Induction of peroxisomal beta-oxidation in rat liver by high-fat diets.
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ABSTRACT:
SUBMITTER: Neat CE
PROVIDER: S-EPMC1161539 | biostudies-other | 1980 Jan
REPOSITORIES: biostudies-other
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Project description:1. The effect on rat liver peroxisomal beta-oxidation of feeding diets containing various amounts of dietary oils was investigated. With increasing amounts (5-25%, w/w) of soya-bean oil an apparent, but not statistically significant, increase of 1.5-fold was found both in specific activity, and in total liver activity. Increasing amounts of partially hydrogenated marine oil revealed a sigmoidal dose-response-curve, giving a 4-6-fold increase in the peroxisomal beta-oxidation activity at 20% or more of this oil in the diet. 2. Addition of small amounts of soya-bean oil to the marine-oil diet had no effect on the peroxisomal beta-oxidation activity, but decreased the C20:3(5,8,11) fatty acid/C20:4(5,8,11,14) fatty acid ratio in liver phospholipids from 0.74 to 0.01. 3. Starvation for 2 days led to a 1.5-1.8-fold increase in the peroxisomal beta-oxidation activity in rats previously fed on a standard pelleted diet, but had no effect in rats given high-fat diets. 4. Feeding partially hydrogenated marine oil or partially hydrogenated rape-seed oil resulted in higher activities than the corresponding unhydrogenated oils. 5. No significant differences in the effect on peroxisomal beta-oxidation could be detected between diets containing rape-seed oils with 15 or 45% erucic acid respectively. 6. These findings are discussed in relation to the possible effects of C22:1 and trans fatty acids in the process leading to increased peroxisomal beta-oxidation activity in the liver.
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Project description:The capability of (4R)-4-(2,3,4,6,6a beta,7,8,9,9a alpha,9b beta-decahydro-6a beta-methyl-3-oxo-1H-cyclopental[f]quinolin-7 beta-yl)valeric acid (DCQVA), a catabolite of cholic acid produced by enterobacteria, to induce peroxisome proliferation in vivo and in vitro was studied. Rats given 0.3% DCQVA in the diet for 2 weeks showed marked increases in peroxisomal beta-oxidation, mitochondrial 2,4-dienoyl-CoA reductase and microsomal laurate omega-oxidation activities in the liver compared with control rats given the diet without DCQVA. Cultured rat hepatocytes treated with DCQVA for 72 h also exhibited greatly enhanced beta-oxidation activity. The increased activity was concentration-dependent and the effective concentrations were comparable with those of clofibric acid that produced the same degree of induction in the assay. The results demonstrate that DCQVA is a potent peroxisome proliferator that occurs naturally in rat intestine.
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Project description:Retinoic acid is reported here to induce peroxisomal beta-oxidation activities in cultured rat hepatocytes, with a concomitant increase in respective peroxisomal mRNAs. The concentrations of retinoic acid required for inducing liver peroxisomal acyl-CoA oxidase were similar to those required for inducing liver transglutaminase. A putative 5'-flanking response element for retinoic acid may be found within the enhancer region involved in the induction of peroxisomal genes by xenobiotic amphipathic carboxylates.
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Project description:Lingguizhugan decoction (LGZG), a classic traditional Chinese medicine (TCM) formula, has been used to treat obesity and hyperlipidemia in recent years, but the related mechanisms underlying the regulation of lipid metabolism by LGZG are not clear yet. Here, we reported the effectiveness and possible mechanisms of LGZG on rats with fatty liver disease induced by high-fat diet (HFD). Our results demonstrated that LGZG significantly attenuated HFD-induced fatty liver disease, as measured by body weight, liver index, epididymal fat pad-body weight ratio (EFP/BW), liver injury, and hepatic triglycerides (TG) probably through increasing serum thyroid hormone levels, improving beta-oxidation (via modulation of TR β 1 and CPT1A expression), metabolism and transport (through modulation of SREBP-1c, ACSL and ApoB100 expression) of fatty acid. In addition, we discovered the herbal combination with the properties of warming yang to relieve water retention in the formula and proposed the biological basis of LGZG conventional effect via further study on disassembled formula. This study, for the first time, revealed the mechanisms through which LGZG regulates lipid metabolism. Furthermore, our study suggested that it might be feasible to understand the scientific implications of TCM from the perspective of classic formulas' conventional efficacy.
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Project description:Non-alcoholic fatty liver disease (NAFLD) is common in Metabolic Syndrome and type 2 diabetes (T2DM), driven by energy imbalance, saturated fats and simple carbohydrates. NAFLD requires screening and monitoring for late complications. Liver fat indices may predict NAFLD avoiding expensive or invasive gold-standard methods, but they are poorly validated for use in interventional settings. Recent data indicate a particular insensitivity to weight-independent liver fat reduction. We evaluated 31 T2DM patients, completing a randomized intervention study on isocaloric high-protein diets. We assessed anthropometric measures, intrahepatic lipid (IHL) content and serum liver enzymes, allowing AUROC calculations as well as cross-sectional and longitudinal Spearman correlations between the fatty liver index, the NAFLD-liver fat score, the Hepatosteatosis Index, and IHL. At baseline, all indices predicted NAFLD with moderate accuracy (AUROC 0.731-0.770), supported by correlation analyses. Diet-induced IHL changes weakly correlated with changes of waist circumference, but no other index component or the indices themselves. Liver fat indices may help to easily detect NAFLD, allowing cost-effective allocation of further diagnostics to patients at high risk. IHL reduction by weight-independent diets is not reflected by a proportional change in liver fat scores. Further research on the development of treatment-sensitive indices is required.Trial registration: The trial was registered at clinicaltrials.gov: NCT02402985.
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Project description:The enzyme targets for chlorpromazine inhibition of rat liver peroxisomal and mitochondrial oxidations of fatty acids were studied. Effects of chlorpromazine on total fatty acyl-CoA synthetase activity, on both the first and the third steps of peroxisomal beta-oxidation, on the entry of fatty acyl-CoA esters into the peroxisome and on catalase activity, which allows breakdown of the H2O2 generated during the acyl-CoA oxidase step, were analysed. On all these metabolic processes, chlorpromazine was found to have no inhibitory action. Conversely, peroxisomal carnitine octanoyltransferase activity was depressed by 0.2-1 mM-chlorpromazine, which also inhibits mitochondrial carnitine palmitoyltransferase activity in all conditions in which these enzyme reactions are assayed. Different patterns of inhibition by the drug were, however, demonstrated for both these enzyme activities. Inhibitory effects of chlorpromazine on mitochondrial cytochrome c oxidase activity were also described. Inhibitions of both cytochrome c oxidase and carnitine palmitoyltransferase are proposed to explain the decreased mitochondrial fatty acid oxidation with 0.4-1.0 mM-chlorpromazine reported by Leighton, Persico & Necochea [(1984) Biochem. Biophys. Res. Commun. 120, 505-511], whereas depression by the drug of carnitine octanoyltransferase activity is presented as the factor responsible for the decreased peroxisomal beta-oxidizing activity described by the above workers.
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Project description:Excessive dietary fat intake causes systemic metabolic toxicity, manifested in weight gain, hyperglycemia, and insulin resistance. In addition, carbohydrate utilization as a fuel is substantially inhibited. Correction or reversal of these effects during high-fat diet (HFD) intake is of exceptional interest in light of widespread occurrence of diet-associated metabolic disorders in global human populations. Here we report that mangiferin (MGF), a natural compound (the predominant constituent of Mangifera indica extract from the plant that produces mango), protected against HFD-induced weight gain, increased aerobic mitochondrial capacity and thermogenesis, and improved glucose and insulin profiles. To obtain mechanistic insight into the basis for these effects, we determined that mice exposed to an HFD combined with MGF exhibited a substantial shift in respiratory quotient from fatty acid toward carbohydrate utilization. MGF treatment significantly increased glucose oxidation in muscle of HFD-fed mice without changing fatty acid oxidation. These results indicate that MGF redirects fuel utilization toward carbohydrates. In cultured C2C12 myotubes, MGF increased glucose and pyruvate oxidation and ATP production without affecting fatty acid oxidation, confirming in vivo and ex vivo effects. Furthermore, MGF inhibited anaerobic metabolism of pyruvate to lactate but enhanced pyruvate oxidation. A key target of MGF appears to be pyruvate dehydrogenase, determined to be activated by MGF in a variety of assays. These findings underscore the therapeutic potential of activation of carbohydrate utilization in correction of metabolic syndrome and highlight the potential of MGF to serve as a model compound that can elicit fuel-switching effects.
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Project description:The NLRP3-inflammasome complex has emerged as an important component of inflammatory processes in metabolic dysfunction induced by high-caloric diets. In this study, we investigate the molecular mechanisms by which NLRP3 inhibition may attenuate diet-induced cardiac injury. Here we show the cardiac damage induced by high sugar diet (HSD), high fat diet (HFD) or high sugar/fat diet (HSFD) over 15 weeks. Genetic ablation of NLRP3 protected against this damage by autophagy induction and apoptotic control. Furthermore, NLRP3 inhibition by the selective small molecule MCC950 resulted in similar autophagy induction and apoptotic control in hearts after diets. These data were reproduced in THP-1 cells treated with MCC950 and cultured in media supplemented with serum from mice dosed with MCC950 and fed with diets. NLRP3 inhibition exerted beneficial metabolic, and autophagic adaptations in hearts from obesogenic diets. The inhibition of NLRP3 activation may hold promise in the treatment of metabolic and cardiovascular diseases.
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Project description:In this study we attempted to determine the number of 2-enoyl-CoA hydratases involved in peroxisomal beta-oxidation. We therefore separated peroxisomal proteins from rat liver on several chromatographic columns and measured hydratase activities on the eluates with different substrates. The results indicate that rat liver peroxisomes contain two hydratase activities: (1) a hydratase activity associated with multifunctional protein 1 (MFP-1) (2-enoyl-CoA hydratase/delta 3, delta 2-enoyl-CoA isomerase/L-3-hydroxyacyl-CoA dehydrogenase) and (2) a hydratase activity associated with MFP-2 (17 beta-hydroxysteroid dehydrogenase/D-3-hydroxyacyl-CoA dehydrogenase/2-enoyl-CoA hydratase). MFP-1 forms and dehydrogenates L-3-hydroxyacyl-CoA species, whereas MFP-2 forms and dehydrogenates D-3-hydroxyacyl-CoA species. A portion of MFP-2 is proteolytically cleaved, most probably in the peroxisome, into a 34 kDa 17 beta-hydroxysteroid dehydrogenase/D-3-hydroxyacyl-CoA dehydrogenase and a 45 kDa D-specific 2-enoyl-CoA hydratase. Finally, the results confirm that MFP-1 is involved in the degradation of straight-chain fatty acids, whereas MFP-2 and its cleavage products seem to be involved in the degradation of the side chain of cholesterol (bile acid synthesis).
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Project description:1. A luminometric assay for acyl-CoA oxidase activity is described. The assay uses the luminol/microperoxidase system to monitor continuously acyl-CoA-dependent generation of H2O2. The assay is rapid, convenient, and lends itself to automation with an LKB 1251 luminometer. The assay is extremely sensitive, requiring at the most 10 micrograms of liver-homogenate protein per assay. 2. The assay can also be used to measure other oxidases, e.g. glycollate oxidase (EC 1.1.3.15), D-aspartate oxidase (EC 1.4.3.1) and urate oxidase (EC 1.7.3.3), the only modification being substitution of substrates to appropriate concentration. 3. With rat liver homogenates, spectrophotometrically measured rates of palmitoyl-CoA-dependent NAD+ reduction and acyl-CoA oxidase activity [Hryb & Hogg (1979) Biochem. Biophys. Res. Commun. 87, 1200-1206] was generally found in good agreement with luminometrically measured acyl-CoA oxidase activity. 4. With liver homogenates from streptozotocin-diabetic rats, however, rates of palmitoyl-CoA-dependent NAD+ reduction were consistently lower than the corresponding acyl-CoA oxidase activity. This difference was most marked with respect to luminometrically assayed acyl-CoA oxidase activity.
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