ascorbic-acid and Fatty-Liver

Non-alcoholic fatty liver disease represents a spectrum of liver diseases, characterized mainly by macrovesicular steatosis in the absence of significant alcohol ingestion. Non-alcoholic fatty liver disease includes both non-alcoholic fatty liver and non-alcoholic steatohepatitis. Non-alcoholic steatohepatitis once considered a benign process is now known to lead to progressive fibrosis and cirrhosis. Histologically indistinguishable from alcoholic liver disease, the exact aetiology of non-alcoholic fatty liver disease remains unknown, but the fundamental pathophysiological process appears to be insulin resistance and oxidative stress related to the metabolic syndrome. Therapy has focused on risk factors, weight reduction and pharmacological intervention. Promising pharmacological treatments have been demonstrated with antioxidants, insulin sensitizers, hepatoprotectants and lipid-lowering agents. However, without larger randomized studies, no pharmacological treatments can be recommended at this time.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Ascorbic Acid; Betaine; Cholagogues and Choleretics; Enzyme Inhibitors; Fatty Liver; Humans; Hypoglycemic Agents; Lipotropic Agents; Metformin; Pentoxifylline; Probucol; Thiazolidinediones; Ursodeoxycholic Acid; Vitamin E

Topics: Acute Disease; Animals; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Bile Acids and Salts; Cholesterol; Cholesterol, Dietary; Chronic Disease; Fatty Liver; Humans; Hypercholesterolemia; Lipid Metabolism; Liver Cirrhosis; Scurvy

Nonalcoholic fatty liver disease (NAFLD) is defined as the spectrum of benign fatty liver to necroinflammation and fibrosis. Its prevalence has been found to be as high as 39%. It is estimated that up to 15% of those affected will go on to have progressive liver disease. Currently, there is no proven therapy for NAFLD. In this study, we aim to determine whether statin therapy may be an effective treatment for NAFLD and identify independent predictors of NAFLD.. In all, 1,005 men and women, aged 50-70 years were randomized to receive either a daily combination of atorvastatin 20 mg, vitamin C 1 g, and vitamin E 1,000 IU vs. matching placebo, as part of the St Francis Heart Study randomized clinical trial. Liver to spleen (LS) ratios were calculated on 455 subjects with available computed tomography scans performed at baseline and follow-up to determine NAFLD prevalence. Baseline and final LS ratios were compared within treatment groups, and results were compared between the treatment and placebo groups using univariate and multivariate analyses. Mean duration of follow-up was 3.6 years.. There were 80 patients with NAFLD at baseline. We identified baseline triglyceride levels (odds ratio (OR)=1.003, P<0.001) and body mass index (OR=0.10, P<0.001) as independent correlates of NAFLD. Treatment with atorvastatin combined with vitamins E and C significantly reduced the odds of NAFLD at the end of follow-up, 70 vs. 34% (OR=0.29, P<0.001).. In conclusion, atorvastatin 20 mg combined with vitamins C and E is effective in reducing the odds of having hepatic steatosis by 71% in healthy individuals with NAFLD at baseline after 4 years of active therapy.

Topics: Administration, Oral; Aged; Analysis of Variance; Antioxidants; Ascorbic Acid; Atorvastatin; California; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Fatty Liver; Female; Follow-Up Studies; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Pyrroles; Risk Assessment; Severity of Illness Index; Tomography, X-Ray Computed; Treatment Outcome; Vitamin D

Nonalcoholic fatty liver disease is associated with the metabolic syndrome. The current standard of care, healthy diet and weight loss, has limited effect. The benefits of pharmacological treatments are unclear due to the difficulty of using liver histology as the main outcome in large randomized controlled trials (RCTs). In this issue, an RCT with atorvastatin and antioxidants (vitamins E+C) vs. placebo shows improvement in liver steatosis based on computed tomography scans. The questions are is this beneficial effect due to the combined treatment or the effect of an individual compound; does this intervention improve nonalcoholic steatohepatitis.

Topics: Antioxidants; Ascorbic Acid; Atorvastatin; Confidence Intervals; Drug Therapy, Combination; Fatty Liver; Female; Follow-Up Studies; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Non-alcoholic Fatty Liver Disease; Odds Ratio; Pyrroles; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Tomography, X-Ray Computed; Treatment Outcome; Vitamin A

No proven treatment exists for nonalcoholic fatty liver disease (NAFLD) in children and adolescents. We sought to determine the efficacy of lifestyle intervention with or without antioxidant therapy in pediatric NAFLD. A total of 53 patients (age 5.7-18.8 years, 37 boys) were included. Lifestyle intervention consisting of a diet tailored to the patient's calorie needs, and increased physical activity was prescribed in all. Patients were concomitantly randomized to alpha-tocopherol 600 IU/day plus ascorbic acid 500 mg/day (n = 25) or placebo (n = 28), and treated for 24 months. The study was an extension of a previous study aimed at evaluating the effect of 12-month lifestyle intervention and antioxidant therapy on serum levels of aminotransferases. The primary end point of the present study was change in liver histology on repeated biopsy at 24 months. Secondary end points were changes in body weight, liver enzymes, and insulin sensitivity indices on 2-hour oral glucose tolerance test. The amount of weight lost at 24 months was similar in the placebo and antioxidant groups (-4.75 [range, -16-4.0] versus -5.5 [range, -12.2-0.4] kg, respectively, P = 0.9). A significant improvement occurred in the grade of steatosis, lobular inflammation, and hepatocyte ballooning, and in the NAFLD activity score in both groups. Levels of aminotransferases, triglycerides, cholesterol, fasting glucose, and insulin, and insulin sensitivity indices improved significantly as well. The improvement in all these parameters was not significantly different between the two groups.. Lifestyle intervention with diet and increased physical activity induces weight loss and is associated with a significant improvement in liver histology and laboratory abnormalities in pediatric NAFLD. Alpha-tocopherol plus ascorbic acid does not seem to increase the efficacy of lifestyle intervention alone.

Topics: Adolescent; alpha-Tocopherol; Antioxidants; Ascorbic Acid; Blood Glucose; Body Weight; Child; Diet, Reducing; Double-Blind Method; Exercise Therapy; Fasting; Fatty Liver; Female; Humans; Insulin; Insulin Resistance; Life Style; Lipids; Liver; Male; Time Factors; Transaminases; Treatment Outcome

Few data are available on the effect of antioxidants in paediatric non-alcoholic fatty liver disease (NAFLD).. To compare the effect of a nutritional programme alone or combined with alpha-tocopherol and ascorbic acid on alanine aminotransferase (ALT) levels, and insulin resistance (IR) in biopsy-proven NAFLD children.. IN a 12-month double-blind placebo study, 90 patients were prescribed a balanced calorie diet (25-30 cal/kg/d), physical exercise, and placebo (group A) or alpha-tocopherol 600 IU/day plus ascorbic acid 500 mg/day (group B). IR was estimated by the homeostasis model assessment (HOMA-IR).. At month 12, ALT (32.67 +/- 8.09 vs. 32.18 +/- 11.39 IU/L; P = NS), HOMA-IR (1.52 +/- 0.66 vs. 1.84 +/- 0.95 IU/L; P = NS), and weight loss (32% vs. 35% of excessive body weight; P = NS) did not differ between the two arms. Among subjects who lost >or=20% of their excessive weight, ALT and body weight percentage changes were significantly related (r(o) = 0.260; P = 0.03). In subjects, who lost more than 1.0 kg, HOMA-IR significantly decreased (2.20 +/- 0.21 to 1.57 +/- 0.13 in group A (P

Topics: Adolescent; Alanine Transaminase; Antioxidants; Ascorbic Acid; Blood Glucose; Child; Child, Preschool; Fatty Liver; Female; Humans; Insulin Resistance; Male; Treatment Outcome; Vitamin E

Despite a proposed role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis, antioxidant approaches have not been investigated sufficiently in the therapy of nonalcoholic steatohepatitis. Our aim was to determine whether vitamin E plus C therapy is effective in normalization of liver enzymes compared to ursodeoxycholic acid treatment in patients with fatty liver disease.. This was an open-labeled, prospective, randomized study enrolling patients with histologically proven fatty liver disease who had chronically elevated alanine aminotransferase, despite a three-month reducing diet. Patients consuming alcohol (more than 20 g/day) were excluded. The patients were randomly prescribed either oral vitamin E (600 IU/day) plus vitamin C (500 mg/day) or ursodeoxycholic acid (10 mg/kg/day). Patients were randomized as two groups to receive vitamin E plus vitamin C combination (28 patients, 10 F) or ursodeoxycholic acid treatment (29 patients, 13 F).. There was no significant change in body mass index before and after the treatment in both groups. At the end of six months of therapy, serum aspartate aminotransferase and aminotransferase levels significantly decreased in both treatment options. Vitamin E and C combination was more efficacious on serum aminotransferase levels than ursodeoxycholic acid, but the difference was not significant. Alanine aminotransferase decreased to normal levels in 17 of 27 (63%) and in 16 of 29 patients (55%), respectively, in the two groups. Gamma-glutamyl transpeptidase decreased in patients receiving ursodeoxycholic acid, but no change was obtained in the vitamin-treated patients.. Vitamin E plus C combination treatment is a safe, inexpensive and effective treatment option in patients with fatty liver disease, with results comparable to those obtained with ursodeoxycholic acid. Since more effective new therapeutic options are lacking, patients with fatty liver disease should be encouraged to take vitamin E and C supplements, which are safe and affordable.

Topics: Administration, Oral; Adult; Alanine Transaminase; Alkaline Phosphatase; Antioxidants; Ascorbic Acid; Aspartate Aminotransferases; Biomarkers; Cholagogues and Choleretics; Drug Therapy, Combination; Fatty Liver; Female; gamma-Glutamyltransferase; Humans; Male; Middle Aged; Oxidative Stress; Prospective Studies; Treatment Outcome; Ultrasonography; Ursodeoxycholic Acid; Vitamin E

Nonalcoholic steatohepatitis (NASH) is a common cause of liver disease. Although usually indolent, this disease can progress to cirrhosis in some patients. There is currently no proven medical therapy for the treatment of NASH. The aim of our study was to evaluate the efficacy of combination alpha-tocopherol (vitamin E) and vitamin C in reducing histologic inflammation and fibrosis.. This was a prospective, double-blind, randomized, placebo-controlled trial with a total enrollment of 49 patients; 45 patients completed the study. All patients were randomized to receive either vitamins E and C (1000 IU and 1000 mg, respectively) or placebo daily for 6 months, based on their initial histologic diagnosis of NASH. Additionally, all patients were given standard weight-loss counseling and encouraged to follow a low fat diet (<30 fat g/day). The pre- and posttreatment liver biopsies were reviewed by a single pathologist, who was blinded to the patient's medication. Biopsies were scored based on a modification of the scoring system published by Brunt et al. (Am J Gastroenterol 1999;94:2467-74). A score of 0-4 was possible for fibrosis, and a score of 0-6 was possible for inflammation and hepatocyte degeneration and necrosis. In addition, body mass index, glycohemoglobin, lipids, and liver enzymes were followed throughout the study.. Forty-five patients completed 6 months of therapy without significant side effects. Vitamin treatment resulted in a statistically significant improvement in fibrosis score (p=0.002). No changes were noted in inflammation with treatment. Vitamin E and vitamin C, in the doses used in this study, were well tolerated and were effective in improving fibrosis scores in NASH patients. No improvement in necroinflammatory activity or ALT was seen with this combination of drug therapy. A larger, multicenter, longer-term trial with vitamin E and vitamin C seems to be warranted.

Topics: Analysis of Variance; Antioxidants; Ascorbic Acid; Biopsy, Needle; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Fatty Liver; Female; Follow-Up Studies; Humans; Liver Cirrhosis; Male; Middle Aged; Probability; Prospective Studies; Reference Values; Severity of Illness Index; Treatment Outcome; Vitamin E

DNA methylation contributes to obesity, but the role of the DNA demethylase ten-eleven translocation protein 1 (Tet1) in obesity remains unclear. Vitamin C is a cofactor for the Tet family of proteins, but whether vitamin C can be used to treat obesity via Tet1 awaits clarification.. Tet1. The results reveal a novel function of Tet1 in obesity and provide a new mechanism for the beneficial role of vitamin C in metabolic diseases through enhanced Tet1 activity.

Topics: Adipogenesis; Adipose Tissue, White; Animals; Ascorbic Acid; Diet, High-Fat; DNA Methylation; DNA-Binding Proteins; Fatty Liver; Haploinsufficiency; Hepatocytes; Lipolysis; Liver; Mice; Mice, Inbred C57BL; Obesity; Proto-Oncogene Proteins

The consumption of fruits is strongly associated with better health and higher bacterial diversity in the gut microbiota (GM). Camu camu (. By using metabolic tests coupled with 16S rRNA gene-based taxonomic profiling and faecal microbial transplantation (FMT), we have assessed the effect of a crude extract of camu camu (CC) on obesity and associated immunometabolic disorders in high fat/high sucrose (HFHS)-fed mice.. Treatment of HFHS-fed mice with CC prevented weight gain, lowered fat accumulation and blunted metabolic inflammation and endotoxaemia. CC-treated mice displayed improved glucose tolerance and insulin sensitivity and were also fully protected against hepatic steatosis. These effects were linked to increased energy expenditure and upregulation of uncoupling protein 1 mRNA expression in the brown adipose tissue (BAT) of CC-treated mice, which strongly correlated with the mRNA expression of the membrane bile acid (BA) receptor TGR5. Moreover, CC-treated mice showed altered plasma BA pool size and composition and drastic changes in the GM (eg, bloom of. Our results show that CC prevents visceral and liver fat deposition through BAT activation and increased energy expenditure, a mechanism that is dependent on the GM and linked to major changes in the BA pool size and composition.

Topics: Animals; Ascorbic Acid; Blood Glucose; Endotoxemia; Energy Metabolism; Fatty Liver; Fecal Microbiota Transplantation; Fruit; Gastrointestinal Microbiome; Homeostasis; Male; Mice, Inbred C57BL; Mice, Obese; Obesity; Panniculitis; Plant Extracts

Aldehyde reductase (Akr1a) has been reported to be involved in the biosynthesis of ascorbic acid (AsA) in the mouse liver. Because Akr1a is expressed at high levels in the liver, we aimed to investigate the role of Akr1a in liver homeostasis by employing a carbon tetrachloride (CCl4)-induced hepatotoxicity model. Akr1a-deficient (Akr1a(-/-)) and wild-type (WT) mice were injected intraperitoneally with CCl4 and the extent of hepatic injury in the acute phase was assessed. Liver damage was heavier in the Akr1a(-/-) mice than in the WT mice. Furthermore, severe hepatic steatosis was observed in the livers of Akr1a(-/-) mice compared to WT mice and was restored to the levels in WT mice by AsA supplementation. Since the presence or absence of AsA had no effect on the decrease in CYP2E1 activity after the CCl4 treatment, it appears that AsA plays a role in the process after the bioactivation of CCl4. Biomarkers for oxidative stress and ER stress were markedly increased in the livers of Akr1a(-/-) mice and were effectively suppressed by AsA supplementation. Based on these collective results, we conclude that Akr1a exerts a protective effect against CCl4-induced hepatic steatosis by replenishing AsA via its antioxidative properties.

Topics: Aldehyde Reductase; Animals; Antioxidants; Ascorbic Acid; Biomarkers; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2E1; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Fatty Liver; Gene Expression; Glutathione; Heat-Shock Proteins; Lipid Peroxidation; Liver; Mice; Mice, Knockout; Oxidative Stress; Perilipin-2; Peroxiredoxins

Owing to its ability to inactivate harmful radicals, vitamin C plays a key role in antioxidant defense. The bioavailability of this vitamin depends upon the nutritional intake and its uptake by cells, mainly through the sodium-dependent transporters SVCT1/Svct1 and SVCT2/Svct2 (human/rat). Here, we investigated the effect of liver metabolic/oxidative stress on the expression of these transporters in extrahepatic tissues.. In Zucker rats, used here as a model of liver steatosis, Svct1-2 mRNA levels were similar in obese and lean animals, except for lung tissue, where Svct2 was up-regulated. Diabetes mellitus, developed by streptozotocin administration, was accompanied by a down-regulation of Svct1 in liver and kidney, together with a down-regulation of Svct2 in kidney and brain. Complete obstructive cholestasis due to bile duct ligation for 1 week induced a significant down-regulation of both Svct1 and Svct2 in ileum, whereas Svct2 was up-regulated in liver, and no significant changes in the expression of either transporter were found in kidney, brain or lung. In rat hepatoma Can-10 cells, bile acids, but not the FXR agonist GW4064, induced an up-regulation of Svct1 and Svct2. In human hepatoma Alexander cells transfected with FXR/RXRα/OATP1B1, neither GW4064 nor unconjugated or glycine-/taurine-conjugated major bile acids were able to up-regulate either SVCT1 or SVCT2.. Pathological circumstances characterized by the presence of metabolic/oxidative stress in the liver induce different responses in the expression of ascorbic acid transporters in intrahepatic and extrahepatic tissues, which may affect the overall bioavailability and cellular uptake of this vitamin.

Topics: Animals; Ascorbic Acid; Bile Acids and Salts; Biological Availability; Carcinoma, Hepatocellular; Cell Line, Tumor; Cholestasis; Diabetes Mellitus, Experimental; Disease Models, Animal; Fatty Liver; Gene Expression; Humans; Kidney; Liver; Liver Neoplasms; Male; Obesity; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Zucker; RNA, Messenger; Sodium-Coupled Vitamin C Transporters; Stress, Physiological

Nonalcoholic steatohepatitis (NASH), a progressive stage of nonalcoholic fatty liver disease (NAFLD), is characterized by steatosis with inflammation. Investigations have suggested that oxidative stress may play an important role in the progress of NAFLD to NASH. To provide further insights into beneficial effects of antioxidants in NASH prevention, we employed two manganese-superoxide dismutase/catalase mimetics, manganese N,N`-bis(salicyldene) ethylene diamine chloride (EUK-8) and manganese-3-methoxy N,N`-bis(salicyldene)ethylenediamine chloride (EUK-134), as two salen representatives and vitamin C as the standard antioxidant.. Experimental NASH was induced in Male N-Mary rats by feeding a methionine/choline-deficient (MCD) diet to rats for 10 weeks. The rats (n = 5, 30 mg/kg/day) were randomly assigned to receive vitamin C, EUK-8, EUK-134 or vehicle orally.. Administration of salens together with the MCD diet reduced the serum aminotransferases, glutathione transferase and alkaline phosphatase, cholesterol, and LDL contents. In addition, the EUK-8 and EUK-134 improved NASH pathological features in liver of MCD-fed rats.. EUK-8 and EUK-134 supplementation reduces NASH-induced abnormalities, pointing out that antioxidant strategy could be beneficial for prevention of NASH.

Topics: Animals; Antioxidants; Ascorbic Acid; Chelating Agents; Choline; Diet; Ethylenediamines; Fatty Liver; Inflammation; Liver; Male; Manganese Compounds; Methionine; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Rats

Poor diet and a sedentary lifestyle can contribute to nonalcoholic fatty liver disease (NAFLD).. Our aim was to compare diet and physical activity of patients with NAFLD and healthy controls with current recommendations.. This was a cross-sectional study.. Seventy-four patients with biopsy-proven NAFLD (33 simple steatosis and 41 steatohepatitis [NASH]) and 27 healthy controls participated between 2003 and 2011.. Food records and activity logs were completed for 7 days. Results were compared with Dietary Reference Intakes and Canadian Physical Activity Guidelines. Plasma vitamin C was measured to assess food record accuracy.. Intake/activity for each participant was compared with the recommendations and proportion of subjects not meeting the requirements was calculated. Groups were compared by Kruskal-Wallis and Mann-Whitney U test or z-test with Bonferroni adjustment.. More patients with NASH (58.5%) were obese compared with patients with simple steatosis (24.2%) and healthy controls (7.4%; P<0.01). Patients with NAFLD showed more insulin resistance than healthy controls. The reported energy intake was below estimated requirements in all groups (P≤0.001). The proportion of subjects from each group exceeding acceptable energy intake from fat was as follows: simple steatosis: 27.3%; NASH: 46.3%; healthy controls: 63.0% (simple steatosis vs health controls; P<0.05) and from saturated fat: simple steatosis: 42.4%; NASH: 70.7%; healthy controls: 63.0% (simple steatosis vs. NASH; P<0.05). In each group, >80% of subjects did not consume enough linoleic or linolenic acid, vitamin D, and vitamin E, and >60% exceeded the upper intake level for sodium. Only 53.1% of patients with simple steatosis and 53.8% of patients with NASH, but 84.6% of healthy controls, met recommendations for physical activity (P=0.020). Plasma vitamin C was normal, similar among groups, and correlated with vitamin C intakes.. All participants followed a similar Western diet with high fat and sodium intakes and suboptimal micronutrient intakes. However, physical activity was lower in NAFLD compared with healthy controls and was associated with higher body mass index and insulin resistance.

Topics: Adult; Aged; Ascorbic Acid; Body Mass Index; Canada; Case-Control Studies; Cross-Sectional Studies; Diet Records; Dietary Fats; Energy Intake; Fatty Liver; Female; Guidelines as Topic; Healthy Volunteers; Humans; Insulin Resistance; Male; Middle Aged; Motor Activity; Non-alcoholic Fatty Liver Disease; Nutrition Assessment; Prospective Studies; Sodium, Dietary; Vitamin D; Vitamin E; Young Adult

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children in the United States. Although changes in diet are often recommended to improve NAFLD, little is known regarding the influence of diet on histologic features of the disease.. This was a prospective, cross-sectional registry-based study. Children (n = 149) enrolled in the multicenter nonalcoholic steatohepatitis (NASH) Clinical Research Network had demographic, anthropometric, clinical, laboratory, and histology data obtained, including the Block Brief Food Questionnaire. Subjects were grouped by presence or absence of steatohepatitis and grades of histologic features according to NASH Clinical Research Network criteria.. No significant differences were found between children with steatosis compared with steatohepatitis for fraction of energy from fat, carbohydrates, and protein. Sugar-sweetened beverage consumption was low and did not correlate with histologic features, although uric acid, a surrogate marker for fructose intake, was significantly increased in those with definite NASH (P = 0.008). For all groups, vitamin E consumption was insufficient compared with the recommended daily allowance. Median consumption of vitamin E was lower in children with higher grade of steatosis (8.4 vs 6.1 vs 6.9 for grades I, II, and III, respectively, P = 0.05). Those consuming less vitamin C had increased ballooning degeneration (P = 0.05).. Children with NAFLD have a diet that is insufficient in vitamin E and this may contribute to the pathophysiology of NAFLD. In children with NAFLD, reported sugar-sweetened beverage consumption is low; however, uric acid, which may reflect total fructose consumption, was significantly associated with NASH and should be further evaluated.

Topics: Adolescent; Ascorbic Acid; Child; Cross-Sectional Studies; Diet; Dietary Sucrose; Energy Intake; Fatty Liver; Female; Fructose; Humans; Liver; Male; Non-alcoholic Fatty Liver Disease; Nutrition Assessment; Prospective Studies; Surveys and Questionnaires; Uric Acid; Vitamin E; Vitamin E Deficiency; Vitamins

Nonalcoholic steatohepatitis (NASH), a progressive stage of nonalcoholic fatty liver disease (NAFLD), is characterized by steatosis (accumulation of triacylglycerols within hepatocytes) along with inflammation and ballooning degeneration. It has been suggested that oxidative stress may play an important role in the progress of NAFLD to NASH. The aim of present study was to determine whether antioxidant supplementations using EUK-8, EUK-134 and vitamin C could improve the biochemical and histological abnormalities associated with diet-induced NASH in rats.. NASH was induced in male N-Mary rats by feeding a methionine - choline deficient (MCD) diet. The rats were fed either normal chow or MCD diet for 10 weeks. After NASH development, the MCD-fed rats were randomly divided into four groups of six: the NASH group that received MCD diet, the EUK-8 group which was fed MCD diet plus EUK-8, the EUK-134 group which was fed MCD diet plus EUK-134 and the vitamin C group which received MCD diet plus vitamin C. EUK-8, EUK-134 and vitamin C (30 mg/kg body weight/day) were administered by gavage for eight weeks.. Treatment of MCD-fed rats with salens reduced the sera aminotransferases, cholesterol, low density lipoprotein contents, the extent of lipid peroxidation and protein carbonylation whereas the HDL-C cholesterol levels were significantly increased. In addition, EUK-8 and EUK-134 improved steatosis, ballooning degeneration and inflammation in liver of MCD-fed rats.. Antioxidant (EUK-8, EUK-134 and vitamin C) supplementation reduces NASH-induced biochemical and histological abnormalities, pointing out that antioxidant strategy could be beneficial in treatment of NASH.

Topics: Animals; Ascorbic Acid; Choline Deficiency; Diet; Disease Models, Animal; Ethylenediamines; Fatty Liver; Humans; Lipid Peroxidation; Methionine; Organometallic Compounds; Oxidative Stress; Rats; Salicylates

Alcoholic liver disease is caused mainly by free radicals. Ascorbic acid (AA) and glutathione (GSH) are the major water-soluble antioxidants in the liver. The impact of AA supplementation on GSH, AA and activities of GSH-dependent enzymes in alcoholic guinea pigs was studied and was compared with alcohol abstention. Guinea pigs were administered ethanol at a dose of 4 g/kg body weight (b.wt)/day for 90 days. After 90 days, alcohol administration was stopped and one-half of the ethanol-treated animals were supplemented with AA (25 mg/100 g b.wt) for 30 days and the other half was maintained as the abstention group. There was a significant increase in the activities of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase in the serum of the ethanol group. In addition, a significant decrease in the GSH content, activities of GSH peroxidase, GSH reductase, and increased activity of GSH-S-transferase were observed in the liver of the ethanol group. Histopathological analysis and triglycerides content in the liver of the ethanol group showed induction of steatosis. But AA supplementation and abstention altered the changes caused by ethanol. However, maximum protective effect was observed in the AA-supplemented group indicating the ameliorative effect of AA in the liver.

Topics: Alanine Transaminase; Animals; Ascorbic Acid; Aspartate Aminotransferases; Dietary Supplements; Fatty Liver; gamma-Glutamyltransferase; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Guinea Pigs; Liver; Liver Diseases, Alcoholic; Male

The cytokines, adipokines, and oxidative stress have been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD); however, such data remain scarce in India. The present study evaluated pro-inflammatory cytokines, adipokines, and markers of oxidative stress in patients with non-alcoholic fatty liver disease (NAFLD), and their association with degree of adiposity, insulin resistance and markers of disease severity.. The present prospective cross-sectional pilot study included 79 subjects; 34 NAFLD, 22 chronic hepatitis B (CH-B) and 23 healthy controls (HC). The parameters studied were adiponectin, leptin, tumour necrosis factor α (TNFα), interleukin-1 and 6 (IL-1, IL-6), and systemic markers of oxidative stress.. The mean body mass index (kg/m 2 ) in NAFLD patients, CHB, and HC were 26.4±3.7, 21.3±2.3, and 22.3±2.7, respectively. The median serum levels of all pro-inflammatory cytokines were significantly higher (P<0.001) in NAFLD compared to control groups. Compared to HC, levels of adiponectin and leptin were significantly (P<0.05, P<0.01) reduced in both NAFLD and CHB. IL-6 showed marked and selective increase only in NAFLD patients. The levels of IL-6 were significantly (P<0.02) higher in NAFLD patients with advanced histology grade and correlated with IR (r=0.42, P=0.02). In a sub-group, markers of oxidative stress were significantly higher, and that of antioxidant potential were significantly lower among NAFLD patients compared to control subjects.. Patients with NAFLD revealed significantly elevated levels of pro-inflammatory cytokines, increased oxidative stress, and a significant association of IL-6 with IR and advanced histopathology.

Topics: Adipokines; Adult; Ascorbic Acid; Cytokines; Fatty Liver; Female; Hepatitis B, Chronic; Humans; India; Inflammation; Insulin; Insulin Resistance; Lipid Peroxidation; Liver; Male; Malondialdehyde; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Statistics as Topic; Superoxide Dismutase

The high fructose-fed rat is widely used as a model of insulin resistance. Genistein, a soy isoflavone, has been shown to improve insulin sensitivity in this model. The present study investigated whether genistein could prevent fatty liver disease in this model.. Male Wistar rats were fed a diet containing starch (control) or 60% fructose (insulin-resistant model). Fifteen days later, rats in each dietary group were divided into two groups and were treated with either genistein (1 mg/kg per day) in dimethylsulfoxide (DMSO) or 30% DMSO alone. After 60 days, markers of liver injury, oxidative stress, interleukin (IL)-6, tumor necrosis factor (TNF)-α, lipids, lipoprotein profile, nitrite, and nitrosothiol in the plasma and liver were quantified. Liver sections were examined for 3-nitrotyrosine (3-NT) expression and pathological lesions.. Fructose-fed rats displayed hyperlipidemia, significant changes in plasma lipoprotein profile, and increases in IL-6 and TNF-α levels compared with control. In addition, the accumulation of lipids, liver injury, a decline in liver function, inactivation of the glyoxalase system, depletion of antioxidants, and increased 3-NT expression were observed in the fructose-fed group. Administration of genistein to fructose-fed rats significantly reduced these biochemical and histological abnormalities.. Genistein activates the antioxidant profile, decreases IL-6 and TNF-α concentrations, prevents oxidative damage, and ameliorates fatty liver in insulin-resistant rats.

Topics: Animals; Ascorbic Acid; Body Weight; Cholesterol; Fatty Liver; Genistein; Glutathione Peroxidase; Glutathione Reductase; Insulin; Insulin Resistance; Interleukin-6; Liver; Liver Function Tests; Male; Non-alcoholic Fatty Liver Disease; Organ Size; Phospholipids; Phytoestrogens; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Vitamin E

Nonalcoholic steatohepatitis (NASH) is a common and potentially severe form of liver disease. This study aimed to determine the effect of ursodeoxycholic acid and its NO-releasing derivative NCX-1000 alone or in combination with antioxidants on cultured mouse hepatocytes treated with amiodarone to mimic certain aspects of hepatocyte injury found in NASH. Isolated mouse hepatocytes were incubated with ursodeoxycholic acid or NCX-1000 (0-100 micromol/L) combined or not combined with the hydrophilic antioxidants butylated hydroxytoluene and ascorbic acid (0-100 micromol/L) or with the lipophilic antioxidant alpha-tocopherol (0-100 micromol/L) 15 min before adding amiodarone (50 micromol/L) to the culture medium. Twenty hours later, necrosis, apoptosis, superoxide anion production, and malondialdehyde levels were assessed in cultured cells. Amiodarone led to a dose-dependent decrease in cell viability with an LD50 of 50 micromol/L and increased production of superoxide anion and lipid peroxidation. NCX-1000 showed a better protective potential than ursodeoxycholic acid against the toxic effects of amiodarone. The hydrophilic antioxidants had no effect on the toxicity of amiodarone, whereas alpha-tocopherol at a concentration >100 micromol/L almost completely suppressed it. Ursodeoxycholic acid and NCX-1000 protection was additive only when they were combined with alpha-tocopherol, not with butylated hydroxytoluene or ascorbic acid. In addition, all the antioxidants tested reduced the superoxide anion detected, but only alpha-tocopherol prevented lipid peroxidation induced by amiodarone. The combination of lipophilic antioxidants with ursodeoxycholic acid or NCX-1000 enhances their protective potential and could represent an interesting therapeutic approach to explore for the treatment of NASH.

Topics: Amiodarone; Animals; Antioxidants; Ascorbic Acid; Butylated Hydroxytoluene; Cells, Cultured; Dose-Response Relationship, Drug; Fatty Liver; Hepatocytes; Male; Malondialdehyde; Mice; Mice, Inbred BALB C; Nitrates; Protective Agents; Superoxides; Ursodeoxycholic Acid

Topics: Ascorbic Acid; Biopsy; Fatty Liver; Hepatitis; Humans; Liver; Transaminases; Ursodeoxycholic Acid; Vitamin E

Topics: Analysis of Variance; Antioxidants; Ascorbic Acid; Biopsy, Needle; Dietary Supplements; Fatty Liver; Female; Humans; Liver Cirrhosis; Male; Probability; Randomized Controlled Trials as Topic; Reference Values; Risk Assessment; Severity of Illness Index; Treatment Outcome; Vitamin E

Oxidative stress is thought to play a role in liver injury. Hepatic iron may promote liver injury, whereas antioxidant vitamins and minerals may inhibit it, but few clinical studies have examined such relationships. We analyzed the associations of serum iron measures and antioxidant concentrations with abnormal serum alanine transaminase (ALT) activity in a large, national, population-based study.. A total of 13,605 adult participants in the third U.S. National Health and Nutrition Examination Survey (NHANES III), 1988-1994, underwent phlebotomy. Exclusions included excessive alcohol consumption, hepatitis B and C, and iron overload.. Elevated ALT levels were found in 3.1% of the population. In univariate analysis, factors associated with abnormal ALT levels (P < 0.05) included higher transferrin saturation and iron and selenium concentrations, and lower vitamin C, alpha and beta carotene, and lutein/zeaxanthin concentrations. In multivariate logistic regression analyses, elevated ALT level was associated positively with increasing deciles of transferrin saturation (odds ratio [OR] per decile, 1.10; 95% confidence interval [CI], 1.03-1.18) and iron concentration (OR, 1.13; 95% CI, 1.06-1.21). Abnormal ALT level was associated negatively with increasing deciles of alpha carotene (OR, 0.82; 95% CI, 0.72-0.94), beta carotene (OR, 0.91; 95% CI, 0.86-0.96), beta cryptoxanthin (OR, 0.91; 95% CI, 0.84-0.99), lutein/zeaxanthin (OR, 0.90; 95% CI, 0.84-0.96), and a variable combining the 5 carotenoid measures (OR, 0.89; 95% CI, 0.83-0.95). Vitamin C was associated inversely, but only at the highest concentrations.. In this large, national, population-based study, the risk for apparent liver injury was associated with increased iron and decreased antioxidants, particularly carotenoids.

Topics: Alanine Transaminase; Antioxidants; Ascorbic Acid; Carotenoids; Fatty Liver; Humans; Iron; Liver; United States; Vitamin E

Topics: Antioxidants; Ascorbic Acid; Fatty Liver; Female; Hepatitis; Humans; Male; Prognosis; Risk Assessment; Treatment Outcome; Vitamin E

Fatty livers in humans and rats are less tolerant of ischemia, endotoxin, and alcohol. We hypothesized that fatty livers of obese (Ob) Zucker rats are oxidatively stressed and oxidative stress could be relieved by antioxidant treatment, leading to improved tolerance to ischemia. Total glutathione (GSH), tocopherol (TOC), ascorbic acid (AA), catalase (CAT), superoxide dismutase (SOD), and selenium-glutathione peroxidase (Se-GPx) were measured in the livers of Ob and lean (Ln) Zucker rats before and after treatment with high-dose TOC and ascorbate. Also, survival in treated Ob rats following a lethal 90 minutes of partial in vivo warm ischemia was examined. Fatty livers of Ob rats contained significantly less GSH, TOC, and CAT, in comparison with livers of Ln rats. Immunoblotting showed significantly decreased CAT protein without changes in mRNA in fatty livers. There were no significant differences in AA, SOD, and Se-GPx between the 2 groups. Pretreatment with TOC and ascorbate over 48 hours completely corrected the decreases in GSH, TOC, and CAT. Most importantly, TOC with or without ascorbate pretreatment significantly improved survival in Ob rats following ischemia in a dose-dependent manner. In conclusion, TOC administration corrected the oxidative stress in fatty livers of Ob Zucker rats and improved survival following lethal ischemia. Additional studies are needed to determine the efficacy of TOC-a relatively inexpensive agent-in treating patients with fatty livers in a variety of clinical conditions, possibly including liver transplantation.

Topics: Animals; Antioxidants; Ascorbic Acid; Catalase; Fatty Liver; Glutathione; Glutathione Peroxidase; Hot Temperature; Ischemia; Liver; Male; Obesity; Oxidative Stress; Rats; Rats, Zucker; Superoxide Dismutase; Vitamin E

Although fatty liver (FL) is considered an innocuous condition, the frequent incidence of graft failure when FL are transplanted has renewed interest in the intracellular disorders causative of or consequent to fatty degeneration. Oxidative stress and nutritional status modulate the tolerance to reperfusion injury in control livers (CL), but very little is known in the case of FL. This study was designed to compare the oxidative balance in CL and FL from fed and food-deprived rats. Serum and liver samples were collected from fed and starved (18 h) rats with CL or FL induced by a choline-deficient diet. Hepatic injury was assessed by transaminase activities and histology. The hepatic concentrations of glutathione (GSH), vitamin C, alpha-tocopherol, thiobarbituric acid-reactive substances (TBARS) and protein carbonyls (PC) were measured. Fed rats with FL had significantly greater TBARS and lower alpha-tocopherol and vitamin C levels than those with CL, whereas GSH and PC concentrations were not affected. Starvation impaired the oxidative balance in both groups. However, compared with the other groups, FL from food-deprived rats generally had the lowest hepatic concentrations of alpha-tocopherol, vitamin C and GSH. Unlike in CL, protein oxidation occurred in FL. These data indicate that fatty liver induced by consumption of a choline-deficient diet is associated with a lower level of antioxidants, which results in lipid peroxidation. Starvation further affects these alterations and extends the damage to proteins. In conclusion, steatosis and starvation may act synergistically on the depletion of antioxidants, predisposing fatty livers to a reduced tolerance to oxidative injury.

Topics: Animals; Antioxidants; Ascorbic Acid; Choline Deficiency; Diet; Fatty Liver; Glutathione; Lipid Metabolism; Lipid Peroxidation; Male; Oxidative Stress; Rats; Rats, Wistar; Starvation; Thiobarbituric Acid Reactive Substances; Transaminases

1. Single comb White Leghorn hens of an inbred line highly susceptible to fatty liver haemorrhagic syndrome (FLHS) were fed supplemented dietary ascorbic acid (200 mg/kg), alpha-tocopherol (75 mg/kg), or L-cysteine (3 g/kg, and 6 g/kg) for 28 d in order to evaluate the potential therapeutic effect of these compounds against the disease. 2. Supplementation of ascorbic acid, alpha-tocopherol, or a low level of L-cysteine (3 g/kg) did not significantly affect any of the hepatic variables evaluated. Hepatic glutathione was not increased by the supplementation of dietary L-cysteine. 3. L-cysteine supplemented at a level of 6 g/kg decreased hepatic dry matter and fat contents without affecting the hepatic malondialdehyde or the liver haemorrhagic score. 4. Because one of the predisposing factors of FLHS is a high hepatic fat content it was concluded that dietary supplementation of L-cysteine (6 g/kg) may be useful in the prevention of the disease.

Topics: Animals; Antioxidants; Ascorbic Acid; Chickens; Cysteine; Fatty Liver; Female; Food, Fortified; Glutathione; Hemorrhage; Liver; Oviposition; Poultry Diseases; Syndrome; Vitamin E

To investigate molecular responses to lipid peroxidative stimuli in neoplastic cells, lipid peroxidation was induced in liver of rats bearing 3'-methyl-4-dimethylaminoazobenzene-induced hepatocellular carcinoma by injecting a high dose of carbon tetrachloride (CCl4), a strong lipoperoxidative reagent. Normal rat livers with or without CCl4 treatment served as controls. CCl4 administration markedly provoked fatty metamorphosis, visualized by oil red O staining, in normal livers while minimal fatty changes were seen in hepatocellular carcinomas, where necrosis was often observed instead. After CCl4 treatment, the thiobarbituric acid values (representing levels of lipid peroxides in the tissue) were increased two-fold in the untreated normal liver, but were unchanged in the cancer tissue. Levels of vitamin C, an acutely reactive antioxidant, measured by high-performance liquid chromatography were not influenced by the CCl4 injection in the cancer tissue whereas a significant decrease was evident in normal livers. The total fatty acid content, measured by gas chromatography, was significantly lower in the cancer tissue than in the normal liver while the ratio of polyunsaturated fatty acids (PUFAs) in total fatty acids was little changed. Resistance of hepatocellular cancer cells to fatty metamorphosis and their susceptibility to necrosis induced by free radicals may be due to the paucity of the target PUFAs in their cell membrane fraction, resulting in low levels of lipid peroxides. Peroxidation of PUFAs might act as a "shock absorber" against free radical-induced toxic cell death in normal cells.

Topics: Animals; Ascorbic Acid; Azo Compounds; Carbon Tetrachloride; Fatty Acids; Fatty Liver; Lipid Peroxidation; Liver; Liver Neoplasms, Experimental; Male; Methyldimethylaminoazobenzene; Necrosis; Rats; Thiobarbiturates

Effects of L-ascorbate 2-sulfate (AAS) on fatty liver and hyperlipidemia induced by various treatments were studied in rats and guinea pigs. L-Ascorbic acid (AA) (50 or 175 mg/kg), a reference compound, lowered the lipid levels in the serum and/or liver in guinea pigs, while AA had little effect in rats. On the other hand, AAS (300 mg/kg) was effective in both animals. In rats, AAS lowered cholesterol and triglycerides in the serum from ethionine-treated animals and in the liver from orotic acid-supplemented animals. In guinea pigs, this compound lowered cholesterol and triglycerides in the serum from ethionine-treated animals, lipids in the liver from cholesterol-supplemented animals, and lipids in the serum and liver from scorbutic animals. AA markedly increased the content of AA in the organs in all experiments, while AAS had a slight effect. Thus, it is suggested that AAS exerts its hypolipidemic and lipotropic effects by the specific actions of AAS.

Topics: Animals; Ascorbic Acid; Cholesterol; Ethionine; Fatty Liver; Female; Guinea Pigs; Hyperlipidemias; Lipids; Male; Orotic Acid; Rats; Scurvy; Sulfuric Acids; Triglycerides

Topics: Alcohols; Animals; Ascorbic Acid; Cholelithiasis; Cholesterol; Cholesterol, Dietary; Cholic Acids; Fatty Liver; Female; Guanidines; Male; Mice; Neomycin; Pectins; Phosphatidylcholines; Sulfonamides

Topics: Alcoholic Intoxication; Alkenes; Animals; Antioxidants; Ascorbic Acid; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Diet; Ethanol; Fatty Liver; Humans; Lipid Metabolism; Lipids; Liver; Neurologic Manifestations; Pyrazoles; Rats; Triglycerides; Vitamin E; Vitamin E Deficiency

Topics: Animals; Ascorbic Acid; Cobalt; Copper; Cysteine; Dactinomycin; Deferoxamine; Dinitrophenols; Edetic Acid; Fatty Liver; Fluorides; Fructose; Glucose; Glutathione; Hemochromatosis; Inflammation; Iodoacetates; Iron; Lipotropic Agents; Liver Cirrhosis; Lung; Macrophages; Microscopy, Electron; Potassium Permanganate; Protein Biosynthesis; Puromycin; Rabbits; RNA; Saponins; Sucrose; Surface-Active Agents; Transferrin; Trypsin

Oral administration of vitamin A (30,000 IU daily for 2 days) to young rats caused a marked increase in hepatic glycogen, cholesterol, and glycerides, while hepatic phospholipid content remained almost unaltered. In an examination of the pathogenesis of the lipid accumulation, it was found that more glucose-(14)C was incorporated into liver lipids in vitamin A-fed rats, whereas incorporation of glucose-(14)C and dl-glycine-(14)C into liver protein remained unaltered. The increase in glucose-(14)C incorporation was confined to the glyceride-glycerol portion of the lipids; incorporation into liver fatty acids was inhibited. Plasma free fatty acid concentrations were elevated. It is postulated that in the vitamin A-fed rats, increased accumulation of lipids in the liver is caused by a stimulation of fatty acid mobilization from adipose tissue and enhanced formation of glycerophosphate through glycolysis, with consequent increase in the glyceride synthesis in the liver. The weight of the adrenals was increased, whereas cholesterol concentration in the gland was decreased, after administration of vitamin A to rats. This indicates adrenocortical stimulation. Interestingly enough, vitamin A feeding did not affect either the level of liver lipids or of plasma FFA in adrenalectomized rats.

Topics: Adrenal Glands; Adrenalectomy; Animals; Ascorbic Acid; Carbon Isotopes; Cholesterol; Depression, Chemical; DNA; Fatty Acids, Nonesterified; Fatty Liver; Glucose; Glycerides; Glycine; Lipids; Liver; Liver Glycogen; Male; Organ Size; Protein Biosynthesis; Rats; Stimulation, Chemical; Vitamin A

Topics: Animals; Ascorbic Acid; Cholesterol; Fatty Liver; Rats