ascorbic-acid and Non-alcoholic-Fatty-Liver-Disease

Obesity and the subsequent reprogramming of the white adipose tissue are linked to human disease-complexes including metabolic syndrome and concurrent non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The dietary imposed dyslipidemia promotes redox imbalance by the generation of excess levels of reactive oxygen species and induces adipocyte dysfunction and reprogramming, leading to a low grade systemic inflammation and ectopic lipid deposition, e.g., in the liver, hereby promoting a vicious circle in which dietary factors initiate a metabolic change that further exacerbates the negative consequences of an adverse life-style. Large epidemiological studies and findings from controlled in vivo animal studies have provided evidence supporting an association between poor vitamin C (VitC) status and propagation of life-style associated diseases. In addition, overweight per se has been shown to result in reduced plasma VitC, and the distribution of body fat in obesity has been shown to have an inverse relationship with VitC plasma levels. Recently, a number of epidemiological studies have indicated a VitC intake below the recommended daily allowance (RDA) in NAFLD-patients, suggesting an association between dietary habits, disease and VitC deficiency. In the general population, VitC deficiency (defined as a plasma concentration below 23 μM) affects around 10% of adults, however, this prevalence is increased by an adverse life-style, deficiency potentially playing a broader role in disease progression in specific subgroups. This review discusses the currently available data from human surveys and experimental models in search of a putative role of VitC deficiency in the development of NAFLD and NASH.

Topics: Adiposity; Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Biomarkers; Comorbidity; Humans; Inflammation; Life Style; Non-alcoholic Fatty Liver Disease; Nutritional Status; Obesity; Prevalence; Prognosis; Risk Assessment; Risk Factors

Nonalcoholic steatohepatitis (NASH) is a frequent liver disease that can progress to cirrhosis and for which effective therapy is still lacking. Despitean important role of oxidative stress in the pathogenesis of NASH, antioxidant approaches have not been investigatedsufficiently. The aim of the study was to compare the efficacy of ursodeoxycholic acid (UDCA) versus vitamin E plus vitamin C in non-diabetic patients with nonalcoholic steatohepatitis. Patients with elevated aminotransferase levels and drinking, less than 40 g alcohol/week with NASH diagnose were randomly assigned to receive either UDCA 15 mg/per kg/day (group A) or vitamin E 800mg/day plus vitamin C 500 mg/day (group B) for 12 months and control group,which did not receive any medical treatment. Lifestyle modification was advised to all groups. The primary study endpoint was improvement in alanine transaminase (ALT) levels, secondary endpoints were improvement in steatosis score and improvement in fibrosis score. Baseline characteristics were not significantly different between groups. After 12 months treatment with vitamin E plus C, as compared with UDCA, was associated with a significant reduction ofmean alanineaminotransferase (ALT) levels. Similarly, there was significant reduction of both mean steatosis score and fibrosis score. Vitamin E plus C combination is aneffective, safe and inexpensive treatmentoption in patients with NASHand may be useful to reduce damage from oxidative stress and slow the process leading to cirrhosis.

Topics: Antioxidants; Ascorbic Acid; Humans; Non-alcoholic Fatty Liver Disease; Treatment Outcome; Ursodeoxycholic Acid; Vitamin E

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

The association between vitamin C and the risk of developing non-alcoholic fatty liver disease remains controversial. The aim of the present study is to examine any correlation between serum vitamin C and the risk of non-alcoholic fatty liver disease.. Our study enrolled 3374 participants aged ≥ 20 years from the National Health and Nutritional Survey (2003-2006). Nonalcoholic fatty liver disease was defined as the US Fatty Liver Index ≥ 30 in the absence of other chronic liver disease. Multivariate logistic regression and the fitted smoothing curves were adopted for analyzing the correlation between serum vitamin C levels and the risk of developing non-alcoholic fatty liver disease.. After adjusting for all the covariates, it was discovered that serum vitamin C was negatively correlated with the risk of nonalcoholic fatty liver disease (odds ratio: 0.664, 95% CI: 0.512-0.860, P = .002). Through smooth curve fitting, it was further noticed that the relationship between serum vitamin C and the risk of non-alcoholic fatty liver disease was non-linear. The inflection point was 0.92, and to its left, a negative correlation was seen between vitamin C and non-alcoholic fatty liver disease (odds ratio: 0.451, 95% CI: 0.288- 0.706, P = .001). To the right of the inflection point, however, the correlation between vitamin C and non-alcoholic fatty liver disease was not found to be significant.. The correlation was non-linear between serum vitamin C levels and the risk of developing non-alcoholic fatty liver disease. Serum vitamin C was negatively correlated with the risk of non-alcoholic fatty liver disease when its level was less than 0.92 mg/dL.

Topics: Ascorbic Acid; Cross-Sectional Studies; Humans; Logistic Models; Non-alcoholic Fatty Liver Disease; Vitamins

Findings on the role of diet in non-alcoholic fatty liver disease (NAFLD) pathogenesis are inconsistent. There are few studies on the dietary habits of pregnant women with NAFLD. Our primary aim was to compare the dietary intakes of pregnant women with and without NAFLD.. This case-control study recruited 60 women (26-34 weeks' gestation) with recently diagnosed gestational diabetes (GDM) before any treatment was implemented. At recruitment, all participants underwent B-mode hepatic ultrasound. We included 30 women with sonographic NAFLD (cases) and 30 women without NAFLD (controls) matched for age, skin color, and pre-pregnancy body mass index. We assessed participants' dietary intakes in the last six months using a validated food frequency questionnaire. Mann-Whitney´s test was used to compare differences in median macro and micronutrient intakes between cases and controls.. Total median daily energy (1965.1 × 1949.2 calories) and lipid (25.1% × 28.3%) intakes were similar in women with and without NAFLD and fell within recommended ranges. Participants with NAFLD reported significantly higher median daily intakes of carbohydrates (59.4% × 53.1% p = 0.003), and significantly lower protein (15.6% × 17.0% p = 0.005), fiber (10.7 × 13.3 g/day p = 0.010), and vitamin C (151.8 × 192.6 mg/day p = 0.008) intakes than those without NAFLD.. Pregnant women with NAFLD ingest more carbohydrates and less protein, fiber, and vitamin C than those without NAFLD. Our findings contribute to understanding the role of diet in the development of NAFLD in pregnant women.

Topics: Ascorbic Acid; Case-Control Studies; Diabetes, Gestational; Eating; Female; Humans; Non-alcoholic Fatty Liver Disease; Pregnancy; Pregnant Women; Vitamins

This study aimed to investigate the association between serum vitamin C and liver fibrosis in patients with NAFLD in the US adults.. We conducted a cross-sectional analysis of data from the 2017 to 2018 cycle of National Health and Nutrition Examination Survey (NHANES). Serum vitamin C and transient elastography (TE)-accessed liver stiffness was taken as independent and dependent variables, respectively. Liver steatosis and fibrosis were detected by controlling attenuation parameter (CAP) and TE. NAFLD was defined by a CAP score of ≥248 dB/m without any indication of other causes of chronic liver disease. The median liver stiffness of ≥8.2 kPa was used to identify significant fibrosis (≥F2) among NAFLD patients. We calculated the adjusted odds ratio (OR) and 95% confidential intervals (CIs) for associations with significant NAFLD fibrosis using multivariable logistic regression models.. Overall, 1926 individuals with NAFLD were included in the analysis and 267 subjects met the definition of significant fibrosis. Serum vitamin C was associated with lower odds of liver fibrosis in NAFLD after adjusting for potential confounders (OR = 0.60, 95% CI, 0.43-0.84), while in the subgroup analysis stratified by gender and body mass index (BMI), this association showed a difference after adjusting for confounders (males: OR = 0.43, 95% CI, 0.26-0.71; females: OR = 0.78, 95% CI, 0.49-1.24). There were no significant associations of serum vitamin C with liver fibrosis in NAFLD with underweight or normal (OR = 1.34, 95% CI, 0.19-9.34).. This cross-sectional study indicated an association of serum vitamin C with significant fibrosis in men and overweight or obese patients with NAFLD.

Topics: Adult; Ascorbic Acid; Cross-Sectional Studies; Elasticity Imaging Techniques; Female; Humans; Liver; Liver Cirrhosis; Male; Non-alcoholic Fatty Liver Disease; Nutrition Surveys

In previous studies, the increasing clinical importance of nonalcoholic fatty liver disease (NAFLD) has been recognized. However, the specific therapeutic strategies or drugs have not been discovered. Vitamin C is a water-soluble antioxidant and is a cofactor in many important biosynthesis pathways. Recently, many researchers have reported that the mega-dose vitamin C treatment had positive effects on various diseases. However, the precise relationship between mega-dose vitamin C and NAFLD has not been completely elucidated. This study has been designed to discover the effects of mega-dose vitamin C on the progression of NAFLD. Twelve-week-old wild-type C57BL6 mice were fed chow diets and high-fat and high-fructose diet (fast-food diet) ad libitum for 11 weeks with or without of vitamin C treatment. Vitamin C was administered in the drinking water (1.5 g/L). In this study, 11 weeks of the mega-dose vitamin C treatment significantly suppressed the development of nonalcoholic steatohepatitis (NASH) independently of the catabolic process. Vitamin C supplements in fast-food diet fed mice significantly decreased diet ingestion and increased water intake. Histopathological analysis revealed that the mice fed a fast-food diet with vitamin C water had a mild renal injury suggesting osmotic nephrosis due to fructose-mediated purine derivatives. These data suggest that the mega-dose vitamin C treatment suppresses high-fructose-diet-mediated NAFLD progression by decreasing diet ingestion and increasing water intake.

Topics: Animals; Ascorbic Acid; Diet; Diet, High-Fat; Disease Models, Animal; Fructose; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Vitamins; Water

Clinical research results on the relationship between folate and non-alcoholic fatty liver disease are contradictory. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a recently proposed concept. Evidence about the relationship between serum folate and MAFLD, especially considering the status of serum vitamin C, is scarce. This study was aimed to investigate the association of serum folate levels with the prevalence of MAFLD, and further to analyze the potential impact of serum vitamin C status on their association.. Totally 2,797 participants from National Health and Nutrition Examination Survey (NHANES) 2017-2018 were included. Vibration-controlled transient elastography was used to detect liver steatosis and fibrosis. Participants were divided in groups based on the tertiles of serum folate or vitamin C, and the serum folate or vitamin C level in T1 was low. Logistic regression analysis in the complex sample module was performed to illustrate the association of serum folate levels with the prevalence of MAFLD. Stratification analysis by serum vitamin C status was performed as well.. Compared with the serum folate levels of T1 group, participants in the T3 group had 47.9% lower risk of MAFLD [OR = 0.521 (95% CI: 0.401-0.677)]. However, when participants were stratified by serum vitamin C levels, there was no association between the serum folate levels and MAFLD in the T1 or T2 group. Among participants in the T3 group of vitamin C status, participants in the T3 group of serum folate had a 63.6% lower risk of MAFLD compared with the T1 group [OR = 0.364 (95% CI: 0.147-0.903)].. High serum folate level is associated with lower prevalence of MAFLD, especially in participants with sufficient vitamin C.

Topics: Adult; Ascorbic Acid; Cross-Sectional Studies; Folic Acid; Humans; Non-alcoholic Fatty Liver Disease; Nutrition Surveys; Vitamin B 12; Vitamin B 12 Deficiency

Obesity is associated with an increased risk of metabolic abnormalities. The citrus fruit calamondin contains nobiletin and hesperidin, which are involved in lipid metabolism, and vitamin C, which is an antioxidant. We investigated the metabolic profiles of C57BL/6 mice fed a normal diet, high-fat diet (HFD), HFD + 1% (w/w) calamondin puree (HFD + CL1), or HFD + 5% (w/w) calamondin puree (HFD + CL5). Glucose tolerance was significantly higher in HFD + CL than in HFD-fed mice. Histological analysis revealed less lipid accumulation in the livers of HFD + CL-fed mice than in those of HFD-fed control mice. Hepatocyte ballooning and large lipid droplets - key non-alcoholic fatty liver disease characteristics - were observed in HFD-fed mice after 4 weeks; however, they were nearly absent in HFD + CL-fed mice. The serum expression level of inflammation-associated Ccl2 was lower in HFD + CL-fed mice than in HFD-fed mice. Thus, calamondin may ameliorate HFD-induced metabolic disturbances, including the progression of non-alcoholic fatty liver disease.

Topics: Adipose Tissue; Alanine Transaminase; Animals; Antioxidants; Ascorbic Acid; Body Weight; Chemokine CCL2; Citrus; Diet; Diet, High-Fat; Dietary Supplements; Gene Expression; Inflammation; Insulin; Lipid Metabolism; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity

Type 2 diabetes is clinically associated with progressive necroinflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Advanced glycation end-products (AGEs) accumulate during prolonged hyperglycemia, but the mechanistic pathways that lead to accelerated liver fibrosis have not been well defined. In this study, we show that the AGEs clearance receptor AGER1 was downregulated in patients with NASH and diabetes and in our NASH models, whereas the proinflammatory receptor RAGE was induced. These findings were associated with necroinflammatory, fibrogenic, and pro-oxidant activity via the NADPH oxidase 4. Inhibition of AGEs or RAGE deletion in hepatocytes in vivo reversed these effects. We demonstrate that dysregulation of NRF2 by neddylation of cullin 3 was linked to AGER1 downregulation and that induction of NRF2 using an adeno-associated virus-mediated approach in hepatocytes in vivo reversed AGER1 downregulation, lowered the level of AGEs, and improved proinflammatory and fibrogenic responses in mice on a high AGEs diet. In patients with NASH and diabetes or insulin resistance, low AGER1 levels were associated with hepatocyte ballooning degeneration and ductular reaction. Collectively, prolonged exposure to AGEs in the liver promotes an AGER1/RAGE imbalance and consequent redox, inflammatory, and fibrogenic activity in NASH.

Topics: Animals; Ascorbic Acid; Cholecalciferol; Dehydroepiandrosterone; Diabetes Mellitus, Type 2; Disease Models, Animal; Down-Regulation; Hepatocytes; Liver Cirrhosis; Mice; Mice, Knockout; NF-E2-Related Factor 2; Nicotinic Acids; Non-alcoholic Fatty Liver Disease; Plant Extracts; Receptor for Advanced Glycation End Products

Non-alcoholic fatty liver disease (NAFLD) caused by consumption of high levels of fat and sugars (HFHS) in diet is considered one of the most dangerous medical complications among children and adolescents. Nicotinamide is among the promising candidates in ameliorating HFHS diet-induced NAFLD, but its use is limited by the possibility of prompting hepatotoxicity in high doses. Ascorbic acid is another promising candidate, however its use as a hepatoprotective agent is limited by its chemical instability. Therefore, the aim of the study was to overcome their delivery limitations and enhance their hepatoprotective activity by loading into nanoparticles.. In the present study, upon incorporating nicotinamide or ascorbic acid in chitosan nanoparticles, they ameliorated the insulin-resistant status induced in rats by a high-fat-high-fructose (HFHF) diet. Both formulae decreased serum level of ALT and AST, as well as liver tissue total cholesterol, triglycerides and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. They also decreased oxidative and nitrosative stresses along with a significant increase in the hepatocellular energy. The biochemical findings were further confirmed by histopathological examination. Finally from the obtained data it could be concluded that chitosan nicotinamide nanoparticles at a dose level (10 mg/kg, p.o.) demonstrated beneficial pharmacological effect with safer toxicity profile than chitosan ascorbic acid nanoparticles.. Nicotinamide chitosan nanoparticles could be recommended as daily supplement in the recovery from NAFLD.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Diet, High-Fat; Dietary Supplements; Fructose; Male; Nanoparticles; Niacinamide; Non-alcoholic Fatty Liver Disease; Protective Agents; Rats; Sweetening Agents; Vitamin B Complex

Topics: Ascorbic Acid; Diet, Reducing; Humans; Lipids; Liver; Non-alcoholic Fatty Liver Disease; Obesity; Selenomethionine; Silymarin; Ubiquinone; Vitamin E

Epidemiological studies support the association between inadequate vitamin C (Vc) intake and non-alcoholic fatty liver disease (NAFLD). However, the intervention dose of Vc, and the prophylactic and therapeutic effects on NAFLD are unclear. This study aimed to investigate the prophylactic and therapeutic effects of low (LVc), medium (MVc) and high (HVc) doses of Vc on NAFLD. C57BL/6 mice were randomly assigned to prophylactic groups (mice received a high-fat diet (HFD) concomitant with different doses of Vc) and therapeutic groups (HFD-induced NAFLD mice treated with different doses of Vc). Results showed that prophylactic LVc and MVc administration reduced the risk of NAFLD development in HFD-fed mice, as evidenced by significantly lowered body weight, perirenal adipose tissue mass, and steatosis, whereas prophylactic HVc administration did not prevent HFD-induced NAFLD development. Furthermore, therapeutic MVc administration significantly ameliorated HFD-induced increase in body weight, perirenal adipose tissue mass and steatosis, whereas therapeutic LVc and HVc administration did not ameliorate NAFLD symptoms. In fact, therapeutic HVc administration significantly increased body weight, perirenal adipose tissue mass, and lobular inflammation. Moreover, prophylactic LVc administration was more effective than therapeutic LVc administration as evidenced by significantly lower body weight, perirenal adipose tissue mass, steatosis, ballooned hepatocytes, and lobular inflammation in prophylactic LVc administration. The same trends were observed between prophylactic HVc administration and therapeutic HVc administration. In addition, all Vc-administered mice exhibited low blood glucose, triglycerides and homeostasis model assessment of insulin resistance values and high adiponectin levels compared to HFD-fed mice. Our study suggested that MVc was beneficial for HFD-induced NAFLD prophylaxis and therapy. LVc prevented HFD-induced NAFLD development, while HVc for NAFLD management was risky. This study offers valuable insight into the effect of various Vc doses on NAFLD management.

Topics: Adiponectin; Animals; Antioxidants; Ascorbic Acid; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Inflammation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Triglycerides; Weight Gain

Ascorbic acid is a known cofactor in the biosynthesis of carnitine, a molecule that has an obligatory role in fatty acid oxidation. Our previous studies have demonstrated that obesity is regulated effectively through peroxisome proliferator-activated receptor α (PPARα)-mediated fatty acid β-oxidation. Thus, this study aimed to determine whether ascorbic acid can inhibit obesity and nonalcoholic fatty liver disease (NAFLD) in part through the actions of PPARα.. After C57BL/6J mice received a low-fat diet (LFD, 10% kcal fat), a high-fat diet (HFD, 45% kcal fat), or the same HFD supplemented with ascorbic acid (1% w/w) (HFD-AA) for 15 weeks, variables and determinants of visceral obesity and NAFLD were examined using metabolic measurements, histology, and gene expression.. Compared to HFD-fed obese mice, administration of HFD-AA to obese mice reduced body weight gain, visceral adipose tissue mass, and visceral adipocyte size without affecting food consumption profiles. Concomitantly, circulating ascorbic acid concentrations were significantly higher in HFD-AA mice than in HFD mice. Ascorbic acid supplementation increased the mRNA levels of PPARα and its target enzymes involved in fatty acid β-oxidation in visceral adipose tissues. Consistent with the effects of ascorbic acid on visceral obesity, ascorbic acid not only inhibited hepatic steatosis but also increased the mRNA levels of PPARα-dependent fatty acid β-oxidation genes in livers. Similarly, hepatic inflammation, fibrosis, and apoptosis were also decreased during ascorbic acid-induced inhibition of visceral obesity. In addition, serum levels of alanine aminotransferase, aspartate aminotransferase, total cholesterol, and LDL cholesterol were lower in HFD-AA-fed mice than in those of HFD-fed mice.. These results suggest that ascorbic acid seems to suppress HFD-induced visceral obesity and NAFLD in part through the activation of PPARα.

Topics: Animals; Ascorbic Acid; Diet, Fat-Restricted; Diet, High-Fat; Dietary Supplements; Fatty Acids; Gene Expression; Intra-Abdominal Fat; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity, Abdominal; Oxidation-Reduction; PPAR alpha; Weight Gain

Although antioxidants have a protective potential in nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), there is limited evidence regarding the role of dietary intake of antioxidants. The aim was to test the association between dietary vitamins E and C intake and NAFLD, NASH and fibrosis markers.. Cross-sectional study of a large cohort of subjects undergoing colonoscopy. The presence of NAFLD was evaluated by ultrasonography. The level of steatosis was defined using SteatoTest, moderate-severe NASH using new quantitative NashTest and borderline-significant fibrosis ≥ F1-F2 using FibroTest. Nutritional intake was measured by food frequency questionnaire (FFQ).. Overall, 789 subjects were included (52.6% men, age 58.83 ± 6.58 years), 714 had reliable FibroMax. Adjusting for BMI, dietary and lifestyle factors, the upper tertile of vitamin E intake/1000 Kcal was associated with lower odds of NASH (OR = 0.64, 0.43-0.94, P = 0.024). There was an inverse association between reaching the recommended vitamin E intake and NASH (OR = 0.48, 0.30-0.77, P = 0.002). The upper tertile of vitamin C intake/1000 Kcal was associated with lower odds of NAFLD and NASH (OR = 0.68, 0.47-0.99, P = 0.045; OR = 0.57, 0.38-0.84, P = 0.004, respectively). Both vitamins were related with the level of steatosis according to SteatoTest.. Vitamin E and C intake may be protective from NAFLD-related liver damage.

Topics: Antioxidants; Ascorbic Acid; Correlation of Data; Cross-Sectional Studies; Diet; Female; Humans; Israel; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Nutrition Assessment; Protective Factors; Severity of Illness Index; Ultrasonography; Vitamin E

Increasing prevalence of obesity‑induced non‑alcoholic fatty liver disease (NAFLD) and non‑alcoholic steatohepatitis (NASH) has been reported. Ascorbic acid (AA), also known as vitamin C, an excellent antioxidant, has been shown to exert beneficial effects on NAFLD; however, the underlying mechanisms are yet to be fully elucidated. In the present study, the role of AA on cell stress in tumor necrosis factor α (TNFα)‑treated HepG2 cells was investigated. Our findings revealed that exposure to AA effectively ameliorated TNFα‑induced cell stresses, including hypoxia, inflammation and endoplasmic reticulum (ER) stress by reducing the expression of Hif1α and its target genes (glucose transporter 1), pro‑inflammatory genes (monocyte chemoattractant 1) and ER stress‑related genes (glucose‑regulated protein, 78 kDa). AA also decreased the protein level of HIF1α. Additionally, AA significantly increased the secretion of total adiponectin and high molecular weight (HMW) adiponectin. Mechanistically, AA was determined to increase the expression of fibroblast growth factor 21 (FGF21) and its receptor, fibroblast growth factor receptor 2 (FGFR2). Knockdown of FGFR2 not only decreased the levels of total adiponectin and HMW adiponectin, but almost abolished the beneficial effects of AA in ameliorating cell stress. Collectively, the findings of our study demonstrated that AA may attenuate hepatocyte stress induced by TNFα via activation of the FGF21/FGFR2/adiponectin pathway. This could a novel mechanism of action of AA, and its potential for the treatment of NAFLD/NASH.

Topics: Adiponectin; Antioxidants; Ascorbic Acid; Fibroblast Growth Factors; Hep G2 Cells; Hepatocytes; Humans; Non-alcoholic Fatty Liver Disease; Receptor, Fibroblast Growth Factor, Type 2; Signal Transduction

Nonalcoholic fatty liver disease (NAFLD) has become highly prevalent, now considered the most common liver disease in the western world. Approximately one-third of patients with NASH develop non-alchoholic steatohepatitis (NASH), histologically defined by lobular and portal inflammation, and accompanied by marked oxidative stress. Patients with NASH are at increased risk for cirrhosis and hepatocellular carcinoma, and diagnosis currently requires invasive biopsy. In animal models of NASH, particularly the methionine-choline deficient (MCD) model, profound changes are seen in redox enzymes and key intracellular antioxidants. To study antioxidant status in NASH non-invasively, we applied the redox probe hyperpolarized [1-

Topics: Animals; Ascorbic Acid; Carbon-13 Magnetic Resonance Spectroscopy; Choline Deficiency; Dehydroascorbic Acid; Diet; Disease Models, Animal; Lipid Metabolism; Liver; Magnetic Resonance Imaging; Male; Methionine; Mice; Non-alcoholic Fatty Liver Disease; Oxidative Stress

Non-alcoholic fatty liver disease (NAFLD) has become one of the most prevalent chronic liver disease all over the world. The objective of this study was to evaluate the association between dietary vitamin C intake and NAFLD.. Subjects were diagnosed with NAFLD by abdominal ultrasound examination and the consumption of alcohol was less than 40g/day for men or less than 20g/day for women. Vitamin C intake was classified into four categories according to the quartile distribution in the study population: ≤74.80 mg/day, 74.81-110.15 mg/day, 110.16-146.06 mg/day, and ≥146.07 mg/day. The energy and multi-variable adjusted odds ratio (OR), as well as their corresponding 95% confidence interval (CI), were used to determine the relationship between dietary vitamin C intake and NAFLD through logistic regression.. The present cross-sectional study included 3471 subjects. A significant inverse association between dietary vitamin C intake and NAFLD was observed in the energy-adjusted and the multivariable model. The multivariable adjusted ORs (95%CI) for NAFLD were 0.69 (95%CI: 0.54-0.89), 0.93 (95%CI: 0.72-1.20), and 0.71 (95%CI: 0.53-0.95) in the second, third and fourth dietary vitamin C intake quartiles, respectively, compared with the lowest (first) quartile. The relative odds of NAFLD was decreased by 0.71 times in the fourth quartile of dietary vitamin C intake compared with the lowest quartile. After stratifying data by sex or the status of obesity, the inverse association remained valid in the male population or non-obesity population, but not in the female population or obesity population.. There might be a moderate inverse association between dietary vitamin C intake and NAFLD in middle-aged and older adults, especially for the male population and non-obesity population.

Topics: Adult; Aged; Aged, 80 and over; Antioxidants; Ascorbic Acid; Cross-Sectional Studies; Dietary Supplements; Energy Intake; Female; Humans; Male; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Obesity; Odds Ratio; Risk Factors; Vitamins

Oxidative stress and insulin resistance (IR) are major contributors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The purpose of this study was to find the relation between oxidative stress parameters and histopathological findings in NAFLD patients with and without insulin resistance (IR).. Thirty-two patients with no alcohol intake and biopsy-proven diagnosis of NAFLD were studied (M/F: 17/15; mean age 46.5±11.4 years). Twenty-one NAFLD patients with IR were compared with 11 patients without IR. The fasting insulin level was measured, and the insulin resistance index was calculated using the homeostasis model assessment (HOMA) method. Malondialdehyde (MDA) and superoxide dismutase (SOD) activities were measured in tissue and serum specimens. Glutathione (GH) was measured in tissue homogenates. Nitric oxide (NO), vitamin E and C levels were measured in serum.. Patients with IR had significantly higher tissue MDA levels (p=0.001) and significantly decreased tissue SOD and GH levels (p=0.001 and 0.002, respectively) than those without IR. The steatosis grade, necroinflammatory grade and stage were significantly higher in patients with IR (p=0.035, 0.003 and 0.001, respectively). HOMA IR significantly correlated with the necroinflammatory grade, stage, tissue MDA, SOD and GH (p=0.013, 0.001, 0.008, 0.001 and 0.001, respectively). Serum MDA (β=1.88, p=0.002), serum SOD (β=0.57, p=0.006), tissue MDA (β=0.22, p=0.006), tissue SOD (β=1.48, p=0.071) and stage (β=2.81, p=0.003) were independently associated with increased HOMA IR. Increased MDA [OR: 1.51; 95% CI: (1.03-2.22); p=0.034] was a risk factor for non-alcoholic steatohepatitis (NASH), and increased SOD activity had a preventive effect against NASH [OR: 0.008; 95% CI: (0.001-0.98); p=0.04].. This study shows that insulin resistance in NAFLD correlates with enhanced oxidative stress. Histopathological disease severity significantly correlated with oxidative stress parameters. These data show that NAFLD patients with IR may have increased risk for disease progression.

Topics: Adult; Ascorbic Acid; Female; Glutathione; Humans; Insulin; Insulin Resistance; Liver; Male; Malondialdehyde; Middle Aged; Nitric Oxide; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Severity of Illness Index; Superoxide Dismutase; Vitamin E

We have previously shown that in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-elicited NAFLD progression, central carbon, glutaminolysis, and serine/folate metabolism are reprogrammed to support NADPH production and ROS defenses. To further investigate underlying dose-dependent responses associated with TCDD-induced fibrosis, female C57BL/6 mice were gavaged with TCDD every 4 days (d) for 28 d or 92 d. RNA-Seq, ChIP-Seq (2 h), and 28 d metabolomic (urine, serum, and hepatic extract) analyses were conducted with complementary serum marker assessments at 92 d. Additional vehicle and 30 µg/kg treatment groups were allowed to recover for 36 d following the 92-d treatment regimen to examine recovery from TCDD-elicited fibrosis. Histopathology revealed dose-dependent increases in hepatic fat accumulation, inflammation, and periportal collagen deposition at 92 days, with increased fibrotic severity in the recovery group. Serum proinflammatory and profibrotic interleukins-1β, -2, -4, -6, and -10, as well as TNF-α and IFN-γ, exhibited dose-dependent induction. An increase in glucose tolerance was observed with a concomitant 3.0-fold decrease in hepatic glycogen linked to increased ascorbic acid biosynthesis and proline metabolism, consistent with increased fibrosis. RNA-Seq identified differential expression of numerous matrisome genes including an 8.8-fold increase in Tgfb2 indicating myofibroblast activation. Further analysis suggests reprogramming of glycogen, ascorbic acid, and amino acid metabolism in support of collagen deposition and the use of proline as a substrate for ATP production via the proline cycle. In summary, we demonstrate that glycogen, ascorbic acid, and amino acid metabolism are also reorganized to support remodeling of the extracellular matrix, progressing to hepatic fibrosis in response to chronic injury from TCDD.

Topics: Animals; Ascorbic Acid; Cellular Reprogramming; Chemical and Drug Induced Liver Injury; Collagen; Cytokines; Dose-Response Relationship, Drug; Energy Metabolism; Extracellular Matrix; Female; Gene Expression Regulation; Glucose; Glycogen; Inflammation Mediators; Liver; Liver Cirrhosis; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Polychlorinated Dibenzodioxins; Proline; Time Factors; Transcriptome

Topics: Ascorbic Acid; Bias; Conflict of Interest; Humans; Informed Consent; Non-alcoholic Fatty Liver Disease; Patient Selection; Private Practice; Randomized Controlled Trials as Topic; Therapeutic Misconception; Treatment Outcome; United States; Vitamin E; Vitamins; Weight Loss

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

Dietary factors are closely associated with the risk of non-alcoholic fatty liver disease (NAFLD). Asian and Western diets differ in energy-nutrient composition, fatty-acid composition, and main nutritional sources; therefore, the implications would be limited if the Western-oriented study results were applied to Asian patients. We aimed to identify the nutrient and food group intakes of a typical Asian diet and assess their effects on NAFLD risk.. In total, 348 subjects were recruited from 5 participating hospitals. Information on sociodemographic characteristics and health-related behaviors were obtained through face-to-face interviews. NAFLD was diagnosed by ultrasound. Dietary intakes were assessed with a 24-h recall applying a multiple-pass approach and 4-day food records that included 1 or 2 weekend days.. There were no significant differences in health-related behaviors between the cases and controls except for smoking behavior. The cases had elevated triacylglycerol, fasting glucose, and low-density lipoprotein cholesterol levels compared with the controls. In men, after adjusting for variables, low intakes of vitamin C (odds ratio [OR], 4.23), vitamin K (OR, 3.93), folate (OR, 3.37), omega-3 fatty acids (OR, 2.16), and nuts and seeds (OR, 3.66) were associated with a significantly higher risk for developing NAFLD. In women, vitamin K (OR, 2.54) and vegetable (OR, 4.11) intakes showed a significant beneficial effect for lowering NAFLD risk.. Adequate intakes of vitamin C, vitamin K, folate, omega-3 fatty acids, nuts and seeds, and vegetables may help in preventing NAFLD in Korean adults.

Topics: Adult; Aged; Ascorbic Acid; Asian People; Case-Control Studies; Diet; Fatty Acids, Omega-3; Female; Folic Acid; Food; Humans; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Nuts; Republic of Korea; Risk; Seeds; Vegetables; Vitamin K; 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

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