Effect of hypolipidemic drugs on key enzyme activities related to lipid metabolism in normolipidemic rabbits

Alegret, Marta; Verd, Joan C; Dı́az, Cristina; Hernández, Gonzalo; Adzet, T.; Sánchez, Rosa María Galán; Laguna, Juan C.

doi:10.1016/s0014-2999(98)00096-x

Cited by 22 publications

(27 citation statements)

References 50 publications

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“…On the other hand, it was shown that fibrates possess hypocholesterolemic (Krause and Princen 1998) and hypotriglyceridemic (Frøyland et al 1997) effects in rats. An explanation for this discrepancy may be a dosage of fibrates (10-500 mg/kg) usually used in other experimental studies (Fujioka et al 1995;Alegret et al 1998) and highly exceeding the recommended daily dosage for human which was given in our study (0.3 mg/kg).…”

Section: Discussioncontrasting

confidence: 61%

“…Number of papers have described the effect of hypolipidemic drugs on levels of cholesterol and triacylglycerols in serum (Illingworth and Tobert 1994) and on the liver lipid metabolism (Alegret et al 1998), but there are only a few studies focused on other tissues e.g. skin (Wolf et al 1999), vascular wall (Bellosta et al 1998) and eye-lens (De Vries and Cohen 1993).…”

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confidence: 99%

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Hypolipidemic Drugs Can Change the Composition of Rat Brain Lipids

Vecka

Tvrzická

Staňková

et al. 2004

Tohoku J. Exp. Med.

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Hypolipidemic drugs are potent serum cholesterol lowering agents used for prevention of coronary heart disease. In addition to their cholesterol lowering effect, these drugs exhibit both pleiotropic beneficial and various neurological side effects. Therefore, we analysed effect of the hypolipidemic drugs, fenofibrate and statins, on membrane lipid composition in the rat brain tissue. Male Wistar rats were given 0.1 mg of fenofibrate, lovastatin, pravastatin, fluvastatin or placebo (control) once daily for six weeks. In rats treated with lovastatin or pravastatin, decreased cholesterol and increased ceramide monohexoside contents in the brain tissue were observed in comparison with control. Treatment with fluvastatin or lovastatin resulted in increased sphingomyelin and decreased diphosphatidylglycerol contents. The most important changes in the fatty acid profile were observed in ceramide monohexosides; treatment with fluvastatin decreased the content of saturated and increased the content of polyunsaturated fatty acids. Fenofibrate treatment led to decreased content of saturated fatty acids in phosphatidylethanolamines. In conclusion, statin treatment resulted in the decreased content of cholesterol and diphosphatidylglycerol associated with the increased content of sphingolipids in the rat brain tissue. As cholesterol and sphingolipids are important components of brain membranes, the observed alterations in the composition brain lipids might be involved in genesis of neurological and mental symptoms following statin therapy.statin; fibrate; brain; lipids; fatty acid

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Section: Discussioncontrasting

confidence: 61%

mentioning

confidence: 99%

Hypolipidemic Drugs Can Change the Composition of Rat Brain Lipids

Vecka

Tvrzická

Staňková

et al. 2004

Tohoku J. Exp. Med.

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“…A similar increase in LPL activity has been seen in rats treated with simvastatin (27). However, neither drug has been shown to affect postheparin LPL activity in normolipidemic rabbits (28).…”

Section: Discussionsupporting

confidence: 61%

The effect of high-dose simvastatin on triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus

Isley

Miles

Patterson

et al. 2006

Journal of Lipid Research

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Statins decrease triglycerides (TGs) in addition to decreasing low density lipoprotein-cholesterol. Although the mechanism for the latter effect is well understood, it is still unclear how TG decrease is achieved with statin therapy. Because hypertriglyceridemia is common in obese patients with type 2 diabetes mellitus, we studied triglyceride-rich lipoprotein triglyceride (TRL-TG) turnover in 12 such subjects using stable isotopically labeled glycerol. The diabetic subjects were studied after 12 weeks of placebo and after a similar course of therapy with simvastatin (80 mg daily) in a single-blind design. The results were compared with those from six nonobese nondiabetic control subjects. Simvastatin therapy reduced serum TGs by 35% in the diabetic subjects. Compared with the control subjects, TRL-TG secretion was almost 2-fold higher in the diabetic subjects (45.4 6 4.9 vs. 24.4 6 1.9 mmol/min; P , 0.002) and was unaffected by simvastatin therapy. However, TRL-TG clearance was significantly increased in the diabetic subjects during simvastatin treatment compared with placebo (0.25 6 0.03 vs. 0.16 6 0.02 pools/h; P , 0.002). This change was accompanied by a 49% increase in preheparin plasma lipase activity (P , 0.03) and a 21% increase in postheparin LPL activity (P , 0.01). Together, these findings provide strong evidence that the effect of statins on serum TGs is related to an increase in LPL activity, resulting in accelerated delipidation of TRL particles. HMG-CoA reductase inhibitors, or statins, are widely used in diabetic patients and have been shown to decrease cardiovascular morbidity in individuals with type 2 diabetes (5, 6). The major effect of statins is a reduction in low density lipoprotein-cholesterol (LDL-C) concentrations, primarily mediated by inhibition of the rate-limiting step in cholesterol biosynthesis, resulting in an increase in LDL receptors in the liver (7). In addition, statins can reduce TGs and increase HDL-C (8, 9), all of which lead to a reduced risk for coronary heart disease (CHD) in patients with type 2 diabetes mellitus (5, 6, 10).The mechanism responsible for the TG-lowering effect of statins is poorly defined. In theory, it could be related to decreased VLDL production (presumably secondary to decreased availability of hepatic free cholesterol for particle assembly), increased clearance of VLDL through the LDL receptor (or other lipoprotein receptors), increased delipidation of VLDL particles via LPL, or a combination of these mechanisms. To address these questions, we determined triglyceride-rich lipoprotein triglyceride (TRL-TG, which is predominantly VLDL) production and clearance in subjects with type 2 diabetes mellitus and hypertriglyceridemia on placebo and high-dose simvastatin therapy (80 mg daily) for 12 weeks and in nondiabetic controls. RESEARCH DESIGN AND METHODS Study subjects

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“…Two key differences between rabbits and humans is that the plasma CETP activity level in rabbits is 3 to 4 times higher than in humans, and although lipoprotein lipase activities are similar between the 2 species, hepatic lipase activity is greatly diminished in the rabbit. 14 Two previous studies 22,23 in the normolipidemic chow-fed NZW rabbit examined HDL cholesterol responses (but not apoA-I responses or HDL apoA-I turnover) after atorvastatin treatment. Although atorvastatin treatment did not result in a significant change in HDL cholesterol in these studies, it is difficult to compare the previous studies with the present one because of differences in drug dosage, length of treatment, and the ages and weights of the NZW rabbits (Ϸ2 kg versus 4 to 5 kg in the present study) used among the studies.…”

Section: Discussionmentioning

confidence: 99%

“…An increase in HDL triglycerides has previously been demonstrated in response to atorvastatin treatment in humans 30 ; however, the mechanism of the atorvastatin-induced HDL triglyceride enrichment is not clear. Atorvastatin appears to inhibit CETP activity in humans, which should decrease HDL triglycerides, 31 and fails to alter hepatic and lipoprotein lipase levels in the rabbit model, 22 which should leave the HDL triglyceride content unchanged. Nonetheless, triglyceride enrichment of HDL has previously been shown to enhance HDL apoA-I catabolism in vivo, 32 and combined with other drug-induced effects, could have contributed to the enhanced HDL apoA-I clearance in the present study.…”

Section: Discussionmentioning

confidence: 99%

Effect of Atorvastatin on High-Density Lipoprotein Apolipoprotein A-I Production and Clearance in the New Zealand White Rabbit

et al. 2002

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Background-HMG-CoA reductase inhibitors reduce the incidence of cardiovascular disease predominantly by their LDL-lowering effect. Recently, there has been great interest in the pleiotropic effects of statins, which appear to differ among the various agents in this class. Unlike other statins, atorvastatin exhibits a decline in its HDL-raising effect at higher doses in humans. Whether atorvastatin-mediated alterations in HDL turnover in vivo contribute to this effect has not previously been investigated. We therefore studied the effect of atorvastatin on HDL apolipoprotein (apo) A-I production and clearance in normolipidemic male New Zealand White rabbits. Methods and Results-Kinetic studies of HDL-apoA-I radiolabeled with 131 I were performed in chow-fed rabbits after 3 weeks of atorvastatin treatment of 5 mg · kg Ϫ1 · d Ϫ1 (nϭ7) versus placebo-treated rabbits (nϭ7). Our results showed a significantly (PϽ0.001) more rapid clearance (Ϸ2-fold) of HDL apoA-I in atorvastatin-treated animals compared with the control group (0.121Ϯ0.012 versus 0.061Ϯ0.004 pools/h, respectively), accompanied by a lesser 48% increase in the apoA-I production rate (3.84Ϯ0.38 versus 2.59Ϯ0.41 mg · kg Ϫ1 · h

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Effect of hypolipidemic drugs on key enzyme activities related to lipid metabolism in normolipidemic rabbits

Cited by 22 publications

References 50 publications

Hypolipidemic Drugs Can Change the Composition of Rat Brain Lipids

Hypolipidemic Drugs Can Change the Composition of Rat Brain Lipids

The effect of high-dose simvastatin on triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus

Effect of Atorvastatin on High-Density Lipoprotein Apolipoprotein A-I Production and Clearance in the New Zealand White Rabbit

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