Differences in the response of Sprague-Dawley and Lewis rats to bezafibrate: The hypolipidemic effect and the induction of peroxisomal enzymes

Pill, Johannes; Völkl, Alfred; Hartig, F.; Fahimi, H. Dariush

doi:10.1007/bf01973627

Cited by 13 publications

(6 citation statements)

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“…It is interesting that this hormone is a peroxisome proliferator [12,15,24,25,31]. Most peroxisome proliferators including clofibrate [9,27] and bezafibrate [13,22,23] are hypolipidemic agents, and decrease serum triglycerides and cholesterol. Some of these peroxisome proliferators were reported to be capable of metabolizing and diminishing intracellular lipid droplets [6,7].…”

Section: Resultsmentioning

confidence: 99%

Prevention of Orotic-Acid-Induced Fatty Liver in Male Rats by Dehydroepiandrosterone and/or Phenobarbital.

Goto

Yamashita

Makita

1998

The Journal of Veterinary Medical Science

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ABSTRACT. Dehydroepiandrosterone (DHEA) is a steroid hormone which induces the peroxisome proliferation in rodents. The fatty liver induced by orotic acid and a high sucrose diet in male rats was prevented by the administration of DHEA and/or phenobarbital (PB). A significant increase in the liver weight was induced in the DHEA group (relative weight) and the DHEA + PB group (absolute and relative weight). The liver weight increased more conspicuously in the DHEA + PB group than in the DHEA group. The increase in the liver weight was caused by an increase in the cell size and peroxisome number. In addition, the administration of DHEA alone and the combination of DHEA and PB prevented the lipid droplet accumulation in hepatocytes. The administration of PB alone also prevented the accumulation of lipid droplets without any increase in the liver weight. -KEY WORDS: dehydroepiandrosterone, fatty liver, orotic acid, peroxisome proliferator, phenobarbital.J. Vet. Med. Sci. 60(4): 513-517, 1998 to 60%, a ventilation frequency of 13 to 15 air exchanges/ hr, and a 12-hr light/12-hr dark cycle (lights on: 07:00 to 19:00 hr). Control animals were fed the standard food for 2 weeks, and DHEA group rats were fed the standard food with 0.5% DHEA (Sigma Chemical Co.). Animals in the PB group were fed the standard food and intraperitoneally injected with 6% PB (Wako Pure Chemicals Co.) at 60 mg/ kg, once a day, 5 days a week, for 2 weeks. The DHEA + PB group were fed standard food with concomitant treatment with DHEA and PB. Body weight and food consumption were measured every 7 days. The final body weight was measured on the day of necropsy to calculate the relative organ weight. All animals were euthanized by exsanguination from abdominal veins and arteries following ether anesthesia and laparotomy. They were then examined for gross findings, and the absolute of the liver and organto-body weight ratio (relative weight) were determined. The liver of all animals was fixed in 10% neutral formalin, embedded in paraffin, sectioned at 3 µm, and stained with hematoxylin and eosin. For peroxisome visualization in the control and DHEA + PB groups, 45-µm-thick tissue slices fixed in 2.5% glutaraldehyde were reacted for 60 min at 37°C in alkaline 3,3'-diaminobenzidine medium [20] and postfixed in 1% OsO 4 . They were then embedded in epoxy resin, and 1 µm semi-thin sections were stained with toluidine blue. Statistical analysis: Body weight gain, food consumption, and organ weight were analyzed by one-way analysis of variance. When one-way analysis yielded a significant difference (P<0.05), the values were analyzed by Dunnett's test. RESULTSIn comparison with the control group, significant Dehydroepiandrosterone (3β-hydroxy-5-androsten-17-one, DHEA) is a metabolic intermediate in the testosterone, estrone, and estradiol synthesis pathway mainly in the human adrenal cortex and rodent gonads [1,28]. The actions of this hormone reported thus far included a possible antiobesity effect [2,16], preventive action on the development of athero...

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Section: Resultsmentioning

confidence: 99%

Prevention of Orotic-Acid-Induced Fatty Liver in Male Rats by Dehydroepiandrosterone and/or Phenobarbital.

Goto

Yamashita

Makita

1998

The Journal of Veterinary Medical Science

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“…Despite these similarities, clofibrate elevated microsomal epoxide hydrolase activity accompanied by a decrease in glutathione transferase activity only in the Sprague-Dawley strain. Similarly, Pill et al (1992) found that LEW rats were far more susceptible to peroxisomal proliferation than Sprague-Dawley animals, as evidenced by the marked rise in hepatic total peroxisomal oxidation activities and cytochro me c oxidase activity in LEW rats. In a comparison of various strains Makowska et al (1990) demonstrated that ciprofibrate induced a ninefold increase in peroxisomal fatty acid-oxidase in Sprague-Dawley, Wistar, and F344 strains, whereas a marked 35-fold elevation was noted in Long-Evan s rats.…”

Section: Peroxisomal Proliferationmentioning

confidence: 86%

Editorial

Kacew

Festing²

1996

Journal of Toxicology and Environmental Health

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The development of drugs to combat diseases, chemicals to improve food production, or compounds to enhance the quality of life necessitates, by law, the use of laboratory animals to test their safety. In order to simulate the human condition it is necessary to choose a species in which pharmacokinetic and toxicokinetic mechanisms are established and resemble those of humans. The advantages of the use of the rat in drug and chemical toxicity testing include (a) metabolic pathway similarities to humans; (b) numerous similar anatomical and physiological characteristics; (c) a large database, which is extremely important for comparative purposes; and (d) the ease of breeding and maintenance of animals at relatively low cost. However, the choice of rat can be complicated, especially when over 200 different strains of rat are known to exist. The aim of this review is to summarize genetically determined differences in the responsiveness of rat strains to drugs and naturally occurring chemicals and to show that susceptibility is dependent on the target organ sensitivities, which may also be strain dependent. It is suggested that detailed studies of strain differences may help to clarify toxic mechanisms. Such studies are usually best conducted using inbred strains in which the genetic characteristics have been fixed, rather than in outbred stocks in which individual samples of animals may differ, the phenotype is variable, and the stocks are subject to substantial genetic drift. The fact that strains may differ also needs to be taken into account in assessing the potential hazard of the chemical, particularly when a study involves only a single strain and therefore provides no assessment of likely strain variation.

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“…The impact of bezafibrate on hyperlipidemic hamsters has not yet been evaluated, and a previous dose–response study with fenofibrate suggested that the dose commonly used in mouse was efficacious in hamsters [15], [17], [18], [41]. We thus reasoned this may also be the case for bezafibrate, and selected daily dosing of 25 and 50 mg kg − 1 bezafibrate based on earlier rodent models’ studies in which 10 mg kg − 1 was the lowest effective dose for lowering serum lipids in rats [29], [42]–[45]. According to present results, we thus can presume that the dyslipidemia in hamsters may be more severe than that in mice or rats.…”

Section: Discussionmentioning

confidence: 99%

Novel PPAR Pan Agonist, ZBH Ameliorates Hyperlipidemia and Insulin Resistance in High Fat Diet Induced Hyperlipidemic Hamster

Chen¹,

Fan²,

Xie³

et al. 2014

PLoS ONE

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Effective and safe pharmacological interventions for hyperlipidemia remains badly needed. By incorporating the key pharmacophore of fibrates into the natural scaffold of resveratrol, a novel structural compound ZBH was constructed. In present study, we found ZBH reserved approximately one third of the sirtuin 1 (SIRT1) activation produced by resveratrol at in-vitro enzyme activity assay, directly bound to and activated all three peroxisome proliferator-activated receptor (PPAR) subtypes respectively in PPAR binding and transactivation assays. Moreover, ZBH (EC50, 1.75 µM) activate PPARα 21 fold more efficiently than the well-known PPAR pan agonist bezafibrate (EC50, 37.37 µM) in the cellular transactivation assays. In the high fat diet induced hyperlipidemic hamsters, 5-week treatment with ZBH significantly lowered serum triglyceride, total cholesterol, LDL-C, FFA, hyperinsulinemia, and improved insulin sensitivity more potently than bezafibrate. Meanwhile, serum transaminases, creatine phosphokinase and CREA levels were found not altered by ZBH intervention. Mechanism study indicated ZBH promoted the expression of PPARα target genes and SIRT1 mRNA. Hepatic lipogenesis was markedly decreased via down-regulation of lipogenic genes, and fatty acid uptake and oxidation was simultaneously increased in the liver and skeletal muscle via up-regulation of lipolysis genes. Glucose uptake and utilization was also significantly promoted in skeletal muscle. These results suggested that ZBH significantly lowered hyperlipidemia and ameliorated insulin resistance more efficiently than bezafibrate in the hyperlipidemic hamsters primarily by activating of PPARα, and SIRT1 promotion and activation. ZBH thus presents a potential new agent to combat hyperlipidemia.

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Differences in the response of Sprague-Dawley and Lewis rats to bezafibrate: The hypolipidemic effect and the induction of peroxisomal enzymes

Cited by 13 publications

References 41 publications

Prevention of Orotic-Acid-Induced Fatty Liver in Male Rats by Dehydroepiandrosterone and/or Phenobarbital.

Prevention of Orotic-Acid-Induced Fatty Liver in Male Rats by Dehydroepiandrosterone and/or Phenobarbital.

Editorial

Novel PPAR Pan Agonist, ZBH Ameliorates Hyperlipidemia and Insulin Resistance in High Fat Diet Induced Hyperlipidemic Hamster

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