Effect of long-term clofibric acid treatment on serum and tissue lipid and cholesterol levels in obese Zucker rats

Cleary, Margot P.; Kasiske, Bertram L.; O’Donnell, Michael P.; Keane, William F.

doi:10.1016/0021-9150(87)90185-7

Cited by 11 publications

(5 citation statements)

References 35 publications

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“…In the literature fibrate effects reported on serum lipid concentrations in rats are quite inconsistent: In investigations on healthy Fischer 344, Wistar or Sprague-Dawley rats [24,35,83] as well as on lean and obese Zucker rats [83][84][85][86] both cholesterol and triglyceride concentrations were decreased after treatment with different fibrates, including ciprofibrate and clofibric acid, over periods ranging from 7 days to 4 weeks, whereas in a study on Wistar rats receiving ciprofibrate for one week only serum triglycerides but not cholesterol were lowered [78]. Other authors, in contrast, were able to demonstrate a decrease in cholesterol concentrations after administration of clofibric acid or fenofibrate over a period ranging from 2 to 30 weeks in lean and obese Zucker rats but no effect on [87][88][89] or even an increase in triglyceride concentrations [90]. The reasons for these discrepancies (especially with respect to the divergent effects seen in Zucker rats) are unclear, since similar dosages of the fibrates and mostly also rats of the same age were used.…”

Section: Discussionmentioning

confidence: 99%

Ciprofibrate, Clofibric Acid and Respective Glycinate Derivatives

Lupp

Karge

Deufel

et al. 2011

Arzneimittelforschung

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Fibrates are widely prescribed in hyperlpidemic patients to prevent atherosclerosis. Their therapeutic use, however, can be associated with adverse effects like gastrointestinal disorders, myalgia, myositis and hepatotoxicity. In rodents large doses can even cause hepatocellular carcinoma. Additionally, interactions with the biotransformation of other compounds at the cytochrome P450 (CYP) system have been observed. Thus, the discovery of new substances or derivatives with less side effects is of great interest. In the present study the influence of a four-week daily oral administration of 2 mg/kg body weight ciprofibrate (CAS 52214-84-3) or of 100 mg/kg body weight clofibric acid (CAS 882-09-7) was compared to that of the respective doses of their newly synthesized glycine conjugates in adult male lean and obese Zucker rats. Although obese rats displayed distinctly higher serum lipid concentrations, after fibrate treatment values were significantly lowered in lean animals only. Livers of obese rats were significantly enlarged, histologically showing a fine-droplet like fatty degeneration and an increase in glycogen content, but no signs of inflammation. After fibrate administration histologically a hypertrophy, an eosinophilia, a reduced glycogen content and also hepatocyteapoptosis were observed. Livers of obese rats displayed higher CYP1A1 andCYP2E1 expression, but lower immunostaining for CYP2B1 and CYP3A2. No differences between the two groups of rats were seen with respect to CYP4A1 expression. Due to fibrate treatment especially CYP2E1 and CYP4A1, but also CYP1A1, 2B1 and 3A2 were induced. Resulting CYP mediated monooxygenase activities were also elevated in most cases. In general, effects of clofibric acid and clofibric acid glycinate (CAS 4896-55-3) were less distinct than those of ciprofibrate and its glycinate (CAS 640772-36-7). With no parameterinvestigated major differences were seen between the parent fibrates and their glycine conjugates. Thus, the present investigations revealed no noticeable advantages of the glycinates over ciprofibrate or clofibric acid.

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Section: Discussionmentioning

confidence: 99%

Ciprofibrate, Clofibric Acid and Respective Glycinate Derivatives

Lupp

Karge

Deufel

et al. 2011

Arzneimittelforschung

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“…For chronic experiments, we fed male wild-type and PPAR-a 2/2 mice with a D12492 high-fat diet (60 kcal % fat; Research Diets) for 7 weeks. Body mass indices 30 were 0.36 ^0.01 g cm 22 for wild-type (n ¼ 13) and 0.41 ^0.01 g cm 22 for PPAR-a 2/2 (n ¼ 15) mice. We divided the mice into four groups (n ¼ 7-8 each) and treated them for 4 weeks with vehicle (saline/polyethylene glycol/Tween 80 (90/5/5); 1 ml per kg) or OEA (5 mg per kg i.p., once daily).…”

Section: Feeding Experimentsmentioning

confidence: 99%

“…If OEA enhances expression of PPAR-a target genes, it should also reproduce the corrective effects of PPAR-a agonists on serum lipid levels [21][22][23] . Consistent with this prediction, in genetically obese Zucker (fa/fa) rats, a 2-week regimen of OEA administration decreased serum cholesterol and triglyceride along with food intake and body weight gain (Supplementary Fig.…”

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confidence: 99%

Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α

Gaetani

Oveisi

et al. 2003

Nature

988

1,048

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Oleylethanolamide (OEA) is a naturally occurring lipid that regulates satiety and body weight. Although structurally related to the endogenous cannabinoid anandamide, OEA does not bind to cannabinoid receptors and its molecular targets have not been defined. Here we show that OEA binds with high affinity to the peroxisome-proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor that regulates several aspects of lipid metabolism. Administration of OEA produces satiety and reduces body weight gain in wild-type mice, but not in mice deficient in PPAR-alpha. Two distinct PPAR-alpha agonists have similar effects that are also contingent on PPAR-alpha expression, whereas potent and selective agonists for PPAR-gamma and PPAR-beta/delta are ineffective. In the small intestine of wild-type but not PPAR-alpha-null mice, OEA regulates the expression of several PPAR-alpha target genes: it initiates the transcription of proteins involved in lipid metabolism and represses inducible nitric oxide synthase, an enzyme that may contribute to feeding stimulation. Our results, which show that OEA induces satiety by activating PPAR-alpha, identify an unexpected role for this nuclear receptor in regulating behaviour, and raise possibilities for the treatment of eating disorders.

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“…Obese male Zucker (OZ) rats spontaneously develop hypercholesterolemia, hypertriglyceridemia, proteinuria and a glomerular lesion histologically similar to that seen in human FGS [4,[6][7][8]. Previous studies strongly suggest that the renal disease is a consequence of the hyperlipi demia since the lowering of the serum cholesterol results in significant amelioration of the glomerular disease [8].…”

Section: Introductionmentioning

confidence: 99%

Monocytes and Macrophages in Focal Glomerulosclerosis in Zucker Rats

Magil

Fröhlich²

1991

Nephron

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It has been recently suggested that focal glomerulosclerosis (FGS) is analogous to atherosclerosis. Obese Zucker (OZ) rats spontaneously develop hyperlipidemia, proteinuria and FGS. To evaluate the role of the monocyte (MO) and its derivatives in the pathogenesis of the lesion, 30 OZ rats and 15 lean littermates (LZ) were followed for up to 240 days of age. At 75,120 and 240 days of age, groups of 10 OZ and 5 LZ were assessed with respect to serum total and free cholesterol (TC and FC), triglyceride, lipoprotein electrophoresis, renal histology, histochemistry and immunohistochemistry. All serum lipids were raised at 75 days in OZ rats and increased progressively at 120 and 240 days. The early lesions of FGS were first demonstrated in OZ at 120 days with more advanced lesions at 240 days. FGS was seen in LZ only at 240 days when their serum lipids were raised. Intraglomerular MO infiltration was significantly higher in OZ than in LZ at all time periods (p < 0.01) and greater in glomeruli with FGS lesions than in those without (p < 0.01 and 120 days and p < 0.05 at 240 days). Staining for ED1 and la antigens with monoclonal antibodies demonstrated increasing numbers of intraglomerular ED1⁺ and Ia⁺ cells with increasing age and extent of FGS. The findings suggest a role for intraglomerular macrophages in the pathogenesis of FGS in OZ.

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Effect of long-term clofibric acid treatment on serum and tissue lipid and cholesterol levels in obese Zucker rats

Cited by 11 publications

References 35 publications

Ciprofibrate, Clofibric Acid and Respective Glycinate Derivatives

Ciprofibrate, Clofibric Acid and Respective Glycinate Derivatives

Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α

Monocytes and Macrophages in Focal Glomerulosclerosis in Zucker Rats

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