Oxidative stress:New insights on the association of nonalcoholic fatty liver disease and atherosclerosis

Non-alcoholic fatty liver disease(NAFLD) represents the most common and emerging chronic liver disease worldwide. It includes a wide spectrum of liver diseasesranging from simple fatty liver to non-alcoholic steatohepatitis(NASH),which may progress to fibrosis and more severe liver complications such as cirrhosis,hepatocellular carcinoma and liver mortality. NAFLD is strongly associated with obesity,insulin resistance,hypertension,and dyslipidaemia,and is now regarded as the liver manifestation of the metabolic syndrome. The increased mortality of patients with NAFLD is primarily a result of cardiovascular disease and,to a lesser extent,to liver related diseases. Increased oxidative stress has been reported in both patients with NAFLD and patient with cardiovascular risk factors. Thus,oxidative stress represents a shared pathophysiological disorder between the two conditions. Several therapeutic strategies targeting oxidative stress reduction in patients with NAFLD have been proposed,with conflicting results. In particular,vitamin E supplementation has been suggested for the treatment of non-diabetic,non-cirrhotic adults with active NASH,although this recommendation is based only on the results of a single randomized controlled trial. Other antioxidant treatments suggested are resveratrol,silybin,L-carnitine and pentoxiphylline. No trial so far,has evaluated the cardiovascular effects of antioxidant treatment in patients with NAFLD. New,large-scale studies including as end-point also the assessment of the atherosclerosis markers are needed.

Pathogenesis of alcoholic hepatitis:Role of inflammatory signaling and oxidative stress

Inflammatory signaling and oxidative stress are two major components in the pathogenesis of alcoholic he-patitis.Alcohol consumption results in translocation of gut bacteria into the portal system along with lipopolysaccharides that interact with toll-like receptors and results in the production of inflammatory and immunogenic mediators such as tumor necrosis factor-alpha(TNF-α) and interferons.Chronic consumption of alcohol causes priming of this process in which there is enhanced production of cytokines,interferon,interleukins,and TNF-α.Oxidative stress,genetic predisposition,and the unfolded protein response are other contributory mechanisms.Novel therapies aimed at these pathways may prevent,decrease,or delay the complications of alcoholic hepatitis.

Is It Workplace Stress a Trigger for Alcohol and Drug Abuse?

Those workers most vulnerable to pressure tend to suffer from scarce social and personal resources with which to respond adaptively to stress. In this case, the effects of psychoactive substances may exceed the stressed worker’s positive expectations. Thus, the aim is to analyze the scientific evidence on the relationship between drug abuse and workplace stress, based on an integrative review of the literature. Data were collected in February 2016 from the databases of the Virtual Health Library and PubMed. The final sample of 16 articles was divided into two categories: alcohol and drugs abuse in professions with high degree of psychosocial hazards and risks, and alcohol and drugs abuse for workplace stress in other professions. A relationship between precarious conditions, the nature of the work and its influence on drug abuse could be seen. However, other variables may strengthen psychoactive drug use as a coping strategy for stress.

Influence of Early Life Stress on Alcohol and Crack Dependents

Background: Early life stress is a significant public health problem associated with increased rates of psychiatric disorders, especially those related to drug abuse. Objective: To identify the prevalence of early life stress in drug users, to compare the intensity of trauma in alcohol and crack users, and to relate the power of injury to the severity of drug dependence. Method: Cross-sectional analytical study with a sample of 105 alcohol and crack users treated by an outpatient service. The instruments for data collection were sociodemographic data questionnaire, the Mini-International Neuropsychiatric Interview, and the Severity of Dependence Scale. The categorical variables association was analyzed using the Chi-squared test, considering p Results: High prevalence of early stress and severity of dependence were identified, with higher rates among crack users. The early stress revealed in the Alcohol group high rates of emotional (88.7%) and physical (94.3%) neglect and in the Crack group significant frequency of physical (61.5%) emotional abuse (51.9%), sexual (46.2%), and emotional (78.8%) and physical (90.4%) neglect. Crack users are 2.6 times more likely to have been emotionally abused, and 2.1 times more likely to have been sexually abused during childhood when compared to the alcohol group. Conclusion: Early stress was prevalent with significant intensity in drug users, and evaluation of this problem is essential for a better understanding of these disorders.

Therapeutic Effects of"Soothing the Liver Method"on Stress-related Non-alcoholic Fatty Liver on Neuroendocrine-metabolic Level

OBJECTIVE: To study the therapeutic effects of "soothing the liver method" on stress-related non-alcoholic fatty liver and its treatment mechanism on neuroendocrine-metabolic level. METHODS: The animal model of stress-related nonalcoholic fatty liver which is more in line with the modern social and clinical conditions was established by the method of chronic restraint compound high-fat feed. AST and ALT were detected by automatic biochemical analyzer. Serum cortisol and TNF-a were detected by radioimmunoassay. The relative expression of Nr3 c1 mRNA was detected by real-time quantitative PCR. RESULTS: Compared with the blank group, the scores of open field test, Nr3 c1 mRNA decreased, and AST, ALT, FFA were significantly increased in model group. Compared with model group, the open field test scores, Nr3 c1 mRNA increased,and Cor, AST, FFA, LDL, TNF-a, were significantly decreased in SNS group. CONCLUSIONS: "Soothing the liver method" can exert its therapeutic effect on stress-related non-alcoholic fatty liver on neuroendocrine-metabolic level.

Regulation of heme oxygenase expression by alcohol,hypoxia and oxidative stress

AIM:To study the effect of both acute and chronic alcohol exposure on heme oxygenases(HOs) in the brain,liver and duodenum.METHODS:Wild-type C57BL/6 mice,heterozygous Sod2 knockout mice,which exhibit attenuated manganese superoxide dismutase activity,and liver-specific ARNT knockout mice were used to investigate the role of alcohol-induced oxidative stress and hypoxia.For acute alcohol exposure,ethanol was administered in the drinking water for 1 wk.Mice were pair-fed with regular or ethanol-containing Lieber De Carli liquid diets for 4 wk for chronic alcohol studies.HO expression was analyzed by real-time quantitative polymerase chain reaction and Western blotting.RESULTS:Chronic alcohol exposure downregulated HO-1 expression in the brain but upregulated it in the duodenum of wild-type mice.It did not alter liver HO-1 expression,nor HO-2 expression in the brain,liver or duodenum.In contrast,acute alcohol exposure decreased both liver HO-1 and HO-2 expression,and HO-2 expression in the duodenum of wild-type mice.The decrease in liver HO-1 expression was abolished in ARNT+/-mice.Sod2+/-mice with acute alcohol exposure did not exhibit any changes in liver HO-1 and HO-2 expression or in brain HO-2 expression.However,alcohol inhibited brain HO-1 and duodenal HO-2 but increased duodenal HO-1 expression in Sod2+/-mice.Collectively,these findings indicate that acute and chronic alcohol exposure regulates HO expression in a tissue-specific manner.Chronic alcohol exposure alters brain and duodenal,but not liver HO expression.However,acute alcohol exposure inhibits liver HO-1 and HO-2,and also duodenal HO-2 expression.CONCLUSION:The inhibition of liver HO expression by acute alcohol-induced hypoxia may play a role in the early phases of alcoholic liver disease progression.

Advanced Progress on Adaptive Stress Response of Oenococcus oeni

Oenoccoccus oeni is an alcohol-tolerant, acidophilic lactic acid bacterium with its ability to perform malolactic fermentation in wine, which is of fundamental importance in oenology. As a representative of the wine bacterium with remarkable adaptability to the very harsh physicochemical conditions of wine, many studies were carded out for its applied interest and focused mainly on its stress response mechanisms of O. oeni. on both physiological and molecular levels. In this review, three main stress response mechanisms in O. oeni during culturing process were addressed. Of them, various solute transporters and secondary metabolic energy-generating systems were utilized to control the intracellular environment and the energetic status of O. oeni. The changes in cell membrane fatty acid composition profiles and synthesis of stress proteins, especially small heat shock proteins were required for active cell response to maintain membrane integrity and function under stress conditions. The study on stress response of O. oeni played an important role on culture bacteria selection, making inoculation culture and construction of other engineering bacteria.

叶酸对非酒精性脂肪肝大鼠SOD、GSH-Px、GSH、MDA水平的影响

目的研究叶酸对非酒精性脂肪肝(NAFLD)大鼠超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、谷胱甘肽(GSH)、丙二醛(MDA)水平的影响。方法取SD大鼠用高脂饲料喂养8周构建NAFLD模型,随机分为模型组、叶酸低剂量组(10 mg/kg)、叶酸中剂量组(20 mg/kg)、叶酸高剂量组(40 mg/kg)、奥利司他组(阳性对照药物,60 mg/kg),每组10只,再次取10只SD大鼠用正常饲料喂养8周作为对照组,使用叶酸和奥利司他分组处理后检测大鼠血脂总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、三酰甘油(TG)及游离脂肪酸(FFA)水平与肝功能指标谷丙转氨酶(ALT)、谷氨酰转肽酶(γ-GT)、谷草转氨酶(AST)水平;采用HE染色、油红O染色分别检测大鼠肝组织形态及脂肪变性,比较各组NAFLD活动度积分;采用试剂盒检测大鼠血清及肝组织SOD、GSH-Px、GSH、MDA水平。结果与对照组相比,模型组大鼠肝组织发生明显脂肪变性与病理损伤,血清TC、LDL-C、TG、FFA、ALT、γ-GT与AST水平、NAFLD活动度积分、血清与肝组织MDA水平显著升高(P<0.05),血清与肝组织SOD、GSH-Px、GSH水平显著降低(P<0.05);与模型组相比,叶酸低、中、高剂量组大鼠肝组织脂肪变性与病理损伤均减轻且其减轻程度随剂量升高而增强,血清TC、LDL-C、TG、FFA、ALT、γ-GT与AST水平、NAFLD活动度积分、血清与肝组织MDA水平均降低(P<0.05),血清与肝组织SOD、GSH-Px、GSH水平均升高(P<0.05),并呈剂量依赖性(P<0.05);与叶酸高剂量组相比,奥利司他组大鼠各指标无明显变化(P>0.05)。结论叶酸可降低NAFLD大鼠血脂水平,增强其抗氧化酶活性并降低脂质过氧化水平,抑制其氧化应激,进而减轻大鼠肝组织脂肪变性、病理损伤并改善其肝功能。

Peroxisome proliferator-activated receptor α,a potential therapeutic target for alcoholic liver disease

Alcoholic liver injury represents a progressive process with a range of consequences including hepatic steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Targeting key molecular regulators involved in the development of alcoholic liver injury may be of great value in the prevention of liver injury. Peroxisome proliferator-activated receptor &#x003b1; (PPAR&#x003b1;) plays a pivotal role in modulation of hepatic lipid metabolism, oxidative stress, inflammatory response and fibrogenesis. As such, PPAR&#x003b1; may be a potential therapeutic target for the treatment of alcoholic liver disease.

Chronic liver inflammation:Clinical implications beyond alcoholic liver disease

Chronic alcohol exposure can lead to alcoholic liver disease, including hepatitis, cirrhosis and hepatocellular carcinoma, and chronic inflammation can simultaneously cause systemic medical illness. Recent evidence suggests that alcoholic liver disease is a predictor for liver-related diseases, cardiovascular disease, immunologic disease, and bone disease. Chronic inflammation in alcoholic liver disease is mediated by a direct inflammatory cascade from the alcohol detoxification process and an indirect inflammatory cascade in response to gut microflora-derived lipopolysaccharides (LPS). The pathophysiology of alcoholic liver disease and its related systemic illness is characterized by oxidative stress, activation of the immune cascade, and gut-liver interactions. Integrative therapeutic strategies for alcoholic liver disease include abstaining from alcohol consumption; general anti-inflammatories such as glucocorticoid, pentoxifylline, and tumour necrosis factor-&#x003b1; antagonist; antioxidants such as N- acetylcysteine; gut microflora and LPS modulators such as rifaximin and/or probiotics. This review focuses on the impact of chronic liver inflammation on systemic health problems and several potential therapeutic targets.

Role of alcohol in pathogenesis of hepatitis B virus infection

Hepatitis B virus(HBV)and alcohol abuse often contribute to the development of end-stage liver disease.Alcohol abuse not only causes rapid progression of liver disease in HBV infected patients but also allows HBV to persist chronically.Importantly,the mechanism by which alcohol promotes the progression of HBVassociated liver disease are not completely understood.Potential mechanisms include a suppressed immune response,oxidative stress,endoplasmic reticulum and Golgi apparatus stresses,and increased HBV replication.Certainly,more research is necessary to gain a better understanding of these mechanisms such that treatment(s)to prevent rapid liver disease progression in alcohol-abusing HBV patients could be developed.In this review,we discuss the aforementioned factors for the higher risk of liver diseases in alcohol-induced HBV pathogenies and suggest the areas for future studies in this field.

Hepatic non-parenchymal cells:Master regulators ofalcoholic liver disease?

Chronic alcohol consumption is one of the most common causes of the progression of alcoholic liver disease(ALD). In the past, alcohol-mediated hepatocyte injury was assumed to be a significantly major cause of ALD. However, a huge number of recent and brilliant studies have demonstrated that hepatic non-parenchymal cells including Kupffer cells, hepatic stellate cells, liver sinusoidal endothelial cells and diverse types of lymphocytes play crucial roles in the pathogenesis of ALD by producing inflammatory mediators such as cytokines, oxidative stress, micro RNA, and lipid-originated metabolites(retinoic acid and endocannabinoids) or by directly interacting with parenchymal cells(hepatocytes). Therefore, understanding the comprehensive roles of hepatic nonparenchymal cells during the development of ALD will provide new integrative directions for the treatment of ALD. This review will address the roles of nonparenchymal cells in alcoholic steatosis, inflammation, and liver fibrosis and might help us to discover possible therapeutic targets and treatments involving modulating the non-parenchymal cells in ALD.

Oxidative stress and antioxidants in hepatic pathogenesis

Long term hepatitis B virus (HBV) infection is a major risk factor in pathogenesis of chronic liver diseases,including hepatocellular carcinoma (HCC). The HBV encod-ed proteins,hepatitis B virus X protein and preS,appear to contribute importantly to the pathogenesis of HCC. Both are associated with oxidative stress,which can damage cellular molecules like lipids,proteins,and DNA during chronic infection. Chronic alcohol use is another important factor that contributes to oxidative stress in the liver. Previous studies reported that treatment with antioxidants,such as curcumin,silymarin,green tea,and vitamins C and E,can protect DNA from damage and regulate liver pathogenesis-related cascades by reducing reactive oxygen species. This review summarizes some of the relationships between oxidative stress and liver pathogenesis,focusing upon HBV and alcohol,and suggests antioxidant therapeutic approaches.

Antioxidant axis Nrf2-keap1-ARE in inhibition of alcoholic liver fibrosis by IL-22

AIM To explore the effect of interleukin(IL)-22 on in vitro model of alcoholic liver fibrosis hepatic stellate cells(HSCs), and whether this is related to regulation of Nrf2-keap1-ARE.METHODS HSC-T6 cells were incubated with 25, 50, 100, 200 and 400 μmol/L acetaldehyde. After 24 and 48 h, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay was used to detect proliferation of HSCs to choose the best concentration and action time. We used the optimal concentration of acetaldehyde(200 μmol/L) to stimulate HSCs for 24 h, and treated the cells with a final concentration of 10, 20 or 50 ng/m L IL-22. The cell proliferation rate was detected by MTT assay. The cell cycle was analyzed by flow cytometry. The expression of nuclear factor-related factor(Nrf)2 and α-smooth muscle antigen was detected by western blotting and immunocytochemistry. The levels of malondialdehyde(MDA) and glutathione(GSH) were measured by spectrophotometry. RESULTS In the MTT assay, when HSCs were incubated with acetaldehyde, activity and proliferation were higher than in the control group, and were most obvious after 48 h treatment with 200 μmol/L acetaldehyde. The number of cells in G0/G1 phases was decreased and the number in S phase was increased in comparison with the control group. When treated with different concentrations of IL-22, HSC-T6 cell activity and proliferation rate were markedly decreased in a dosedependent manner, and cell cycle progression was arrested from G1 to S phase. Western blotting and immunocytochemistry demonstrated that expression of Nrf2 total protein was not significantly affected. Expression of Nrf2 nuclear protein was low in thecontrol group, increased slightly in the model group(or acetaldehyde-stimulated group), and increased more obviously in the IL-22 intervention groups. The levels of MDA and GSH in the model group were significantly enhanced in comparison with those in the control group. In cells treated with IL-22, the MDA level was attenuated but the GSH level was further increased. These changes were dose-dependent. CONCLUSION IL-22 inhibits acetaldehyde-induced HSC activation and proliferation, which may be related to nuclear translocation of Nrf2 and increased activity of the antioxidant axis Nrf2-keap1-ARE.

Autophagy activation by Jiang Zhi Granule protects against metabolic stress-induced hepatocyte injury

AIM To elucidate the potential role of autophagy and the protective effects of Jiang Zhi Granule(JZG) in metabolic stress-induced hepatocyte injury.METHODS An in vitro and in vivo approach was used in this study. Hep G2 cells were incubated in culture medium containing palmitate(PA; 0, 0.1, 0.2, 0.3, 0.4 or 0.5 mmol/L) and treated with or without JZG(100 μg/m L) for 24 h or 48 h, and the progression of autophagy was visualized by stable fluorescence-expressing cell lines LC3 and p62. Western blot analyses were performed to examine the expression of LC3-Ⅱ/LC3-Ⅰ, p62, m TOR and PI3 K, while mitochondrial integrity and oxidative stress were observed by fluorescence staining of JC-1 and reactive oxygen species. C57 BL/6 mice were divided into three groups: control group(n = 10), high fat(HF) group(n = 13) and JZG group(n = 13); and, histological staining was carried out to detect inflammation and lipid content in the liver.RESULTS The cell trauma induced by PA was aggravated in a dose-and time-dependent manner, and hepatic function was improved by JZG. PA had dual effects on autophagy by activating autophagy induction and blocking autophagic flux. The PI3 K-AKT-m TOR signaling pathway and the fusion of isolated hepatic autophagosomes and lysosomes were critically involved in this process. JZG activated autophagy progression by either induction of autophagosomes or co-localization of autophagosomes and lysosomes as well as degradation of autolysosomes to protect against PA-induced hepatocyte injury, and protected mitochondrial integrity against oxidative stress in PA-induced mitochondrial dysfunction. In addition, JZG ameliorated lipid droplets and inflammation induced by HF diet in vivo, leading to improved metabolic disorder and associated liver injury in a mouse model of non-alcoholic fatty liver disease(NAFLD).CONCLUSION Metabolic stress-induced hepatocyte injury exhibited dual effects on autophagy and JZG activated the entire process, resulting in beneficial effects in NAFLD.

Fermented papaya preparation halts the progression of non-alcoholic steatohepatitis in rats

Non-alcoholic steatohepatitis (NASH) can progress to cirrhosis or hepatocellular carcinoma. Oxidative stress is implicated in NASH progression. Fermented papaya preparation (FPP) has oxygen radical scavenging activity and is effective in oxidative stress-related diseases. We investigated the effects of FPP on NASH progression using a rat NASH model. Plasma biochemical parameters and lipid peroxidation in the liver were elevated in NASH rats. Histologically, the liver of NASH rats showed liver fibrosis, mitochondrial dysfunction and over-expression of microsomal CYP2E1. Myeloperoxidase activity and nuclear factor-kappaB activation were also markedly increased in NASH. Oral administration of FPP ameliorated these changes in NASH rats. These results suggest that FPP halts NASH progression through its anti-oxidative and antiinflammatory properties.

The protection of Thymus vulgaris leaves alcoholic extract against hepatotoxicity of alcohol in rats

Objective:This study was performed to investigate the protective effect of Thymus vulgaris(T.vulgaris) leaves 70%alcoholic extract against alcohol-mediate hepatotoxicity rats.Methods:The protective effect of extract was investigated at dose of 500 mg/kg/day orally against alcohol-mediate hepatotoxicity using adult male Wister albino rats during 21 days.Protective effect of T.vulgaris extract was evaluated comparing with silymarin standard drug al recommended dose(25 mg/kg/day) orally for 21 days.Results:Alcohol-mediate hepatotoxicity rats(alcohol-control) showed hepatocytes distortion represented as marked increment on liver biomarkers;alkaline phosphatase(ALP),aspartate transaminase(AST) and alanine transaminase(ALT) activities,as well as pronounced reduction on total protein and its fractions albumin and globulin corresponding to normal ranges.Addition to oxidative stress status as depletion on glutathione concentration,catalase(CAT),superoxide dismutase(SOD),glutathione reductase(GR),glutathione-S-transferase(GST) and glutathione peroxidase(GPx)activities,concurrence with augmentation oxidative stress parameters;malondyaldchydc(MDA) and hydrogen peroxide(H_2O_2) concentrations comparing to normal values.Alcohol administration elevated total cholesterol(TC),low density lipoprotein cholesterol(LDL-C) and high density lipoprotein cholesterol(HDL-C) comparing to normal ranges.Co-administration T.vulgaris extract with alcohol showed protective effect on hepatocytes manifested as minimizing on ALP.AST and ALT activities and increment on total protein,albumin and globulin production compared to alcohol-control.Antioxidant enzymes activities;CAT.SOD.GR,GST and GPx were significantly magnified,while MDA and H_2O_2 concentration were lessened corresponding to alcohol-control.Also,lipid profile was markedly improved and risk ratio was lowered compared to alcohol-control.These results were confirmed by normalization of degenerated and fibrotic liver tissue as of alcohol-control.Conclusion:T.vulgaris extract appeared hepatoprotective,hypolipidemic and antioxidant activities on alcohol-mediate hepatotoxicity rats compared to silymarin.

Beneficial mechanisms of aerobic exercise on hepatic lipid metabolism in non-alcoholic fatty liver disease

BACKGROUND：Non-alcoholic fatty liver disease（NAFLD）refers to any fatty liver disease that is not due to excessive use of alcohol.NAFLD probably results from abnormal hepatic lipid metabolism and insulin resistance.Aerobic exercise is shown to improve NAFLD.This review aimed to evaluate the molecular mechanisms involved in the beneficial effects of aerobic exercise on NAFLD.DATA SOURCE：We searched articles in English on the role of aerobic exercise in NAFLD therapy in Pub Med.RESULTS： The mechanisms of chronic aerobic exercise in regulating the outcome of NAFLD include： （i） reducing in- trahepatic fat content by down-regulating sterol regulatory element-binding protein-lc and up-regulating peroxisome proliferator-activated receptor y expression levels; （ii） decreas- ing hepatic oxidative stress through modulating the reactive oxygen species, and enhancing antioxidant enzymes such as catalase and glutathione peroxidase; （iii） ameliorating hepatic inflammation via the inhibition of pro-inflammatory media- tors such as tumor necrosis factor-alpha and interleukin-1 beta; （iv） attenuating mitochondrial dependent apoptosis by reducing cytochrome C released from the mitochondria to the cytosol; and （v） inducing hepato-protective autophagy. CONCLUSION： Aerobic exercise, via different mechanisms, significantly decreases the fat content of the liver and improves the outcomes of patients with NAFLD.

Smallanthus sonchifolius roots ameliorate non-alcoholic fatty liver disease by reducing redox imbalance and hepatocyte damage in rats fed with a high fructose diet

Objective: To evaluate the potential of Smallanthus sonchifolius(S. sonchifolius) roots in ameliorating hepatic damage of rats fed with a high fructose diet.Methods: The effect of S. sonchifolius roots on energy intake, body weight, fat and liver mass was determined in male rats fed with a high-fructose diet. Plasma glucose, triglycerides, total cholesterol, lipoproteins and aspartate aminotransferase and alanine aminotransferase were analyzed. Histological changes of the livers were evaluated by electronic microscopy and apoptosis was examined using the TUNEL method. The levels of malondialdehyde, reducedglutathione and antioxidant enzymes(catalase, superoxide dismutase, glutathione peroxidase, glutathione S-transferase) activities were also determined.Results: S. sonchifolius roots significantly decreased energy intake, body weight, fat and liver mass(P < 0.05). S. sonchifolius roots ameliorated liver steatosis and mitochondrial morphology, avoiding cellular apoptosis and normalizing transaminase activity in the liver of rats fed with high fructose. Enzymatic assays revealed that S. sonchifolius roots had a modulatory effect on the oxidative stress induced by fructose-feeding by reducing lipid peroxidation(P < 0.05) and antioxidant enzyme activities(P < 0.05) in liver.Conclusions: S. sonchifolius roots can ameliorate non-alcoholic fatty liver disease by improving oxidative stress and liver injury.

Prolonged high-fat-diet feeding promotes non-alcoholic fatty liver disease and alters gut microbiota in mice

BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has become an epidemic largely due to the worldwide increase in obesity. While lifestyle modifications and pharmacotherapies have been used to alleviate NAFLD, successful treatment options are limited. One of the main barriers to finding safe and effective drugs for long-term use in NAFLD is the fast initiation and progression of disease in the available preclinical models. Therefore, we are in need of preclinical models that (1) mimic the human manifestation of NAFLD and (2) have a longer progression time to allow for the design of superior treatments. AIM To characterize a model of prolonged high-fat diet (HFD) feeding for investigation of the long-term progression of NAFLD. METHODS In this study, we utilized prolonged HFD feeding to examine NAFLD features in C57BL/6 male mice. We fed mice with a HFD (60% fat, 20% protein, and 20% carbohydrate) for 80 wk to promote obesity (Old-HFD group, n = 18). A low-fat diet (LFD)(14% fat, 32% protein, and 54% carbohydrate) was administered for the same duration to age-matched mice (Old-LFD group, n = 15). An additional group of mice was maintained on the LFD (Young-LFD, n = 20) for a shorter duration (6 wk) to distinguish between age-dependent and age-independent effects. Liver, colon, adipose tissue, and feces were collected for histological and molecular assessments.RESULTS Prolonged HFD feeding led to obesity and insulin resistance. Histological analysis in the liver of HFD mice demonstrated steatosis, cell injury, portal and lobular inflammation and fibrosis. In addition, molecular analysis for markers of endoplasmic reticulum stress established that the liver tissue of HFD mice have increased phosphorylated Jnk and CHOP. Lastly, we evaluated the gut microbial composition of Old-LFD and Old-HFD. We observed that prolonged HFD feeding in mice increased the relative abundance of the Firmicutes phylum. At the genus level, we observed a significant increase in the abundance of Adercreutzia, Coprococcus, Dorea, and Ruminococcus and decreased relative abundance of Turicibacter and Anaeroplasma in HFD mice. CONCLUSION Overall, these data suggest that chronic HFD consumption in mice can mimic pathophysiological and some microbial events observed in NAFLD patients.