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Schematic representation of the mechanism of pathogenesis of NASH from obesity-induced simple steatosis. Obesity results in insulin resistance and increased hepatic uptake of free fatty acids (FFA), which induces simple steatosis. Steatosis upregulates CYP2E1 and also generates oxidative stress. When an obese individual consumes excessive alcohol on an occasion (binge drinking), the increased CYP2E1 metabolizes ethanol into acetaldehyde through the microsomal ethanol oxidizing system, which in turn aggravates oxidative stress and produces ROS. The excess ROS along with toxic acetaldehyde causes hepatic injury and induces pathogenesis of NASH. Therefore, obesity plays as the "first hit" and a binge serves as the "second hit" toward pathogenesis of NASH in obese individuals.
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The pathogenesis of nonalcoholic steatohepatitis (NASH) is a two-stage process in which steatosis is the "first hit" and an unknown "second hit". We hypothesized that "a binge" could be a "second hit" to develop NASH from obesity induced simple steatosis. Thirty weeks old male OLETF rats were administered 10 ml of 10% ethanol orally for 5, 3, and 2...
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Citations
... Increased oxidative stress and marked decreases in the levels of antioxidants are common features during the pathogenesis of MASH and the accompanied hepatic fibrosis. 27 The generation of free radicals, including a variety of ROS, leading to cellular oxidative stress and subsequent lipid peroxidation are characteristic features of MASH. 27 An increased level of serum MDA is an indication of elevated oxidative stress and membrane lipid peroxidation. ...
... 27 The generation of free radicals, including a variety of ROS, leading to cellular oxidative stress and subsequent lipid peroxidation are characteristic features of MASH. 27 An increased level of serum MDA is an indication of elevated oxidative stress and membrane lipid peroxidation. ...
Metabolic dysfunction‐associated steatotic liver disease (MASLD) is characterized by intense deposition of fat globules in the hepatic parenchyma that could potentially progress to liver cirrhosis and hepatocellular carcinoma. Here, we evaluated a rat model to study the molecular pathogenesis of the spectrum of MASLD and to screen therapeutic agents. SHRSP5/Dmcr rats were fed a high‐fat and cholesterol (HFC) diet for a period of 12 weeks and evaluated for the development of steatosis (MASLD), steatohepatitis, fibrosis and cirrhosis. A group of animals were sacrificed at the end of the 4th, 6th, 8th and 12th weeks from the beginning of the experiment, along with the control rats that received normal diet. Blood and liver samples were collected for biochemical and histopathological evaluations. Immunohistochemical staining was performed for α‐SMA and Collagen Type I. Histopathological examinations demonstrated steatosis at the 4th week, steatohepatitis with progressive fibrosis at the 6th week, advanced fibrosis with bridging at the 8th week and cirrhosis at the 12th week. Biochemical markers and staining for α‐SMA and Collagen Type I demonstrated the progression of steatosis to steatohepatitis, hepatic fibrosis and liver cirrhosis in a stepwise manner. Control animals fed a normal diet did not show any biochemical or histopathological alterations. The results of the present study clearly demonstrated that the HFC diet‐induced model of steatosis, steatohepatitis, hepatic fibrosis and cirrhosis is a feasible, quick and appropriate animal model to study the molecular pathogenesis of the spectrum of MASLD and to screen potent therapeutic agents.
... CYP2E1 is also induced by alcohol consumption [89], which is another risk factor for breast cancer [3,4]. In fatty liver disease, oxidative damage to the liver is thought to arise in part from CYP2E1-mediated oxidative stress [90], which is elevated with obesity and excess alcohol consumption [55,[91][92][93][94]. Further, alcohol consumption under conditions of obesity worsens the severity of fatty liver disease through CYP2E1 activation in rodent models [95][96][97] and in humans [98]. These studies imply that the breast cancer risk factors of obesity and alcohol intake could interact through CYP2E1-associated oxidative stress to promote tumorigenesis. ...
Obesity and environmental toxins are risk factors for breast cancer, however there is limited knowledge on how these risk factors interact to promote breast cancer. Acrylamide, a probable carcinogen and obesogen, is a biproduct in foods prevalent in the obesity-inducing Western diet. Acrylamide is metabolized by cytochrome P450 2E1 (CYP2E1) to the genotoxic epoxide, glycidamide, and is associated with increased risk for breast cancer. To investigate how acrylamide and obesity interact to increase breast cancer risk, female mice were fed a low-fat (LFD) or high-fat diet (HFD) and 0.7mM acrylamide-supplemented water or control water. While HFD significantly enhanced weight gain in mice, the addition of acrylamide did not significantly alter body weights compared to respective controls. Mammary epithelial cells from obese, acrylamide-treated mice had increased DNA strand breaks and oxidative DNA damage compared to all other groups. In vitro, glycidamide-treated COMMA-D cells showed significantly increased DNA strand breaks while acrylamide-treated cells demonstrated significantly higher levels of intracellular reactive oxygen species. Knockdown of CYP2E1 rescued the acrylamide-induced oxidative stress. These studies suggest that long-term acrylamide exposure through foods common in the Western diet may enhance DNA damage and CYP2E1-induced generation of oxidative stress in mammary epithelial cells, potentially enhancing obesity-induced breast cancer risk.
... Otsuka Long-Evans Tokushima fatty (OLETF) rats spontaneously develop obesity with simple steatosis in the liver. When the animals were administered 10 mL of 10% ethanol orally for 3 consecutive weeks, massive steatohepatitis and hepatocyte ballooning were observed, whereas the same courses of ethanol administration did not induce steatohepatitis in their wild-type control Otsuka Long-Evans Tokushima (OLET) rats (101). In another model of obesity, obese fa/fa rats and lean Fa/? rats were treated with six doses of ethanol (4 g/kg every 12 h for 3 days), liver injury was observed in the obese fa/fa rats but not in the lean Fa/? rats (102). ...
Fatty acid oxidation (FAO) releases the energy stored in fat to maintain basic biological processes. Dehydrogenation is a major way to oxidize fatty acids, which needs NAD ⁺ to accept the released H ⁺ from fatty acids and form NADH, which increases the ratio of NADH/NAD ⁺ and consequently inhibits FAO leading to the deposition of fat in the liver, which is termed fatty liver or steatosis. Consumption of alcohol (ethanol) initiates simple steatosis that progresses to alcoholic steatohepatitis, which constitutes a spectrum of liver disorders called alcohol-associated liver disease (ALD). ALD is linked to ethanol metabolism. Ethanol is metabolized by alcohol dehydrogenase (ADH), microsomal ethanol oxidation system (MEOS), mainly cytochrome P450 2E1 (CYP2E1), and catalase. ADH also requires NAD ⁺ to accept the released H ⁺ from ethanol. Thus, ethanol metabolism by ADH leads to increased ratio of NADH/NAD ⁺ , which inhibits FAO and induces steatosis. CYP2E1 directly consumes reducing equivalent NADPH to oxidize ethanol, which generates reactive oxygen species (ROS) that lead to cellular injury. Catalase is mainly present in peroxisomes, where very long-chain fatty acids and branched-chain fatty acids are oxidized, and the resultant short-chain fatty acids will be further oxidized in mitochondria. Peroxisomal FAO generates hydrogen peroxide (H 2 O 2 ), which is locally decomposed by catalase. When ethanol is present, catalase uses H 2 O 2 to oxidize ethanol. In this review, we introduce FAO (including α-, β-, and ω-oxidation) and ethanol metabolism (by ADH, CYP2E1, and catalase) followed by the interaction between FAO and ethanol metabolism in the liver and its pathophysiological significance.
... WHR might better reflect metabolic health than BMI 2,3 . Metabolic dysfunction might sensitize the liver to the harmful effects of alcohol, as suggested by animal studies 20,21 and human experimental studies 22 and substantiated by recent epidemiologic evidence [23][24][25] . ...
Background
Obesity is associated with liver disease, but the best obesity-related predictor remains undefined. Controversy exists regarding possible synergism between obesity and alcohol use for liver-related outcomes (LRO). We assessed the predictive performance for LROs, and synergism with alcohol use, of abdominal obesity (waist-hip ratio, WHR), and compared it to overall obesity (body mass index, BMI).
Methods
Forty-thousand nine-hundred twenty-two adults attending the Finnish health-examination surveys, FINRISK 1992–2012 and Health 2000 studies, were followed through linkage with electronic healthcare registries for LROs (hospitalizations, cancers, and deaths). Predictive performance of obesity measures (WHR, waist circumference [WC], and BMI) were assessed by Fine-Gray models and time-dependent area-under-the-curve (AUC).
Results
There are 355 LROs during a median follow-up of 12.9 years (509047.8 person-years). WHR and WC emerge as more powerful predictors of LROs than BMI. WHR shows significantly better 10-year AUC values for LROs (0.714, 95% CI 0.685–0.743) than WC (0.648, 95% CI 0.617–0.679) or BMI (0.550, 95% CI 0.514–0.585) both overall and separately among men and women. WHR is predictive also in BMI strata. Absolute 10-year risks of LROs are more dependent on WHR than BMI. Moreover, WHR shows a significant supra-additive interaction effect with harmful alcohol use for liver-related outcomes (excess 10-year cumulative incidence of 2.8% from the interaction), which is not seen between BMI and harmful alcohol use.
Conclusions
WHR is a better predictor than BMI or WC for LROs, and WHR better reflects the synergism with harmful alcohol use. WHR should be included in clinical assessment when evaluating obesity-related risks for liver outcomes.
... Однако избыточная масса тела и ожирение также являются независимыми факторами риска развития и прогрессирования АБП. Показано, что у лиц с ожирением алкогольное поражение печени развивается в 2-3 раза чаще, чем у людей с нормальной массой тела [38]. Данные заболевания взаимосвязаны: употребление этанола, особенно в сочетании с гиподинамией и пристрастием к жирной пище, является важнейшим фактором, приводящим к избытку массы тела. ...
Alcohol consumption is one of the main causes leading to chronic liver disease. Alcoholic liver disease is a set of cascading events, consisting first of alcoholic hepatic steatosis and then mainly through alcoholic steatohepatitis, leading to cirrhosis and hepatocellular carcinoma. This review considers chronic alcohol intoxication as the main factor in the development of liver disease. Modern data on the prevalence of forms of alcoholic liver damage in Russia and in the world are presented. The role of the consumed dose of ethanol, the nature of the alcoholic beverage, as well as the pattern of alcohol consumption in the formation of liver damage is assessed, predisposing factors are presented. The leading risk factors for alcoholic liver damage are: female gender, hereditary predisposition (ethnicity), trophological status (underweight or obesity), taking certain hepatotoxic drugs, the amount and duration of alcohol consumption and the type of alcohol consumed, smoking. The presence of concomitant viral hepatitis, environmental toxico-ecological influence and prenatal intoxication also predispose to alcoholic liver damage. The article provides a detailed assessment of the role of the presented risk factors in the development of alcoholic liver damage. However, it is not possible to identify the dominant risk factor for alcoholic liver damage, since the development of liver pathology directly depends not only on the amount of alcohol consumed, but also on the individual combination of predisposing factors. Understanding the etiology of the disease and the contribution of modifiable risk factors to its development will allow the development of effective strategies aimed at reducing the incidence and mortality from liver diseases.
... Alcoholic liver disease was enhanced in CYP2E1-transgenic mice [21]. CYP2E1 may play a role in alcohol-enhanced steatohepatitis [22] and potentiate TNF-induced liver injury [23]. Autophagy also demonstrates a protective effect on CYP2E1-dependent liver injury after chronic ethanol treatment [23]. ...
Alcohol is the one of the major causes of liver diseases and promotes liver cirrhosis and hepatocellular carcinoma (HCC). In hepatocytes, alcohol is converted to acetaldehyde, which causes hepatic steatosis, cellular apoptosis, endoplasmic reticulum stress, peroxidation, production of cytokines and reduces immune surveillance. Endotoxin and lipopolysaccharide produced from intestinal bacteria also enhance the production of cytokines. The development of hepatic fibrosis and the occurrence of HCC are induced by these alcohol metabolites. Several host genetic factors have recently been identified in this process. Here, we reviewed the molecular mechanism associated with HCC in alcoholic liver disease.
... Hepatic fibrosis is the outcome of a continuous wound healing process to a chronic liver injury and is marked with increased synthesis and deposition of extracellular proteins, especially collagens in the liver [1][2][3]. The pathogenesis of hepatic fibrosis is a complex and dynamic process in response to a chronic stimuli such as steatosis, viral hepatitis, drugs, toxins, alcohol, cholestasis, and metabolic disorders [4,5]. The chronic stimuli responsible for the initiation of fibrosis leads to generation of reactive oxygen species (ROS) that triggers several molecular events involved in the process of fibrogenesis [6][7][8]. ...
Osteopontin (OPN) is a matricellular cytokine and a stress-induced profibrogenic molecule that promotes activation of stellate cells during the pathogenesis of hepatic fibrosis. We studied the protective effects of epigallocatechin-3-gallate (EGCG) to suppress oxidative stress, inhibit OPN expression, and prevent experimentally induced hepatic fibrosis. Liver injury was induced with intraperitoneal injections of N-nitrosodimethylamine (NDMA) in a dose of 1 mg/100 g body weight on 3 consecutive days of a week for 28 days. A group of rats received 0.2 mg EGCG/100 g body weight orally everyday during the study. The animals were sacrificed on day 28th from the beginning of exposure. Serum levels of AST, ALT, OPN, malondialdehyde, collagen type IV, and hyaluronic acid were measured. Immunohistochemistry and/or real-time PCR were performed for α-SMA, 4-HNE, OPN, collagen type I, and type III. Serial administrations of NDMA produced well developed fibrosis and early cirrhosis in rat liver. Treatment with EGCG significantly reduced serum/plasma levels of AST, ALT, OPN, malondialdehyde, collagen type IV, and hyaluronic acid and prevented deposition of collagen fibers in the hepatic tissue. Protein and/or mRNA levels demonstrated marked decrease in the expression of α-SMA, 4-HNE, OPN, collagen type I, and type III. Treatment with EGCG prevented excessive generation of reactive oxygen species, suppressed oxidative stress, significantly reduced serum and hepatic OPN levels, and markedly attenuated hepatic fibrosis. The results indicated that EGCG could be used as a potent therapeutic agent to prevent hepatic fibrogenesis and related adverse events.
... In addition to chemical exposures, the oxidative stress imbalance exceeding the antioxidant defense mechanisms may also be associated with a suite of lifestyle and behavioral risk factors, such as alcohol or smoking [69]. A positive association was found earlier between smoking/tobacco exposure [70][71][72] and alcohol [73,74] consumption with increased levels of oxidative damage (4HNE). Moreover, a significant association was found between BMI and oxidative damage, with studies reporting a positive effect of obesity on increased 4HNE [73,75]. ...
... A positive association was found earlier between smoking/tobacco exposure [70][71][72] and alcohol [73,74] consumption with increased levels of oxidative damage (4HNE). Moreover, a significant association was found between BMI and oxidative damage, with studies reporting a positive effect of obesity on increased 4HNE [73,75]. However, the majority of our study population was composed of non-active smokers and non-obese, thus their lifestyle characteristics were anticipated to have little influence on the variation of the observed 4HNE levels. ...
Much evidence on the adverse health effects of endocrine-disrupting chemicals (EDCs) has accumulated during recent decades. EDCs are commonly found in various foods and personal care products (PCP). Data documenting a diurnally varying EDC metabolism in humans is scarce. This study examined (i) the time-of-day effect on the diurnal magnitude and variance of urinary biomarkers of exposure to EDCs, and (ii) the association between EDC exposures and oxidative damage in a Norwegian adult subpopulation. This was a cross-sectional panel study using biobanked samples from the EuroMix project. During a typical weekday, participants were asked to collect all day’s urine voids and record dietary and PCP habitual uses in a diary. Collected time stamps of urine voids were classified into three distinct periods in the day (morning 6 a.m.–12 p.m., mid-day 12 p.m.–6 p.m., evening 6 p.m.–6 a.m.). Questionnaires regarding demographic characteristics, personal care product usage, and dietary habits were completed. Urinary levels of EDCs (phthalates, parabens, and bisphenols) were measured using mass spectrometry and adjusted for urinary volume using specific gravity. Urinary 4-hydroxynonenal (4HNE), a lipid peroxidation marker, was measured using an immunoassay kit. Linear mixed-effect models identified EDCs under the influence of a diurnal variation effect that was adjusted for dietary habits and PCP use and examined associations between EDC and 4HNE. p-values were FDR-adjusted. Most phthalates appeared to be diurnally varying with higher urinary levels towards the evening (q < 0.001) than those measured during mid-day; this strong diurnal variation effect was not present for parabens and bisphenols. Significant (q < 0.001) positive associations were observed between all phthalates, parabens, and bisphenols (except bisphenol S) and 4HNE. This study’s findings highlighted the diurnal variation of excretion for certain EDC, but not for others, in real-life conditions. The degree of EDC chronotoxicity in distinct diurnal windows of the day warrants further investigation with longitudinal human studies.
... However, they prevented the subsequent inflammatory response, leading to macrophage accumulation and liver fibrosis. If the two-hit theory applies to NASH development [40], it could be suggested that dietary nitrite and captopril suppress the immune responses following the initiation of the AT 1 R and NF-κB mediated pathway (the second hit), rather than suppressing toxic lipid deposition in the liver (the first hit) in this rat NASH model. Important issues related to the findings of the present study are the use of dietary nitrite instead of dietary nitrate, the doses of nitrite in drinking water, and the complications associated with dietary nitrite intake, such as methemoglobinemia and carcinogenicity, in clinical settings. ...
Abstract: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that leads to liver cirrhosis and hepatocellular carcinoma. Endothelial dysfunction caused by hepatic lipotoxicity is an underlying
NASH pathology observed in the liver and the cardiovascular system. Here, we evaluated the effect of dietary nitrite on a rat NASH model. Stroke-prone, spontaneously hypertensive 5/Dmcr rats were fed
a high-fat/high-cholesterol diet to develop the NASH model, with nitrite or captopril (100 mg/L, each) supplementation in drinking water for 8 weeks. The effects of nitrite and captopril were evaluated using immunohistochemical analyses of the liver and heart tissues. Dietary nitrite suppressed liver fibrosis in the rats by reducing oxidative stress, as measured using the protein levels of nicotinamide adenine dinucleotide phosphate oxidase components and inflammatory cell accumulation in the liver. Nitrite lowered the blood pressure in hypertensive NASH rats and suppressed left ventricular chamber enlargement. Similar therapeutic effects were observed in a captopril-treated rat NASH model, suggesting the possibility of a common signaling pathway through which nitrite and captopril improve NASH pathology. In conclusion, dietary nitrite attenuates the development of NASH with cardiovascular involvement in rats and provides an alternative NASH therapeutic strategy.
... There is now strong evidence that alcohol abuse and obesity (or metabolic syndrome) synergistically increase the risk and severity of different hepatic diseases, including fatty liver, steatohepatitis, cirrhosis and hepatocellular carcinoma [192][193][194][195]. Experimental investigations attempted to determine how ethanol and obesity synergistically increase hepatic toxicity in particular regarding steatosis, hepatocyte cell death and inflammation. Unsurprisingly, different mechanisms have been proposed, including impaired mitochondrial function and biogenesis [196,197], reduced expression of PPARα [196,198] or AMPactivated protein kinase (AMPK) [199], induction of CYP2E1 and oxidative stress [200,201], unfolded protein response and ER stress [196,202], increased expression of tumor necrosis factor alpha (TNF-α) [203] or Fas ligand [204,205] and activation of different proinflammatory pathways [206][207][208][209]. Interestingly, ethanol exerts different deleterious effects on WAT such as lipoatrophy, increased lipolysis and enhanced secretion of proinflammatory adipokines [210][211][212], which might also explain why alcohol intoxication is particularly hepatotoxic in obese individuals [195]. ...
Metabolic-associated fatty liver disease (MAFLD), which is often linked to obesity, encompasses a large spectrum of hepatic lesions, including simple fatty liver, steatohepatitis, cirrhosis and hepatocellular carcinoma. Besides nutritional and genetic factors, different xenobiotics such as pharmaceuticals and environmental toxicants are suspected to aggravate MAFLD in obese individuals. More specifically, pre-existing fatty liver or steatohepatitis may worsen, or fatty liver may progress faster to steatohepatitis in treated patients, or exposed individuals. The mechanisms whereby xenobiotics can aggravate MAFLD are still poorly understood and are currently under deep investigations. Nevertheless, previous studies pointed to the role of different metabolic pathways and cellular events such as activation of de novo lipogenesis and mitochondrial dysfunction, mostly associated with reactive oxygen species overproduction. This review presents the available data gathered with some prototypic compounds with a focus on corticosteroids and rosiglitazone for pharmaceuticals as well as bisphenol A and perfluorooctanoic acid for endocrine disruptors. Although not typically considered as a xenobiotic, ethanol is also discussed because its abuse has dire consequences on obese liver.
