Targeting endoplasmic reticulum stress in liver disease

Wu, Fa-Ling; Liu, Wen-Yue; Poucke, Sven Van; Braddock, Martin; Jin, Weimin; Xiao, Jian; Li, Xiaokun; Zheng, Ming‐Hua

doi:10.1080/17474124.2016.1179575

Cited by 36 publications

(24 citation statements)

References 146 publications

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“…Previous studies have shown that GP73 is up‐ or down‐regulated in hepatocytes in response to liver diseases, viral infection, and cytokine treatments . ER stress UPR has been implicated in the pathogenesis of several different types of liver diseases, including nonalcoholic fatty liver disease (NAFLD), chronic viral hepatitis, and alcohol‐induced liver injury . Existing evidence indicates that ER stress can also be induced upon viral infection or cytokine treatment .…”

Section: Resultsmentioning

confidence: 99%

“…(14,24) ER stress UPR has been implicated in the pathogenesis of several different types of liver diseases, including nonalcoholic fatty liver disease (NAFLD), chronic viral hepatitis, and alcoholinduced liver injury. (25) Existing evidence indicates that ER stress can also be induced upon viral infection or cytokine treatment. (26,27) In addition, both UPR activation and GP73 up-regulation lead to transcriptional activation of sterol regulatory element-binding proteins.…”

Section: Gp73 Secretion Is Promoted By Er Stressmentioning

confidence: 99%

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Tumor Microenvironment Regulation by the Endoplasmic Reticulum Stress Transmission Mediator Golgi Protein 73 in Mice

Wei¹,

Yang

Liu

et al. 2019

Hepatology

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The unfolded protein response (UPR) signal in tumor cells activates UPR signaling in neighboring macrophages, which leads to tumor‐promoting inflammation by up‐regulating UPR target genes and proinflammatory cytokines. However, the molecular basis of this endoplasmic reticulum (ER) stress transmission remains largely unclear. Here, we identified the secreted form of Golgi protein 73 (GP73), a Golgi‐associated protein functional critical for hepatocellular carcinoma (HCC) growth and metastasis, is indispensable for ER stress transmission. Notably, ER stressors increased the cellular secretion of GP73. Through GRP78, the secreted GP73 stimulated ER stress activation in neighboring macrophages, which then released cytokines and chemokines involved in the tumor‐associated macrophage (TAM) phenotype. Analysis of HCC patients revealed a positive correlation of GP73 with glucose‐regulated protein 78 (GRP78) expression and TAM density. High GP73 and CD206 expression was associated with poor prognosis. Blockade of GP73 decreased the density of TAMs, inhibited tumor growth, and prolonged survival in two mouse HCC models. Conclusion: Our findings provide insight into the molecular mechanisms of extracellular GP73 in the amplification and transmission of ER stress signals.

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Section: Resultsmentioning

confidence: 99%

Section: Gp73 Secretion Is Promoted By Er Stressmentioning

confidence: 99%

Tumor Microenvironment Regulation by the Endoplasmic Reticulum Stress Transmission Mediator Golgi Protein 73 in Mice

Wei¹,

Yang

Liu

et al. 2019

Hepatology

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“…The Function of liver and kidney is one of important indicator of toxicity 24 . As a sign of liver damage, oxidative stress causes multiple lesions in the plasma membrane 25,26 . One of the important targets of oxygen is glyceraldehyde-3-phosphate (GAPDH), which is also an important index of liver damage 27,28 .…”

Section: Discussionmentioning

confidence: 99%

Hepatotoxicity and nephrotoxicity of 3-bromopyruvate in mice

Pan¹,

Sun²,

Jin³

et al. 2016

Acta Cir. Bras.

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PURPOSE:To investigate the hepatotoxicity and nephrotoxicity of 3-Bromopyruvate (3BP) in mice. hours later, the blood were used for the determination of hepatic damage serum biomarkers. Livers were stored in 4 % formalin solution for the later detection. METHODS: RESULTS:3BP at the dose of 8mg/kg had a good effect on inhibiting tumor growth in nude mice and did not damage liver and kidney tissues. Kunming mice experiment showed 3BP at the dose of 16mg/kg did damage to liver tissues. CONCLUSION:3-Bromopyruvate at the dose of suppressing tumor growth did not exhibit hepatotoxicity and nephrotoxicity in nude mice, and the effect on liver was confirmed in Kunming mice.

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“…Despite the potential benefits of this strategy for reducing circulating LDL levels, ER storage diseases (ERSDs) are a common end point of ER protein retention and contribute to a wide range of human disorders (15,16). The accumulation of retained/misfolded proteins in the ER leads to ER stress and triggers the UPR (17)(18)(19). A well-described form of ERSD occurs as a result of ER arginine vasopressin (VP) retention arising from mutations such as VP G14R and VP G17V .…”

Section: The Proprotein Convertase Subtilisin/kexin Type-9 (Pcsk9) Plmentioning

confidence: 99%

Loss-of-function PCSK9 mutants evade the unfolded protein response sensor GRP78 and fail to induce endoplasmic reticulum stress when retained

Lebeau

Platko

Al‐Hashimi

et al. 2018

Journal of Biological Chemistry

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The proprotein convertase subtilisin/kexin type-9 (PCSK9) plays a central role in cardiovascular disease (CVD) by degrading hepatic low-density lipoprotein receptor (LDLR). As such, loss-of-function (LOF) PCSK9 variants that fail to exit the endoplasmic reticulum (ER) increase hepatic LDLR levels and lower the risk of developing CVD. The retention of misfolded protein in the ER can cause ER stress and activate the unfolded protein response (UPR). In this study, we investigated whether a variety of LOF PCSK9 variants that are retained in the ER can cause ER stress and hepatic cytotoxicity. Although overexpression of these PCSK9 variants caused an accumulation in the ER of hepatocytes, UPR activation or apoptosis was not observed. Furthermore, ER retention of endogenous PCSK9 via splice switching also failed to induce the UPR. Consistent with these studies, overexpression of PCSK9 in the livers of mice had no impact on UPR activation. To elucidate the cellular mechanism to explain these surprising findings, we observed that the 94-kDa glucose-regulated protein (GRP94) sequesters PCSK9 away from the 78-kDa glucose-regulated protein (GRP78), the major activator of the UPR. As a result, GRP94 knockdown increased the stability of GRP78-PCSK9 complex and resulted in UPR activation following overexpression of ER-retained PCSK9 variants relative to WT secreted controls. Given that overexpression of these LOF PCSK9 variants does not cause UPR activation under normal homeostatic conditions, therapeutic strategies aimed at blocking the autocatalytic cleavage of PCSK9 in the ER represent a viable strategy for reducing circulating PCSK9.

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Targeting endoplasmic reticulum stress in liver disease

Cited by 36 publications

References 146 publications

Tumor Microenvironment Regulation by the Endoplasmic Reticulum Stress Transmission Mediator Golgi Protein 73 in Mice

Tumor Microenvironment Regulation by the Endoplasmic Reticulum Stress Transmission Mediator Golgi Protein 73 in Mice

Hepatotoxicity and nephrotoxicity of 3-bromopyruvate in mice

Loss-of-function PCSK9 mutants evade the unfolded protein response sensor GRP78 and fail to induce endoplasmic reticulum stress when retained

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