Mutual interaction between oxidative stress and endoplasmic reticulum stress in the pathogenesis of diseases specifically focusing on non-alcoholic fatty liver disease

Reactive oxygen species(ROS) are produced during normal physiologic processes with the consumption of oxygen. While ROS play signaling roles, when they are produced in excess beyond normal antioxidative capacity this can cause pathogenic damage to cells. The majority of such oxidation occurs in polyunsaturated fatty acids and sulfhydryl group in proteins, resulting in lipid peroxidation and protein misfolding, respectively. The accumulation of misfolded proteins in the endoplasmic reticulum(ER) is enhanced under conditions of oxidative stress and results in ER stress, which, together, leads to the malfunction of cellular homeostasis. Multiple types of defensive machinery are activated in unfolded protein response under ER stress to resolve this unfavorable situation. ER stress triggers the malfunction of protein secretion and is associated with a variety of pathogenic conditions including defective insulin secretion from pancreatic β-cells and accelerated lipid droplet formation in hepatocytes. Herein we use nonalcoholic fatty liver disease(NAFLD) as an illustration of such pathological liver conditions that result from ER stress in association with oxidative stress. Protecting the ER by eliminating excessive ROS viathe administration of antioxidants or by enhancing lipidmetabolizing capacity via the activation of peroxisome proliferator-activated receptors represent promising therapeutics for NAFLD.     

Endoplasmic reticulum stress and fungal pathogenesis

The gateway to the secretory pathway is the endoplasmic reticulum (ER), an organelle that is responsible for the accurate folding, post-translational modification and final assembly of up to a third of the cellular proteome. When secretion levels are high, errors in protein biogenesis can lead to the accumulation of abnormally folded proteins, which threaten ER homeostasis. The unfolded protein response (UPR) is an adaptive signaling pathway that counters a buildup in misfolded and unfolded proteins by increasing the expression of genes that support ER protein folding capacity. Fungi, like other eukaryotic cells that are specialized for secretion, rely upon the UPR to buffer ER stress caused by fluctuations in secretory demand. However, emerging evidence is also implicating the UPR as a central regulator of fungal pathogenesis. In this review, we discuss how diverse fungal pathogens have adapted ER stress response pathways to support the expression of virulence-related traits that are necessary in the host environment.     

Endoplasmic reticulum stress activates telomerase

Telomerase contributes to cell proliferation and survival through both telomere‐dependent and telomere‐independent mechanisms. In this report, we discovered that endoplasmic reticulum (ER) stress transiently activates the catalytic components of telomerase (TERT) expression in human cancer cell lines and murine primary neural cells. Importantly, we show that depletion of hTERT sensitizes cells to undergo apoptosis under ER stress, whereas increased hTERT expression reduces ER stress‐induced cell death independent of catalytically active enzyme or DNA damage signaling. Our findings establish a functional link between ER stress and telomerase, both of which have important implications in the pathologies associated with aging and cancer.     

Oxidative stress in the pathogenesis of nonalcoholic fatty liver disease,in rats fed with a choline-deficient diet

Background/Aim : The pathogenesis of Nonalcoholic Fatty Liver Disease remains largely unknown, but oxidative stress seems to be involved. The aim of this study was to evaluate the role of oxidative stress in experimental hepatic steatosis induced by a choline-deficient diet. Methods : Fatty liver disease was induced in Wistar rats by a choline-deficient diet. The animals were randomized into three groups: I (G1) and II (G2), n=6 each - fed with a choline-deficient diet for four and twelve weeks respectively; Group III (control-G3; n=6) - fed with a standard diet for twelve weeks. Samples of plasma and liver were submitted to biochemical, histological and oxidative stress analysis. Variables measured included serum levels of aminotransferases (AST, ALT), cholesterol and triglycerides. Oxidative stress was measured by lucigenin-enhanced luminescence and the concentration of hydroperoxides (CE-OOH-cholesteryl ester) in the liver tissue. Results: We observed moderate macro- and microvesicular fatty change in periportal zones G1 and G2 as compared to controls (G3). In G2, fatty change was more severe. The inflammatory infiltrate was scanty and no fibrosis was seen in any group. There was a significant increase of AST and triglycerides in G1 and G2 as compared to control group G3. The lucigenin-amplified luminescence (cpm/mg/min × 10³) was significantly increased in G1 (1393±790) and G2 (7191±500) as compared to controls (513±170), p <0.05. The concentrations of CE-OOH were higher in G1 (5.7±0.9 nmol/mg protein) as compared to control (2.6±0.7 nmol/mg protein), p <0.05. Conclusion: 1) Oxidative stress was found to be increased in experimental liver steatosis; 2) The production of reactive oxygen species was accentuated when liver steatosis was more severe; 3) The alterations produced by oxidative stress could be an important step in the pathogenesis of nonalcoholic fatty liver disease.     

Vitamin E alleviates non-alcoholic fatty liver disease in phosphatidylethanolamine N-methyltransferase deficient mice

Phosphatidylethanolamine N-methyltransferase (PEMT) converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC), mainly in the liver. Pemt^?/? mice are protected from high-fat diet (HFD)-induced obesity and insulin resistance, but develop severe non-alcoholic fatty liver disease (NAFLD) when fed a HFD, mostly due to impaired VLDL secretion. Oxidative stress is thought to be an essential factor in the progression from simple steatosis to steatohepatitis. Vitamin E is an antioxidant that has been clinically used to improve NAFLD pathology. Our aim was to determine whether supplementation of the diet with vitamin E could attenuate HFD-induced hepatic steatosis and its progression to NASH in Pemt^?/? mice. Treatment with vitamin E (0.5?g/kg) for 3?weeks improved VLDL-TG secretion and normalized cholesterol metabolism, but failed to reduce hepatic TG content. Moreover, vitamin E treatment was able to reduce hepatic oxidative stress, inflammation and fibrosis. We also observed abnormal ceramide metabolism in Pemt^?/? mice fed a HFD, with elevation of ceramides and other sphingolipids and higher expression of mRNAs for acid ceramidase (Asah1) and ceramide kinase (Cerk). Interestingly, vitamin E supplementation restored Asah1 and Cerk mRNA and sphingolipid levels. Together this study shows that vitamin E treatment efficiently prevented the progression from simple steatosis to steatohepatitis in mice lacking PEMT.     

Probiotics: A possible specific liver drug for non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is and will continue to be a major liver health issue worldwide in the coming decades. There are no leading drug candidates at this point, although there are several promising concepts in drug development. Recent studies have proposed a possible role of intestinal bacterial overgrowth in the development of non-alcoholic steatohepatitis, thus indicated probiotics maybe a potential specific liver drug for NAFLD in the future.     

Endoplasmic reticulum stress in adipose tissue augments lipolysis

The endoplasmic reticulum (ER) is an organelle important for protein synthesis and folding, lipid synthesis and Ca²⁺ homoeostasis. Consequently, ER stress or dysfunction affects numerous cellular processes and has been implicated as a contributing factor in several pathophysiological conditions. Tunicamycin induces ER stress in various cell types in vitro as well as in vivo. In mice, a hallmark of tunicamycin administration is the development of fatty livers within 24–48 hrs accompanied by hepatic ER stress. We hypothesized that tunicamycin would induce ER stress in adipose tissue that would lead to increased lipolysis and subsequently to fatty infiltration of the liver and hepatomegaly. Our results show that intraperitoneal administration of tunicamycin rapidly induced an ER stress response in adipose tissue that correlated with increased circulating free fatty acids (FFAs) and glycerol along with decreased adipose tissue mass and lipid droplet size. Furthermore, we found that in addition to fatty infiltration of the liver as well as hepatomegaly, lipid accumulation was also present in the heart, skeletal muscle and kidney. To corroborate our findings to a clinical setting, we examined adipose tissue from burned patients where increases in lipolysis and the development of fatty livers have been well documented. We found that burned patients displayed significant ER stress within adipose tissue and that ER stress augments lipolysis in cultured human adipocytes. Our results indicate a possible role for ER stress induced lipolysis in adipose tissue as an underlying mechanism contributing to increases in circulating FFAs and fatty infiltration into other organs.     

The effects of zinc supplementation on metabolic profile and oxidative stress in overweight/obese patients with non-alcoholic fatty liver disease: A randomized,double-blind,placebo-controlled trial

BackgroundEvidence indicates the positive effects of zinc on insulin resistance and oxidative stress in metabolic syndrome or diabetes. Non-alcoholic fatty liver disease (NAFLD) is the main hepatic manifestation of insulin resistance and metabolic syndrome. The present study is the first clinical trial that evaluated the effects of zinc supplementation on metabolic and oxidative stress status in overweight/obese patients with NAFLD undergoing calorie- restriction diet. Methods: Fifty six overweight/obese patients with confirmed mild to moderate NAFLD using ultrasonography were randomly allocated to receive 30 mg elemental zinc supplement (n = 29) or placebo (n = 27) along with weight loss diet for 12 weeks. Serum levels of zinc, homeostasis model of assessment-estimated insulin resistance (HOMA-IR), lipid profile, serum superoxide dismutas1 (SOD1) and malondialdhyde (MDA) levels were assessed.ResultsSerum levels of insulin, SOD1, MDA and HOMA-IR were improved in the treatment group (p < 0.05). Within group comparison showed significant reduction in serum FBS, HbA_1C, TC, LDL-c and TG in the treatment group. Conclusion: Zinc supplementation for three months improved insulin resistance and oxidative stress status in overweight/obese NAFLD patients with no beneficial effects on lipid profiles over weight loss diet. Registration ID in IRCT (IRCT NO: 20181005041238N1).     

Endoplasmic reticulum stress--a double edged sword for Z alpha-1 antitrypsin deficiency hepatoxicity

Several diverse disorders, including the liver disorder Z alpha-1 antitrypsin deficiency as well as cystic fibrosis, Alzheimer's, and Parkinson's disease arise from the same general disease mechanism and are now categorized under the term “conformational diseases”, characterized by abnormal folding and subsequent aggregation of an underlying protein. In recent years, several important research advances in the cell biology of aggregation-prone mutant proteins and pathobiological mechanisms of liver disease in general have proven paramount to our understanding of Z alpha-1 antitrypsin deficiency. This liver disease underlines the principle mechanisms of conformational disorders contained within the four pillars of endoplasmic reticulum stress: (1) protein degradation, (2) endoplasmic overload response, (3) unfolded protein response and (4) cellular death pathway. This four-stage model of Z alpha-1 antitrypsin hepatoxicity is elegant in its simplicity and helps explain the clinical manifestations of this condition. Endoplasmic reticulum stress responses have evolved to be protective, however when they are ineffective, toxic damage occurs demonstrating how these responses can be described as a double edged sword. In this context, one of the most perplexing problems in modern biology is to understand how the cell “chooses” between adaptation and demise in response to stress. When one pathway becomes predominant, a delicate balance is perturbed and either an adaptive or a lethal response ensues. Understanding how the endoplasmic reticulum stress signals potentially play a role in directing a clinical outcome may lead to better prospects of more rational approaches to investigation and therapy for this liver disease.     

酪酸梭菌活菌胶囊辅助治疗对非酒精性脂肪肝病患者氧化应激损伤的保护作用

目的 探讨酪酸梭菌活菌胶囊辅助治疗对非酒精性脂肪肝病(nonalcoholic fatty liver disease,NAFLD)患者氧化应激损伤的保护作用。 方法 选取2017年1月至2019年3月我院内科门诊就诊的NAFLD患者76例,随机分为观察组和对照组,各38例。两组患者均给予饮食调整、纠正不良生活习惯和适当运动锻炼。对照组患者给予多烯磷脂酰胆碱胶囊456 mg/次,3次/d,口服。观察组患者在对照组基础上加用酪酸梭菌活菌胶囊0.6 g/次,2次/d,温水口服。两组患者连用8周。检测两组患者治疗前后肝功能指标[丙氨酸转氨酶(ALT)、碱性磷酸酶(ALP)、γ 谷氨酰转肽酶(γ GT)]及氧化应激指标[氧化低密度脂蛋白(ox LDL)、过氧化脂质(LPO)、丙二醛(MDA)]水平的变化。 结果 治疗8周后,两组患者血清ALT、ALP和γ GT水平较治疗前明显下降,且观察组下降幅度大于比对照组(均P结论 酪酸梭菌活菌胶囊辅助治疗NAFLD患者能降低血清ox LDL、LPO和MDA水平,抑制氧化应激反应亢进,保护肝功能。     

肠道菌群与非酒精性脂肪肝病相关性研究进展

近年来关于肠道菌群与非酒精性脂肪肝疾病关系的研究越来越多。非酒精性脂肪肝是一种无过量饮酒史,肝内脂肪过量堆积的慢性疾病。生理解剖结构上的“肠-肝轴”表明肠道和肝脏有着密不可分的关系。肠道菌群一般情况下处于动态平衡,可以维持肠道正常生理功能。肠道菌群可通过改善肠道通透性、干预脂质代谢、产生内源性乙醇和产生短链脂肪酸等来影响非酒精性脂肪肝疾病的发生与发展。临床上对于治疗非酒精性脂肪肝没有确切的药物,增加有益肠道菌群的因素,如益生元、益生菌等能够调节肠道的微环境,这为非酒精性脂肪肝疾病的治疗开辟了新的方向。     

Endoplasmic reticulum stress and kidney dysfunction

Chronic kidney disease (CKD) affects millions of persons worldwide and constitutes a major public health problem. Therefore, understanding the molecular basis of CKD is a key challenge for the development of preventive and therapeutic strategies. A major contributor to chronic histological damage associated with CKD is acute kidney injury (AKI). At the cellular level, kidney injuries are associated with microenvironmental alterations, forcing cells to activate adaptive biological processes that eliminate the stressor and generate alarm signals. These signalling pathways actively participate in tissue remodelling by promoting inflammation and fibrogenesis, ultimately leading to CKD. Many stresses that are encountered upon kidney injury are prone to trigger endoplasmic reticulum (ER) stress. In the kidney, ER stress both participates in acute and chronic histological damages, but also promotes cellular adaptation and nephroprotection. In this review, we will discuss the implication of ER stress in the pathophysiology of AKI and CKD progression, and we will give a critical analysis of the current experimental and clinical evidence that support ER stress as a mediator of kidney damage.     

Endoplasmic reticulum stress response is involved in the pathogenesis of stress induced gastric lesions in rats

Stress gastric ulcer is a serious complication, but the mechanism involved is not fully clarified. It is well known that mucosal cell apoptosis plays a crucial role in the pathogenesis of gastric ulceration. Recent studies have shown that endoplasmic reticulum (ER) stress is an important pathway leading to cellular apoptosis. To investigate the role of ER stress in the pathogenesis of stress gastric ulcer, we studied the alteration in the expression of ER stress markers GRP78 (glucose-regulated protein 78) and caspase-12 (an ER stress-specific proapoptotic molecule) and their relations with gastric mucosal apoptosis during development of stress gastric lesions in the water-immersion and restraint stress (WRS) model in rats. Rats developed severe gastric lesions after 6 h of WRS. Typical apoptosis was observed at the edge cells of WRS induced gastric lesions. Western blot analysis showed that GRP78 and activated caspase-12 were over-expressed in the gastric tissues of WRS rats. Immunohistochemical analysis demonstrated that increased GRP78 and caspase-12 were distributed only under the lesions. In addition, dithiothreitol and tunicamycin (ER stress inducers), which increased the expression of GRP78 and activated caspase-12, caused gastric mucosal injury and mucosal cell apoptosis in vitro. These findings suggest that ER stress might be involved in the development of stress gastric ulcer through an apoptotic mechanism.