ER stress: Can the liver cope?

Cheng, Ji; Kaplowitz, Neil

doi:10.1016/j.jhep.2006.06.004

Cited by 163 publications

(166 citation statements)

References 149 publications

(168 reference statements)

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“…Additionally, we also examined whether the PERK-eIF2α and IRE1α-XBP-1 pathways could be modulated by ATF6 over-expression. As shown in Figure 2A and 2B, the PERK-phosphorylated eIF2α phosphorylation did not differ in the stable cells with ATF6α or ATF6β over-expres- Figure 2A, 2B, and 2E) at 12 h. These results are consistent with previously reported results [28] . Therefore, we propose that ATF6 function in the insulin pathway might be associated with resistance to ER stress.…”

Section: Resultssupporting

confidence: 92%

Activating transcription factor 6 protects insulin receptor from ER stress-stimulated desensitization via p42/44 ERK pathway

Tang¹,

Shen²,

Chen³

et al. 2011

Acta Pharmacol Sin

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Aim: Activating transcription factor 6 (ATF6) is a key signal transducer of endoplasmic reticulum stress (ER stress). This study was conducted to clarify the potential role of ATF6 in the insulin signaling pathway under chronic ER stress. Methods: ER stress of HEK293 cells was induced with tunicamycin (2 µg/mL). The cells were transfected with ATF6α or ATF6β. The phosphorylation level of insulin receptor (IR) was analyzed using Western blot. The changes in ER stress and ERK signaling pathways were explored using Western blot and quantitative real-time PCR. Results: Tunicamycin-induced chronic ER stress attenuated IR tyrosine phosphorylation in a time-dependent manner, whereas overexpression of ATF6 protected IR from desensitization. ATF6 modulation of IR suppression was associated with insulin-stimulated extracellular signal-regulated kinase (ERK) phosphorylation. The treatment of the cells with a specific ERK inhibitor U0126 (10 µmol/L) mimicked the effect of ATF6 over-expression and restored the insulin-stimulated IR phosphorylation. The treatment of the cells with the ERK activator epidermal growth factor (EGF, 200 ng/mL) decreased the protection effect of ATF6 on IR.Conclusion: Our results demonstrate that ATF6 may serve as a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes.

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Section: Resultssupporting

confidence: 92%

Activating transcription factor 6 protects insulin receptor from ER stress-stimulated desensitization via p42/44 ERK pathway

Tang¹,

Shen²,

Chen³

et al. 2011

Acta Pharmacol Sin

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“…It has also been suggested that ER stress may be involved in hepatocyte injury caused by cholestasis. Two independent factors, JNK and CHOP, are activated in response to ER stress, 9 and JNK transduces hepatocyte cell death caused by reactive oxygen species or bile acids. 30,31 We found that although JNK activation was induced in the liver of BDL mice, the extent of JNK phosphorylation did not differ between control and LIGFREKO mice ( Figure 5A).…”

Section: Igf-1r Induces Cellular Stress Pathways After Bile Duct Ligamentioning

confidence: 99%

“…6 CHOP, also known as growth arrest-and DNA damage-inducible gene 153, is a key factor in ER stress-mediated apoptosis. 7 Recent studies implicate ER stress in neurodegenerative, cardiovascular and liver diseases, 8,9 and CHOPdeficient mice display resistance to apoptosis in animal models of these diseases. 10,11 In particular, CHOP deficiency attenuates cell death induced by alcohol or cholestasis in the liver.…”

mentioning

confidence: 99%

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

Cadoret

Rey

Wendum

et al. 2009

The American Journal of Pathology

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The insulin-like growth factor type 1 receptor (IGF-1R) controls aging and cellular stress, both of which play major roles in liver disease. Stimulation of insulin-like growth factor signaling can generate cell death in vitro. Here, we tested whether IGF-1R contributes to stress insult in the liver. Cholestatic liver injury was induced by bile duct ligation in control and liver-specific IGF-1R knockout (LIGFREKO) mice. LIGFREKO mice displayed less bile duct ligation-induced hepatocyte damage than controls, while no differences in bile acid serum levels or better adaptation to cholestasis by efflux transporters were found. We therefore tested whether stress pathways contributed to this phenomenon; oxidative stress, ascertained by both malondialdehyde content and heme oxygenase-1 expression, was similar in knockout and control animals. However, together with a lower level of eukaryotic initiation factor-2 ␣ phosphorylation, the endoplasmic reticulum stress protein CHOP and its downstream pro-apoptotic target Bax were induced to lesser extents in LIGFREKO mice than in controls. Expression levels of cytokeratin 19, transforming growth factor-␤1, ␣-smooth muscle actin, and collagen ␣1(I) in LIGFREKO mice were all lower than in controls, indicating reduced ductular and fibrogenic responses and increased cholestasis tolerance in these mutants. This stress resistance phenotype was also evidenced by longer post-bile duct ligation survival in mutants than controls. These results indicate that IGF-1R contributes to cholestatic liver injury , and suggests the involvement of both CHOP and

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“…Prolonged hepatic fatty degeneration leads to formation of liver cirrhosis. After adding cholesterol to the feedstuff, it will further increase the requirement for choline due to damage caused by cholesterol to the cell membrane, which will consequently accelerate development of cirrhosis [33] . Thus these complex pathogenic factors induce and intensify hepatic fatty degeneration, and formation of fatty cysts.…”

Section: Discussionmentioning

confidence: 99%

Multiple pathogenic factor-induced complications of cirrhosis in rats: A new model of hepatopulmonary syndrome with intestinal endotoxemia

Zhang¹,

Han

Zhao³

et al. 2007

WJG

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AIM:To develop and characterize a practical model of Hepatopulmonary syndrome (HPS) in rats. METHODS:The experimental animals were randomized into five feeding groups: (1) control (fed standard diet), (2) control plus intraperitoneal injection with lipopolysaccharide (LPS), (3) cirrhosis (fed a diet of maize flour, lard, cholesterol, and alcohol plus subcutaneously injection with carbon tetrachloride (CCl4) oil solution), (4) cirrhosis plus LPS, and (5) cirrhosis plus glycine and LPS. The blood, liver and lung tissues of rats were sampled for analysis and characterization. Technetium 99m-labeled macroaggregated albumin (Tc99m-MAA) was used to test the dilatation of pulmonary microvasculature. RESULTS:Typical cirrhosis and subsequent hepatopulmonary syndrome was observed in the cirrhosis groups after an 8 wk feeding period. In rats with cirrhosis, there were a decreased PaO2 and PaCO2 in arterial blood, markedly decreased arterial O2 content, a significantly increased alveolar to arterial oxygen gradient, an increased number of bacterial translocated within mesenteric lymph node, a significant higher level of LPS and tumor necrosis factor-α (TNF-α) in plasma, and a significant greater ratio of Tc99m-MAA brain-overlung radioactivity. After LPS administration in rats with cirrhosis, various pathological parameters got worse and pulmonary edema formed. The predisposition of glycine antagonized the effects of LPS and significantly alleviated various pathological alterations. CONCLUSION:The results suggest that: (1) a characteristic rat model of HPS can be non-invasively induced by multiple pathogenic factors including high fat diet, alcohol, cholesterol and CCl4; (2) this model can be used for study of hepatopulmonary syndrome and is clinically relevant; and (3) intestinal endotoxemia (IETM) and its accompanying cytokines, such as TNF-α, exert a crucial role in the pathogenesis of HPS in this model.

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ER stress: Can the liver cope?

Cited by 163 publications

References 149 publications

Activating transcription factor 6 protects insulin receptor from ER stress-stimulated desensitization via p42/44 ERK pathway

Activating transcription factor 6 protects insulin receptor from ER stress-stimulated desensitization via p42/44 ERK pathway

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

Multiple pathogenic factor-induced complications of cirrhosis in rats: A new model of hepatopulmonary syndrome with intestinal endotoxemia

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