salicylates and Fatty-Liver

Topics: Adipose Tissue, White; Animals; Body Weight; Cell Line; Diabetes Mellitus, Type 2; Diet, High-Fat; Energy Metabolism; Fatty Liver; Gene Expression; Gluconeogenesis; Glucose; Humans; Insulin; Lipid Metabolism; Liver; Male; Mice; Muscle, Skeletal; Obesity; Pyruvic Acid; Salicylates; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Transduction; Thermogenesis

Fetuin-A was recently identified as a novel hepatokine which is associated with obesity, insulin resistance and non-alcoholic fatty liver disease. Salsalate, a prodrug of salicylate with an anti-inflammatory effect and lower side effect profile, significantly lowers glucose and triglyceride levels, and increased adiponectin concentrations in randomized clinical trials. In this study, we examined the effects and regulatory mechanisms of salsalate and full length-adiponectin (fAd) on fetuin-A expression, steatosis and lipid metabolism in palmitate-treated HepG2 cells. Incubation of hepatocytes with palmitate significantly increased fetuin-A and SREBP-1c expression which lead to steatosis and knock-down of fetuin-A by siRNA restored these changes. Salsalate significantly down-regulated palmitate-induced fetuin-A mRNA expression and secretion in a dose- and time-dependent manner. Inhibition of palmitate-induced fetuin-A by salsalate was mediated by AMPK-mediated reduction of NFκB activity, which was blocked by AMPK siRNA or an inhibitor of AMPK. Salsalate attenuated the excessive steatosis by palmitate through SREBP-1c regulation in hepatocytes. Furthermore, fAd also showed suppression of palmitate-induced fetuin-A through the AMPK pathway and improvement of steatosis accompanied by restoration of SREBP-1c, PAPR-α and CD36. In preliminary in vivo experiments, salsalate treatment inhibited high fat diet (HFD)-induced steatosis as well as fetuin-A mRNA and protein expression in SD rats. In conclusion, salsalate and fAd improved palmitate-induced steatosis and impairment of lipid metabolism in hepatocytes via fetuin-A inhibition through the AMPK-NFκB pathway.

Topics: Adiponectin; alpha-2-HS-Glycoprotein; AMP-Activated Protein Kinases; Animals; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Gene Expression Regulation; Hep G2 Cells; Humans; Lipid Metabolism; Male; Mice; Mice, Mutant Strains; NF-kappa B; Palmitates; Rats; Rats, Sprague-Dawley; Salicylates

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

Owing to the worldwide epidemic of obesity, and the popularity of diets rich in sugar and saturated fat, nonalcoholic fatty liver disease (NAFLD) is increasingly common; it is usually associated with insulin resistance, and may be considered a component of the metabolic syndrome. The pathologies which can complicate hepatic steatosis--steatohepatitis, cirrhosis, and hepatic cancer--appear to result from an interaction of hepatic lipid overload and hepatic oxidative stress. It is therefore proposed that comprehensive regimens which effectively target each of these precipitating factors should achieve the best therapeutic benefit in NAFLD. Appropriate weight loss, and a diet low in saturated fat, glycemic index, and added sugars, should decrease hepatic lipid load. Measures which enhance adipocyte insulin sensitivity--such as pioglitazone, astaxanthin, and spirulina--may also be helpful in this regard, as may agents that boost hepatocyte capacity for fatty acid oxidation, such as metformin, carnitine, hydroxycitrate, long-chain omega-3 fats, and glycine. Astaxanthin and spirulina appear to have considerable potential for controlling the oxidative stress associated with NAFLD - the former because it may help to prevent the mitochondrial damage that renders mitochondria a key source of superoxide in this syndrome, the latter because it is exceptionally rich in phycocyanobilin, a phytochemical inhibitor of NAPDH oxidase. Other antioxidants which show some promise in this syndrome include high-dose folate, lipoic acid, melatonin, N-acetylcysteine, vitamin E, and taurine. Finally, treatment with salsalate, an inhibitor of IkappaB kinase-beta, has potential for blunting the adverse impact of hepatic steatosis on oxidative stress and inflammation.

Topics: Antioxidants; Fatty Liver; Humans; Oxidative Stress; Salicylates; Xanthophylls

1. Earlier studies with liver slices showed that inhibition by NH4+ of the oxidation of palmitate to CO2 was greater than total oxidation, whereas salicylate exerted a stronger inhibitory effect on the latter. We have now investigated the effects of NH4Cl and salicylate on ADP-induced O2 consumption by mitochondria (State 3 rate) respiring on pyruvate, and oxidation of [1-14C]- and [2-14C]-pyruvate to 14CO2. 2. The rate of State 3 respiration was inhibited and plateaued at 45% with 10 mmol/l NH4Cl. 3. Oxidation of [1-14C]pyruvate was not significantly affected by either NH4Cl or salicylate. Oxidation of [2-14C]pyruvate was strongly inhibited and plateaued at 70% with 1 mmol/l NH4Cl (IC50 = 0.125 mmol/l). ADP (1 mmol/l) increased the rate of decarboxylation of [2-14C]pyruvate but the extent of NH4Cl inhibition was not affected. Salicylate had a slight activating effect in the absence or presence of NH4Cl. 4. These results indicate that NH4Cl inhibits the oxidative metabolism of acetyl-CoA in the tricarboxylic acid cycle. Therefore, inhibition of fatty acid oxidation to acetyl-CoA as well as its further oxidative metabolism occurring under hyperammonaemia (> 0.1 mmol-1.49 mmol/l in Reye's syndrome patients) may be one of the causes of fatty acidaemia. 5. The cumulative inhibitory effects of NH4+ and fatty acyl derivatives on mitochondrial oxidative metabolism and production of ATP, as well as the uncoupling effects of salicylate, may contribute to some of the pathophysiology observed in patients with Reye's syndrome, and enzyme defects of the urea cycle.

Topics: Adenosine Diphosphate; Ammonium Chloride; Animals; Carbon Dioxide; Dose-Response Relationship, Drug; Fatty Liver; Male; Mitochondria, Liver; Oxidation-Reduction; Oxygen Consumption; Pyruvates; Pyruvic Acid; Rats; Rats, Sprague-Dawley; Reye Syndrome; Salicylates; Salicylic Acid; Urea

Topics: Amino Acids; Child, Preschool; Chronic Disease; Diagnosis, Differential; Fatty Liver; Humans; Male; Microscopy, Electron; Mitochondria, Liver; Reye Syndrome; Salicylates

Topics: Adipose Tissue; Aspirin; Brain Diseases; Chemical and Drug Induced Liver Injury; Fatty Liver; Humans; Infant; Kidney Diseases; Peritoneal Dialysis; Salicylates

Topics: Aspirin; Brain Diseases; Carbohydrate Metabolism; Coma; Fatty Liver; Heart Diseases; Humans; Kidney Diseases; Salicylates; Toxicology; Viscera