrine neoplasm proliferation, while IGF-1 production and 5-HT 7 expression were examined in an in vivo SCID metastasis model. Our results demonstrated evidence for a functional 5-HT 7 receptor. 5-HT activated cAMP ⁄ PKA activity, pCREB (130-205%, P < 0.05) and pERK ⁄ pAKT (1.2-1.75, P < 0.05). Signaling was reversed by the 5-HT 7 receptor antagonist SB269970. IGF-1 significantly stimulated proliferation of two small intestinal neuroendocrine neoplasm cell lines (EC 50 : 7-70 pg ⁄ mL) and could be reversed by the small molecule inhibitor BMS-754807. IGF-1 and 5-HT were elevated (40-3003) in peri-tumoral hepatic tissue in nude mice, while 5-HT 7 was increased fourfold compared to sham-operated animals. We conclude that hepatocytes express a cAMP-coupled 5-HT 7 receptor, which, at elevated 5-HT concentrations that occur in liver metastases, signals via CREB ⁄ AKT and is linked to IGF-1 synthesis and secretion. Because IGF-1 regulates NEN proliferation, identification of a role for 5-HT 7 in the hepatic metastatic tumor microenvironment suggests the potential for novel therapeutic strategies for amine-producing mid-gut tumors. (Cancer Sci 2013; 104: 844-855) S erotonin, also known as 5-hydroxytryptamine (5-HT), is a biogenic amine produced by enterochromaffin (EC) cells of the gastrointestinal tract.(1) In the blood, 5-HT is carried by platelets (2) and exported to various sites in the body, where it produces mitogenic effects.(3-6) Recently, 5-HT has been considered a modifier of liver function (7) due to the autonomic nervous system input (8) as well as the blood flow within this organ.(9) This amine is thought to regulate proliferation and function of a number of key resident liver cells, including hepatocytes, stellate cells and sinusoidal endothelial cells. (10) 5-HT 1A,1B,1D,1F,2A,2B,2C,3A,3B receptors are known to be expressed on hepatocytes.(10,11) While the 5-HT 1 family inhibits cAMP, (12) 5-HT 2 receptors signal through PLC and 5-HT 4,6,7 receptors stimulate PKA ⁄ cAMP. Neither the complete 5-HT receptor profile nor the intracellular pathways associated with 5-HT-mediated stimulation of hepatocyte function are known.(7) We hypothesized that PKA-dependent as well as PKA-independent cAMP effects and AKT signaling are linked to 5-HT driven hepatocyte st...

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Activation of focal adhesion kinase and JNK contributes to the extracellular matrix and cAMP-GEF mediated survival from bile acid induced apoptosis in rat hepatocytes

Abstract: Background/Aim-Adherence to an extracellular matrix (ECM) rescues hepatocytes from apoptosis, but how hepatocytes adhered to different ECM respond to apoptotic and cytoprotective stimuli is unknown.

Cited by 11 publications

References 46 publications

Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation

Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Serotonin and the 5‐HT7 receptor: The link between hepatocytes, IGF‐1 and small intestinal neuroendocrine tumors

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