The contribution of endoplasmic reticulum stress to liver diseases
TL;DR: A vicious cycle in which ER stress promotes inflammation, cell injury, and steatosis and in which steatogenesis, inflammation, and cell injury aggravate ER stress seems to be at play.
About: This article is published in Hepatology.The article was published on 2011-05-01 and is currently open access. It has received 303 citations till now. The article focuses on the topics: Unfolded protein response & Endoplasmic reticulum.
Citations
More filters
TL;DR: Evidence that liver inflammation has prognostic significance in NAFLD is presented and the origins and components of liver inflammation in NASH are considered, along with mechanistic considerations, which project their implications for the effective treatment of NASH.
Abstract: While non-alcoholic fatty liver disease (NAFLD) is highly prevalent (15% to 45%) in modern societies, only 10% to 25% of cases develop hepatic fibrosis leading to cirrhosis, end-stage liver disease or hepatocellular carcinoma. Apart from pre-existing fibrosis, the strongest predictor of fibrotic progression in NAFLD is steatohepatitis or non-alcoholic steatohepatitis (NASH). The critical features other than steatosis are hepatocellular degeneration (ballooning, Mallory hyaline) and mixed infl ammatory cell infi ltration. While much is understood about the relationship of steatosis to metabolic factors (over-nutrition, insulin resistance, hyperglycemia, metabolic syndrome, hypoadiponectinemia), less is known about infl ammatory recruitment, despite its importance for the perpetuation of liver injury and fi brogenesis. In this review, we present evidence that liver infl ammation has prognostic signifi cance in NAFLD. We then consider the origins and components of liver infl ammation in NASH. Hepatocytes injured by toxic lipid molecules (lipotoxicity) play a central role in the recruitment of innate immunity involving Toll-like receptors (TLRs), Kupffer cells (KCs), lymphocytes and neutrophils and possibly infl ammasome. The key pro-infl ammatory signaling pathways in NASH are nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK). The downstream effectors include adhesion molecules, chemokines, cytokines and the activation of cell death pathways leading to apoptosis. The upstream activators of NF-κB and JNK are more contentious and may depend on the experimental model used. TLRs are strong contenders. It remains possible that infl ammation in NASH originates outside the liver and in the gut microbiota that prime KC/TLR responses, infl amed adipose tissue and circulating infl ammatory cells. We briefl y review these mechanistic considerations and project their implications for the effective treatment of NASH. (Gut Liver 2012;6:149-171)
352 citations
TL;DR: The effects of melatonin on the main ER stress mechanisms are reviewed, focusing on its ability to regulate the autophagic and apoptotic processes.
Abstract: Endoplasmic reticulum (ER) is a dynamic organelle that participates in a number of cellular functions by controlling lipid metabolism, calcium stores, and proteostasis Under stressful situations, the ER environment is compromised, and protein maturation is impaired; this causes misfolded proteins to accumulate and a characteristic stress response named unfolded protein response (UPR) UPR protects cells from stress and contributes to cellular homeostasis re-establishment; however, during prolonged ER stress, UPR activation promotes cell death ER stressors can modulate autophagy which in turn, depending of the situation, induces cell survival or death Interactions of different autophagy- and apoptosis-related proteins and also common signaling pathways have been found, suggesting an interplay between these cellular processes, although their dynamic features are still unknown A number of pathologies including metabolic, neurodegenerative and cardiovascular diseases, cancer, inflammation, and viral infections are associated with ER stress, leading to a growing interest in targeting components of the UPR as a therapeutic strategy Melatonin has a variety of antioxidant, anti-inflammatory, and antitumor effects As such, it modulates apoptosis and autophagy in cancer cells, neurodegeneration and the development of liver diseases as well as other pathologies Here, we review the effects of melatonin on the main ER stress mechanisms, focusing on its ability to regulate the autophagic and apoptotic processes As the number of studies that have analyzed ER stress modulation by this indole remains limited, further research is necessary for a better understanding of the crosstalk between ER stress, autophagy, and apoptosis and to clearly delineate the mechanisms by which melatonin modulates these responses
322 citations
Cites background from "The contribution of endoplasmic ret..."
...Increasing evidence suggests that hepatic ER stress plays an important role in liver disorders such as nonalcoholic and alcoholic liver disease, ischemia/reperfusion injury; drug induced liver injury and viral hepatitis [147]....
[...]
23 Dec 2012
TL;DR: The cell reacts to ER stress by initiating a defensive process, called the unfolded protein response (UPR), which is comprised of cellular mechanisms aimed at adaptation and safeguarding cellular survival or, in cases of excessively severe stress, at initiation of apoptosis and elimination of the faulty cell.
Abstract: The endoplasmic reticulum (ER) is a multifunctional organelle required for lipid biosynthesis, calcium storage, and protein folding and processing. A number of physiological and pathological conditions, as well as a variety of pharmacological agents, are able to disturb proper ER function and thereby cause ER stress, which severely impairs protein folding and therefore poses the risk of proteotoxicity. Specific triggers for ER stress include, for example, particular intracellular alterations (e.g., calcium or redox imbalances), certain microenvironmental conditions (e.g., hypoglycemia, hypoxia, and acidosis), high-fat and high-sugar diet, a variety of natural compounds (e.g., thapsigargin, tunicamycin, and geldanamycin), and several prescription drugs (e.g., bortezomib/Velcade, celecoxib/Celebrex, and nelfinavir/Viracept). The cell reacts to ER stress by initiating a defensive process, called the unfolded protein response (UPR), which is comprised of cellular mechanisms aimed at adaptation and safeguarding cellular survival or, in cases of excessively severe stress, at initiation of apoptosis and elimination of the faulty cell. In recent years, this dichotomic stress response system has been linked to several human diseases, and efforts are underway to develop approaches to exploit ER stress mechanisms for therapy. For example, obesity and type 2 diabetes have been linked to ER stress-induced failure of insulin-producing pancreatic beta cells, and current research efforts are aimed at developing drugs that ameliorate cellular stress and thereby protect beta cell function. Other studies seek to pharmacologically aggravate chronic ER stress in cancer cells in order to enhance apoptosis and achieve tumor cell death. In the following, these principles will be presented and discussed.
317 citations
TL;DR: In this article, the authors summarized intracellular and extracellular events involved in APAP hepatotoxicity, along with emphatic discussions on the possible therapeutic approaches targeting these different cellular events.
Abstract: Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in many developed countries. Mitochondrial oxidative stress is considered to be the predominant cellular event in APAP-induced liver injury. Accordingly, N-acetyl cysteine, a known scavenger of reactive oxygen species (ROS), is recommended as an effective clinical antidote against APAP-induced acute liver injury (AILI) when it is given at an early phase; however, the narrow therapeutic window limits its use. Hence, the development of novel therapeutic approaches that can offer broadly protective effects against AILI is clearly needed. To this end, it is necessary to better understand the mechanisms of APAP hepatotoxicity. Up to now, in addition to mitochondrial oxidative stress, many other cellular processes, including phase I/phase II metabolism, endoplasmic reticulum stress, autophagy, sterile inflammation, microcirculatory dysfunction, and liver regeneration, have been identified to be involved in the pathogenesis of AILI, providing new targets for developing more effective therapeutic interventions against APAP-induced liver injury. In this review, we summarize intracellular and extracellular events involved in APAP hepatotoxicity, along with emphatic discussions on the possible therapeutic approaches targeting these different cellular events.
312 citations
Cites background from "The contribution of endoplasmic ret..."
...ER stress can be observed in various hepatic injury models, including alcoholic liver disease, nonalcoholic fatty liver disease, ischemia-reperfusion injury and cholestatic liver disease [26]....
[...]
Nanjing University of Chinese Medicine1, Shanghai Jiao Tong University2, Southern Medical University3, Central South University4, Second Military Medical University5, China Medical University (PRC)6, Capital Medical University7, Xi'an Jiaotong University8, Chongqing Medical University9, Fudan University10, Hebei Medical University11, Peking University12, Tongji University13, Huazhong University of Science and Technology14, Beijing University of Chinese Medicine15
TL;DR: The CSH guidelines summarized the epidemiology, pathogenesis, pathology, and clinical manifestation and gives 16 evidence-based recommendations on diagnosis, differential diagnosis, treatment, and prevention of DILI.
Abstract: Drug-induced liver injury (DILI) is an important clinical problem, which has received more attention in recent decades. It can be induced by small chemical molecules, biological agents, traditional Chinese medicines (TCM), natural medicines (NM), health products (HP), and dietary supplements (DS). Idiosyncratic DILI is far more common than intrinsic DILI clinically and can be classified into hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the types of injured target cells. The CSH guidelines summarized the epidemiology, pathogenesis, pathology, and clinical manifestation and gives 16 evidence-based recommendations on diagnosis, differential diagnosis, treatment, and prevention of DILI.
185 citations
References
More filters
TL;DR: Together, at least three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids and lipids.
Abstract: The endoplasmic reticulum (ER) responds to the accumulation of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways - cumulatively called the unfolded protein response (UPR). Together, at least three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids and lipids. The arms of the UPR are integrated to provide a response that remodels the secretory apparatus and aligns cellular physiology to the demands imposed by ER stress.
5,701 citations
"The contribution of endoplasmic ret..." refers background in this paper
...These homeostatic responses aim to bring the organelle and the cell into a state of equilibrium by producing more chaperones to increase the folding capacity of the ER, by enhancing ER-associated protein degradation (ERAD) and autophagy, and by decreasing protein entry through affecting the translation and synthesis of new polypeptides.(3) The UPR has three main branches, each of which consists of a transmembrane sensor embedded in the ER, which is kept inactive as long as it is bound to the intraluminal chaperone, glucose-regulated protein 78 (GRP78)/ BIP....
[...]
TL;DR: The complex, interdigitated roles of these three SREBPs have been dissected through the study of ten different lines of gene-manipulated mice and form the subject of this review.
Abstract: Lipid homeostasis in vertebrate cells is regulated by a family of membrane-bound transcription factors designated sterol regulatory element–binding proteins (SREBPs). SREBPs directly activate the expression of more than 30 genes dedicated to the synthesis and uptake of cholesterol, fatty acids, triglycerides, and phospholipids, as well as the NADPH cofactor required to synthesize these molecules (1–4). In the liver, three SREBPs regulate the production of lipids for export into the plasma as lipoproteins and into the bile as micelles. The complex, interdigitated roles of these three SREBPs have been dissected through the study of ten different lines of gene-manipulated mice. These studies form the subject of this review.
4,406 citations
"The contribution of endoplasmic ret..." refers background in this paper
...Once released from Insig, SREBPs are escorted to the Golgi by SCAP where they undergo RIP and promote lipogenesis.(35) In the presence of cholesterol and oxysterols, SCAP undergoes conformational changes causing it to bind Insig, which prevents translocation of the complex to the Golgi....
[...]
TL;DR: It is shown that obesity causes endoplasmic reticulum (ER) stress, which leads to suppression of insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptors substrate–1 (IRS-1).
Abstract: Obesity contributes to the development of type 2 diabetes, but the underlying mechanisms are poorly understood. Using cell culture and mouse models, we show that obesity causes endoplasmic reticulum (ER) stress. This stress in turn leads to suppression of insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptor substrate-1 (IRS-1). Mice deficient in X-box-binding protein-1 (XBP-1), a transcription factor that modulates the ER stress response, develop insulin resistance. These findings demonstrate that ER stress is a central feature of peripheral insulin resistance and type 2 diabetes at the molecular, cellular, and organismal levels. Pharmacologic manipulation of this pathway may offer novel opportunities for treating these common diseases.
3,484 citations
"The contribution of endoplasmic ret..." refers background in this paper
...These mice exhibited insulin resistance and type 2 diabetes.(49) An increase in the ER stress response 1756 DARA, JI, AND KAPLOWITZ HEPATOLOGY, May 2011...
[...]
...Obesity and a high-fat diet have been shown to induce ER stress response with subsequent activation of JNK in mice.(49,53) In rats fed a high-sucrose diet, saturated fatty acids lead to elevation in ER stress markers GRP78, CHOP, and caspase-3....
[...]
...An increase in PERK phosphorylation was demonstrated, as was an increase in JNK activity.(49) ER stress has been shown to cause insulin resistance....
[...]
...markers eIF2a, PERK, and GRP78 has been demonstrated in ob/ob mice as well.(49) Obesity and a high-fat diet have been shown to induce ER stress response with subsequent activation of JNK in mice....
[...]
...ER stress promotes JNK-dependent serine phosphorylation of IRS-1, which in turn inhibits insulin receptor signaling and leads to insulin resistance.(49) Inhibition of the eIF2a arm of the UPR by dephosphorylation of eIF2a via GADD34 leads to improved steatosis and glucose tolerance in mice....
[...]
TL;DR: In this article, the authors quantified the biological sources of hepatic and plasma lipoprotein TAG in NAFLD patients, using stable isotopes for four days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipid TAG.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess liver triacylglycerol (TAG), inflammation, and liver damage The goal of the present study was to directly quantify the biological sources of hepatic and plasma lipoprotein TAG in NAFLD Patients (5 male and 4 female; 44 ± 10 years of age) scheduled for a medically indicated liver biopsy were infused with and orally fed stable isotopes for 4 days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipoprotein TAG Hepatic and lipoprotein TAG fatty acids were analyzed by gas chromatography/mass spectrometry NAFLD patients were obese, with fasting hypertriglyceridemia and hyperinsulinemia Of the TAG accounted for in liver, 590% ± 99% of TAG arose from NEFAs; 261% ± 67%, from DNL; and 149% ± 70%, from the diet The pattern of labeling in VLDL was similar to that in liver, and throughout the 4 days of labeling, the liver demonstrated reciprocal use of adipose and dietary fatty acids DNL was elevated in the fasting state and demonstrated no diurnal variation These quantitative metabolic data document that both elevated peripheral fatty acids and DNL contribute to the accumulation of hepatic and lipoprotein fat in NAFLD
2,870 citations
"The contribution of endoplasmic ret..." refers background in this paper
...SREBP-1c knockout mice are protected against a high-fat diet–induced and alcohol-induced steatosis,(36) favoring the view that de novo lipogenesis is a key mechanism for fat accumulation in the liver.(37,38) It appears that ER stress can override cholesterol inhibition of SREBP processing....
[...]
TL;DR: Malfolded proteins in the endoplasmic reticulum induce cellular stress and activate c-Jun amino-terminal kinases (JNKs or SAPKs), and Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and I RE1alpha-/- fibroblasts were impaired in JNK activation by ER stress.
Abstract: Malfolded proteins in the endoplasmic reticulum (ER) induce cellular stress and activate c-Jun amino-terminal kinases (JNKs or SAPKs). Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and IRE1alpha-/- fibroblasts were impaired in JNK activation by ER stress. The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation. Dominant-negative TRAF2 inhibited activation of JNK by IRE1. Activation of JNK by endogenous signals initiated in the ER proceeds by a pathway similar to that initiated by cell surface receptors in response to extracellular signals.
2,774 citations
"The contribution of endoplasmic ret..." refers background in this paper
...TRAF2 can recruit IjB kinase (IKK) and promote NF-jB– mediated inflammation.(16,17) Proapoptotic Bcl2 proteins, which regulate apoptotic cell death via altering calcium homeostasis, have been linked to the ER stress response and in particular to the IRE1a branch....
[...]