The contribution of endoplasmic reticulum stress to liver diseases

Dara, Lily; Cheng, Ji; Kaplowitz, Neil

doi:10.1002/hep.24279

Cited by 334 publications

(305 citation statements)

References 110 publications

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“…Prolonged ER stress is linked to lipogenesis, oxidative stress, inflammation, and activation of apoptotic pathways, 31 and has been implicated in the pathogenesis of ALD and NAFLD. 14,32 However, it remains unclear whether iron has any role in promoting ER stress-associated liver injury in these disorders. In the absence of ethanol and/or HFD, iron excess in itself had no real effect on the UPR and ER stress proteins.…”

Section: Discussionmentioning

confidence: 99%

“…10 Impaired UPR can lead to ER stress and prolonged ER stress may result in inflammation and apoptosis as implicated in ALD and NAFLD. 11,[12][13][14] The downstream effects of ER stress include activation of autophagy, c-Jun N-terminal kinase (JNK) pathways, modulation of Toll-like receptor (TLR) signaling, and macrophage activation in alcohol-and obesity-induced synergistic liver injury. [15][16][17] Autophagy, on the other hand, is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components through the lysosomal machinery.…”

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confidence: 99%

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Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

Tan

Crawford

Jaskowski

et al. 2013

Laboratory Investigation

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Endoplasmic reticulum (ER) stress is an important pathogenic mechanism for alcoholic (ALD) and nonalcoholic fatty liver disease (NAFLD). Iron overload is an important cofactor for liver injury in ALD and NAFLD, but its role in ER stress and associated stress signaling pathways is unclear. To investigate this, we developed a murine model of combined liver injury by co-feeding the mildly iron overloaded, the hemochromatosis gene-null (Hfe À / ) mouse ad libitum with ethanol and a high-fat diet (HFD) for 8 weeks. This co-feeding led to profound steatohepatitis, significant fibrosis, and increased apoptosis in the Hfe À / À mice as compared with wild-type (WT) controls. Iron overload also led to induction of unfolded protein response (XBP1 splicing, activation of IRE-1a and PERK, as well as sequestration of GRP78) and ER stress (increased CHOP protein expression) following HFD and ethanol. This is associated with a muted autophagic response including reduced LC3-I expression and impaired conjugation to LC3-II, reduced beclin-1 protein, and failure of induction of autophagy-related proteins (Atg) 3, 5, 7, and 12. As a result of the impaired autophagy, levels of the sequestosome protein p62 were most elevated in the Hfe À / À group co-fed ethanol and HFD. Iron overload reduces the activation of adenosine monophosphate protein kinase associated with ethanol and HFD feeding. We conclude that iron toxicity may modulate hepatic stress signaling pathways by impairing adaptive cellular compensatory mechanisms in alcohol-and obesity-induced liver injury.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

Tan

Crawford

Jaskowski

et al. 2013

Laboratory Investigation

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“…2011; Dara et al. 2011; Malhi and Kaufman 2011). One of the main consequences of UPR activation is the inhibition of translation, in order to curb the synthesis of new proteins.…”

Section: Introductionmentioning

confidence: 99%

“…For instance, these genes encode ER‐associated degradation (ERAD) proteins, ER chaperones (BiP/GRP78 and GRP94), and enzymes able to expand protein folding capacity including PDI and foldases (Kaufman 1999; Dara et al. 2011). This physiological response is also called the adaptive UPR.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

189

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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“…Malfunctioning of the ER stress pathway can lead to prevailing apoptosis-promoting actions instead of survival, i.e. an imbalance that can also result in liver injuries [53].…”

Section: Unfolded Protein Response Pathwaymentioning

confidence: 99%

Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

Kuijper

Yang

Water

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Drug-induced liver injury (DILI) is a significant threat to human health and a major problem in drug development. It is hard to predict due to its idiosyncratic nature and which does not show up in animal trials. Hepatic adaptive stress response pathway activation is generally observed in drug-induced liver injury. Dynamical pathway modeling has the potential to foresee adverse effects of drugs before they go in trial. Ordinary differential equation modeling can offer mechanistic insight, and allows us to study the dynamical behavior of stress pathways involved in DILI. Areas covered: This review provides an overview on the progress of the dynamical modeling of stress and death pathways pertinent to DILI, i.e. pathways relevant for oxidative stress, inflammatory stress, DNA damage, unfolded proteins, heat shock and apoptosis. We also discuss the required steps for applying such modeling to the liver. Expert opinion: Despite the strong progress made since the turn of the century, models of stress pathways have only rarely been specifically applied to describe pathway dynamics for DILI. We argue that with minor changes, in some cases only to parameter values, many of these models can be repurposed for application in DILI research. Combining both dynamical models with in vitro testing might offer novel screening methods for the harmful side-effects of drugs. ARTICLE HISTORY

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The contribution of endoplasmic reticulum stress to liver diseases

Cited by 334 publications

References 110 publications

Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

Role of endoplasmic reticulum stress in drug‐induced toxicity

Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

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