Different effects of fibrates on the microsomal fatty acid chain elongation and the acyl composition of phospholipids in guinea-pigs.

1. The effects in vitro and in vivo of three fibric acid derivatives, clofibrate (CFB), bezafibrate (BFB) and gemfibrozil (GFB) on some enzyme activities related to fatty acid biosynthesis, namely palmitoyl-CoA synthetase and hydrolases (microsomal and cytosolic), NADH and NADPH cytochrome c reductases and acyl-CoA elongases were investigated in guinea-pigs. 2. The three fibrates inhibited acyl-CoA elongation in vitro, irrespective of the substrate of elongation used (saturated, monounsaturated, polyunsaturated) and with an order of potency GFB > BFB > CFB. In the case of GFB, inhibition occurred at concentrations that can be reached in vivo. 3. Microsomal palmitoyl-CoA hydrolase and synthetase were also inhibited in vitro (GFB > or = BFB > CFB), whereas NADH cytochrome c reductase activity was increased by GFB. Nevertheless, the magnitude of changes were lower than those observed in elongation activities. 4. Treatment with fibrates did not produce peroxisomal proliferation in guinea-pigs, as measured by peroxisomal beta-oxidation activity and liver weight/body weight ratio. Nevertheless, fibrates provoked a reduction in plasma cholesterol and triglycerides, at least in GFB- and BFB-treated animals. 5. Fatty acid elongation was significantly modified by GFB treatment in vivo. The remaining enzyme activities studied were only slightly changed by fibrate treatment. 6. Treatment with BFB and to a lesser extent with CFB, increased the relative proportion of MUFA (palmitoleic and oleic acids) in microsomal phospholipids, whereas PUFA (mainly linoleic acid) decreased. GFB behaved differently, increasing palmitic and linoleic acids and decreasing stearic and oleic acids. The latter changes are attributable to an inhibition of elongation activity by GFB. 7. The changes observed after fibrate treatment in both rats and guinea-pigs, as they are not directly related to peroxisome proliferation, could be more reliably extrapolated to man than those observed only in rats.     

Selective modification of rat hepatic microsomal fatty acid chain elongation and desaturation by fibrates: relationship with peroxisome proliferation.

1. The time-course of the effect of clofibrate (CFB), bezafibrate (BFB) and gemfibrozil (GFB) on lipid plasma levels and palmitoyl-, palmitoleoyl- and gamma-linolenoyl-CoA elongase, delta-9, delta-6 and delta-5 desaturase activities, and microsomal electron transport chains, as well as the correlation with the peroxisomal proliferation phenomenon have been studied in male Sprague-Dawley rats. 2. As reported in our previous work, the three drugs behave as peroxisomal proliferators (the order of potency was BFB > CFB > or = GFB) and induced a clear reduction in both plasma cholesterol and triglyceride levels. 3. Palmitoyl-CoA elongation activity was increased by the three drugs (BFB = GFB > CFB), whereas palmitoleoyl-CoA elongation activity was only enhanced by GFB. Elongation activity was not modified by fibrates when gamma-linolenoyl-CoA was used as substrate. These results are in accordance with the existence of three different elongation systems for saturated, mono- and polyunsaturated fatty acids. 4. delta-9, delta-6 and delta-5 desaturase activities were increased by the three fibrates, with an order of potency BFB > CFB = GFB for delta-9 and delta-5, and GFB > BFB = CFB for delta-6. 5. Of the enzyme activities integrated in the microsomal electron transport chains, NADH cytochrome b5 reductase was not affected by fibrate treatment, NADPH cytochrome c reductase activity was enhanced (BFB = GFB > CFB), whereas NADH cytochrome c reductase activity was reduced by CFB and BFB.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of fibrates on the acyl composition of microsomal phospholipids in rats.

1. The time-course and comparative effects of treatment with clofibrate (CFB), bezafibrate (BFB), and gemfibrozil (GFB) on the acyl composition of the main microsomal phospholipids, i.e. phosphatidylcholine and phosphatidylethanolamine, have been studied in male Sprague-Dawley rats. 2. The administration of the three fibrates caused a strong peroxisomal induction and a hypolipidaemic effect. Concerning the changes in acyl composition, CFB and BFB behaved in a similar way, with differences which could be attributed to their different potency as peroxisome inducers, whereas GFB showed a somewhat distinct profile. 3. The three drugs increased the relative content of palmitic, palmitoleic and oleic acids, whereas the levels of stearic acid and also those of long chain, highly unsaturated fatty acids docosatetraenoic, docosapentaenoic and docosahexaenoic acids were reduced. In general, these effects appeared from the first day of treatment and were highly correlated with peroxisomal proliferation. In addition, they were more evident in the phosphatidylcholine than in the phosphatidylethanolamine fraction. 4. Fibrates increased total monounsaturated fatty acids, whereas a decrease in total polyunsaturated fatty acids in the phosphatidylcholine fraction was observed in CFB- and BFB-, but not in GFB-treated rats. Clear differences appeared between CFB and BFB on the one hand, and GFB on the other when the influence of fibrate treatment on the molar percentages of linoleic, eicosatrienoic, arachidonic and mead acids was analyzed. 5. GFB increased linoleic acid content in phosphatidylethanolamine, whereas CFB and BFB decreased its level in both phospholipid fractions. In contrast, CFB and BFB enhanced eicosatrienoic and mead acids in both fractions and arachidonic acid in phosphatidylethanolamine, whereas GFB had practically no effect.     

Relationship between plasma lipids and palmitoyl-CoA hydrolase and synthetase activities with peroxisomal proliferation in rats treated with fibrates.

1. The time-course of the effect of clofibrate (CFB), bezafibrate (BFB) and gemfibrozil (GFB) on lipid plasma levels and palmitoyl-CoA hydrolase and synthetase activities, as well as the correlations with the peroxisomal proliferation phenomenon have been studied in male Sprague-Dawley rats. 2. The administration of the three drugs caused a significant reduction in body weight gain, accompanied with a paradoxical increase in food intake in groups treated with BFB and GFB. 3. Drug treatment produced gross hepatomegaly and increase in peroxisomal beta-oxidation, and these parameters were strongly correlated. The order of potency was BFB > CFB > or = GFB. 4. Both plasma cholesterol (BFB approximately CFB > GFB) and triglyceride (BFB approximately GFB > CFB) levels were reduced in treated animals. There was an inverse correlation between these parameters and peroxisomal beta-oxidation, although the peroxisomal proliferation seemed to explain only a small part of the hypolipidemic effect observed. 5. Cytosolic and microsomal (but not mitochondrial) palmitoyl-CoA hydrolase activities were increased by the three drugs (BFB > CFB > GFB), probably by inducing the hydrolase I isoform, which is insensitive to inhibition by fibrates in vitro. The increased hydrolase activities were directly and strongly correlated with peroxisomal beta-oxidation. 6. Palmitoyl-CoA synthetase activity was also increased by the treatment with fibrates (BFB > CFB > GFB), probably as a consequence of the enhancement of hydrolase activities.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fibrates and triglyceride metabolism

Summary Some mechanisms of the triglyceride-lowering effects of fibrates in patients with hypertriglyceridemia are reviewed. One main effect of the fibrates is the stimulation of lipoprotein lipase activities in plasma as well as in adipose tissue. According to this increase in the degradational activity VLDL catabolism is stimulated, as has been demonstrated for VLDL apo B and VLDL triglycerides. In addition, the composition of hypertriglyceridemic LDL is reverted towards normal. Furthermore, the increased degradation via the nonreceptor pathway is decreased by fibrate treatment, thus lowering the atherogenic potential of triglyceride-rich lipoproteins. But additionally the degree of postprandial hypertriglyceridemia is lowered by fibrates.     

Statin-fibrate combination: therapy for hyperlipidemia: a review

Statins and fibrates are well-established treatments for hyperlipidaemias and the prevention of vascular events. However, fibrate + statin therapy has been restricted following early reports of rhabdomyolysis that mainly involved gemfibrozil, originally with bovastatin, and recently, with cerivastatin. Despite this limitation, several reports describing combination therapy have been published. This review considers these studies and the relevant indications and contraindications. Statin + fibrate therapy should be considered if monotherapy or adding other drugs (e.g. cholesterol absorption inhibitors, omega-3 fatty acids ornicotinic acid) did not achieve lipid targets or is impractical. Combination therapy should be hospital-based and reserved for high-risk patients with a mixed hyperlipidaemia characterised by low density lipoprotein cholesterol (LDL) >2.6 mmol/l(100 mg/dl, high density lipoprotein cholesterol (HDL) <1.0 mmol/l (40 mg/dl) and/or triglycerides> 5.6 mmol/l (500 mg/dl. These three 'goals' are individually mentioned in guidelines. Patients should have normal renal, liver and thyroid function tests and should not be receiving therapy with cyclosporine, protease inhibitors or drugs metabolised through cytochrome P450 (especially 3A4). Combination therapy is probably best conducted using drugs with short plasma half-lives; fibrates should be prescribed in the morning and statins at night to minimise peak dose interactions. Both drug classes should be progressively titated from low doses. Regular (3-monthly) monitoring of liver function and creatine kinase is required. In conclusion, fibrate + statin therapy remains an option in high-risk patents. However, long-term studies involving safety monitoring and vascular endpoints are required to demonstrate the efficacy of this regimen.     

Inhibition of rat lipoprotein oxidation after tetradecylthioacetic acid feeding

We have previously shown that tetradecylthioacetic acid (TTA), a sulfur containing saturated fatty acid analogue, inhibits the oxidative modification of human low-density lipoprotein (LDL) in vitro. The oxidative modification of LDL is believed to be a crucial step in the progression of atherosclerosis. In the present study, we investigated the effect of TTA oral administration on the susceptibility of rat lipoprotein to undergo oxidative modification ex vivo. Lipoprotein resistance to copper-induced oxidation was highly improved after TTA administration to rats. Conjugated dienes produced after 150 min of lipoprotein oxidation were dramatically lowered in the TTA treated rats compared to controls. Malondialdehyde and lipid peroxides production by oxidation was highly limited. These effects were independent of any Vitamin E effects. More than 50% relative reduction in polyunsaturated fatty acids of the n-3 family, and more than 30% relative increase in 18:1n-9 fatty acid in the triacylglycerol (TAG)-rich lipoprotein were observed. TAG-rich lipoprotein lipids of TTA fed rats were decreased with more than 50% reduction in TAG. The data reported in this paper indicate a potent in vivo antioxidant capability of TTA that beside its hypolipidemic effect might be of importance in relation to the development of atherosclerosis.     

Comparative studies on the influence of different fibrates on serum lipoproteins in endogenous hyperlipoproteinaemia

Summary Two trials have been performed in the same patients with hyperlipoproteinaemia Types IIb (12 cases), III (6 cases) and IV (11 cases). In the first study the lipid-lowering properties of bezafibrate, fenofibrate, gemfibrozil, etofibrate and etofylline clofibrate were compared and in a separate trial the influence of combined treatment with gemfibrozil plus colestipol and bezafibrate plus probucol on lipoproteins were investigated. The mean percentage lipid-lowering effect of each fibrate on serum and VLDL fraction was significant in the Types IIb, III and IV patients, but there were significant differences between the fibrates. In general, gemfibrozil and bezafibrate decreased plasma lipid levels more than etofibrate and etofylline clofibrate in Type IIb patients. In Type IV cases gemfibrozil and bezafibrate were significantly potent in reducing the triglyceride level than fenofibrate, etofibrate or etofylline clofibrate. All the fibrates produced an increase in HDL cholesterol, but there were significant differences between them were in the Type IV patients. The influence of fibrates on the LDL fraction was much more variable. In hyperlipoproteinaemia Type IIb, a decrease in both LDL cholesterol and LDL apolipoprotein B was observed. In Type III and IV patients, however, an increase in LDL concentration occurred. The addition of colestipol to gemfibrozil therapy led to a further decrease in total cholesterol, LDL cholesterol and LDL apolipoprotein B in Type IIb patients. In patients with hyperlipoproteinaemia Types III and IV colestipol prevented the increase in LDL concentration after treatment with gemfibrozil alone. The effect of probucol on LDL cholesterol was comparable to that of colestipol. Combined treatment with gemfibrozil and colestipol caused an increase in HDL cholesterol concentration in contrast to combined treatment with bezafibrate and probucol. It is concluded that combined therapy with fibrates plus bile acid sequestrant would be of practical value in patients with hyperlipoproteinaemia Types IIb, III and IV.     

Hypolipidemic effect of triphala in experimentally induced hypercholesteremic rats

Hypercholesteremia is one of the risk factors for coronary artery disease. The present study highlights the efficacy of Ayurvedic herbal formulation Triphala (Terminalia chebula, Terminalia belerica, and Emblica officinalis) on total cholesterol, Low density lipoprotein (LDL), Very low density lipoprotein (VLDL), High density lipoprotein (HDL) and free fatty acid in experimentally induced hypercholesteremic rats. Four groups of rats were employed namely control, Triphala treated, hypercholesterolemia rats (4% Cholesterol + 1% cholic acid + egg yolk) and Triphala pre-treatment in hypercholesteremic rats. Results showed significant increase in the total cholesterol, LDL, VLDL, and free fatty acid in hypercholesteremic rats were significantly reduced in Triphala treated hypercholesteremic rats. The data demonstrated that Triphala formulation was associated with hypolipidemic effects on the experimentally induced hypercholesteremic rats.     

Statin-fibrate combination therapy for hyperlipidaemia: a review

SUMMARY

Statins and fibrates are well-established treatments for hyperlipidaemias and the prevention of vascular events. However, fibrate?+?statin therapy has been restricted following early reports of rhabdomyolysis that mainly involved gemfibrozil, originally with lovastatin, and recently, with cerivastatin. Despite this limitation, several reports describing combination therapy have been published. This review considers these studies and the relevant indications and contraindications.

Statin?+?fibrate therapy should be considered if monotherapy or adding other drugs (e.g. cholesterol absorption inhibitors, omega-3 fatty acids or nicotinic acid) did not achieve lipid targets or is impractical. Combination therapy should be hospital-based and reserved for high-risk patients with a mixed hyperlipidaemia characterised by low density lipoprotein cholesterol (LDL)?>?2.6?mmol/l (100?mg/dl), high density lipoprotein cholesterol (HDL)?<?1.0?mmol/l (40?mg/dl) and/or triglycerides?>?5.6?mmol/l (500?mg/dl). These three ‘goals’ are individually mentioned in guidelines. Patients should have normal renal, liver and thyroid function tests and should not be receiving therapy with cyclosporine, protease inhibitors or drugs metabolised through cytochrome P450 (especially 3A4). Combination therapy is probably best conducted using drugs with short plasma half-lives; fibrates should be prescribed in the morning and statins at night to minimise peak dose interactions. Both drug classes should be progressively titrated from low doses. Regular (3-monthly) monitoring of liver function and creatine kinase is required.

In conclusion, fibrate?+?statin therapy remains an option in high-risk patients. However, long-term studies involving safety monitoring and vascular endpoints are required to demonstrate the efficacy of this regimen.     

Protection by scoparone against the alterations of plasma lipoproteins, vascular morphology and vascular reactivity in hyperlipidaemic diabetic rabbit.

1. The in vivo pharmacological effects of scoparone (6,7-dimethoxycoumarin) in a hyperlipidaemic diabetic rabbit model were investigated. 2. Three groups of rabbits were studied: (1) normal, (2) hyperlipidaemic and diabetic-untreated and (3) hyperlipidaemic and diabetic-scoparone treated. The hyperlipidaemic diabetic rabbits were fed with 1% cholesterol and treated with alloxan, a diabetogenic agent. The plasma levels of total cholesterol, total triglyceride, very low-density lipoprotein (VLDL) cholesterol, low density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were markedly increased as soon as the rabbit became diabetic at the second week. Scoparone-treatment (5 mg kg-1 day-1, s.c.) significantly reduced the plasma lipid and lipoprotein cholesterol levels of the hyperlipidaemic diabetic rabbit to 73.3% of total cholesterol, 48.3% of total triglyceride, 66.0% of VLDL cholesterol, 55.7% of LDL cholesterol and 79.5% of HDL cholesterol. 3. Six weeks after cholesterol-feeding, the aortic arch and thoracic aorta were dissected for morphological and functional studies. In vascular rings from the untreated hyperlipidaemic diabetic rabbit, there was intimal thickening with accumulation of fatty streaks, foam cells and migration of smooth muscle cells to the intima. In the rabbits treated with scoparone, there were fewer pathological morphology changes found in vascular segments than in the untreated hyperlipidaemic diabetic rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioanalysis of PUFA metabolism and lipid peroxidation in coronary atherosclerosis

Twenty eight men (age 34-77 years) who underwent an elective coronary angiography for coronary artery disease (CAD), were studied. They were divided into group A (luminal narrowing < 50%; n = 11) and group B (luminal narrowing > 50%; n = 17). Capillary gas chromatography was used for determination of fatty acids. Retinol and alpha-tocopherol were analyzed by reversed-phase high-performance liquid chromatography (HPLC), other parameters were determined spectrofluorometrically and spectrophotometrically. Severe coronary atherosclerosis in group B was associated with higher serum low density lipoprotein/high density lipoprotein (LDL/HDL) cholesterol ratio, triacylglycerols, and phospholipids (P < 0.05). Erythrocyte membrane fatty acids C14:0, C16:1 and C22:6n3 were significantly higher in group B (P < 0.05). We found significantly higher plasma polyunsaturated fatty acids (PUFA) C18:3n6 in group B, whereas plasma linoleic acid was not changed significantly. There was a significant increase of IDL-C18:0, LDL-C14:0 and HDL-C22:6n3 PUFA in group B. We conclude that disturbances in saturated fatty acids (SUFA) and PUFA metabolism are associated with coronary atherogenesis. Such abnormalities may include enhanced extrahepatic transport of C14:0 SUFA via LDL and its incorporation into cell membranes, and enhanced clearance of anti atherosclerotic C22:6n3 PUFA via serum HDL.     

北沙参的脂肪酸特征及产地差异性分析

目的 研究北沙参的脂肪酸特征,比较山东莱阳、河北安国、内蒙古赤峰等三个主产地的北沙参脂肪酸差异。方法 Bligh and Dyer法提取总脂;甲酯化后,利用气相色谱-质谱联用仪（GC-MS）分析;通过与脂肪酸标准品及NIST 11.0质谱数据库比对鉴定脂肪酸种类,采用面积归一法分别计算各成分的相对质量分数。结果 分别从山东莱阳、河北安国和内蒙古赤峰的北沙参药材中鉴定了17、17和18种脂肪酸;三个产地药材的优势脂肪酸种类一致,依次为C18:2 n-6c（亚油酸,49.22~63.96%）、C16:0（棕榈酸,17.43~25.33%）和C18:1 n-9c（油酸,13.85~19.44%）,均未检测到n-3型多不饱和脂肪酸（PUFA）。山东莱阳药材的多不饱和脂肪酸总量（PUFA）低于河北安国及内蒙古赤峰,但饱和脂肪酸（SFA）、 单不饱和脂肪酸（MUFA）和多不饱和脂肪酸（PUFA）三者比值最接近1:1:1。结论 不同产地北沙参的脂肪酸种类相近。亚油酸是北沙参含量优势脂肪酸,提示可以作为北沙参防治胆固醇代谢相关疾病的质量标志物候选分子。     

Lifibrol increases hepatic cholesterol 7α-hydroxylase activity in sprague-dawley rats

The hypocholesterolemic drug lifibrol was administered orally to Sprague-Dawley rats to determine its effects on lipoprotein cholesterol distribution and hepatic HMG-CoA reductase and cholesterol 7α-hydroxylase activities. The effects of lifibrol on those endpoints were compared with the effects of gemfibrozil and lovastatin. When administered to either chow-fed or cholesterol-fed rats, lifibrol (25 or 50 mg/kg/day) caused a redistribution of lipoprotein cholesterol such that HDL increased and VLDL + LDL decreased significantly. Gemfibrozil (30 or 50 mg/kg/day) caused similar changes in lipoprotein cholesterol distribution. In contrast, lovastatin (10 mg/kg/day) decreased both HDL and VLDL + LDL in chow-fed animals, but had no effect in cholesterol-fed animals. Hepatic HMG-CoA reductase activity was increased in rats treated with lifibrol (50 mg/kg/day), gemfibrozil (50 mg/kg/day), and lovastatin (10 mg/kg/day). The most significant finding is that lifibrol was the only drug that increased hepatic cholesterol 7α-hydroxylase activity. This observation in rats separates the mechanism of action of lifibrol from those of the HMG-CoA reductase inhibitors and the fibrates, and suggests that one mechanism of action of lifibrol is to enhance cholesterol elimination through conversion to bile acids. © 1994 Wiley-Liss, Inc.     

Effect of simvastatin and fenofibrate on the fatty acid composition of hypercholesterolaemic patients

1. The effects of simvastatin (one of a new class of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors) and fenofibrate on the fatty acid composition of cholesterol esters, phospholipids and triglycerides of different lipoproteins of 15 patients with primary hypercholesterolaemia were compared in a double-blind study. 2. Fenofibrate (300 mg day-1) increased the relative content of saturated fatty acids of cholesterol esters, phospholipids and triglycerides in VLDL, IDL and HDL. It also increased the relative content of monounsaturated fatty acids of cholesterol esters and phospholipids in all fractions and those of triglycerides in VLDL and IDL. In contrast, it decreased the proportion of polyunsaturated fatty acids of cholesterol esters and phospholipids in all fractions and those of triglycerides in VLDL and IDL. The polyunsaturated/saturated (P/S) ratio was reduced in cholesterol esters and phospholipids in VLDL and in phospholipids in IDL by fenofibrate. The drug significantly increased the 18:1w9/18:2w6 ratio in cholesterol esters and phospholipids in VLDL, LDL and HDL, but produced a non-significant increase in the ratio in IDL. 3. Simvastatin (20 mg day-1) produced a significant decrease in saturated fatty acid and an increase in polyunsaturated fatty acid in triglycerides in VLDL. Simvastatin, in contrast to fenofibrate caused a slight decrease in saturated and monounsaturated fatty acids in the three other lipoprotein fractions, and an increase in polyunsaturated fatty acids. The P/S and 18:1w9/18:2w6 ratios were not modified by simvastatin.     

Influence of dipyridamole on the fatty acid composition of the main lipid classes of chick serum

We have studied the effects of dipyridamole treatment on the fatty acid composition of the main lipid classes of chick serum bearing in mind the relationship between platelet aggregation and eicosanoids production from arachidonic acid. In the free fatty acids, percentages of MUFA and n-6 PUFA fell. The effects of dipyridamole appeared to be less pronounced in triglyceride fraction, but more so in serum phospholipids and cholesterol esters. The percentage of arachidonic acid was significantly reduced by dipyridamole, as well as that of different n-3 PUFA present in phospholipid fraction. The percentage of linoleic acid in serum cholesterol esters was significantly lowered by dipyridamole, whereas that of arachidonic acid did not change significantly. Our results suggest that decreased arachidonic acid in the serum phospholipids and linoleic acid in all lipid classes may be of importance in order to dipyridamole participation in several pathologies characterized by an imbalance in the production of vasodilator and vasoconstrictor prostanoids.     

Guinea pigs as models to study the hypocholesterolemic effects of drugs

Guinea pigs are useful models to investigate the mechanisms of the hypocholesterolemic effects of drugs. Like humans, guinea pigs are one of the few species that carry the majority of cholesterol in LDL. This animal model has also been shown to develop atherosclerosis when challenged with hypercholesterolemic diets. In addition, plasma lipid profiles in males, females and ovariectomized guinea pigs, a model for menopause, follow similar patterns to those observed in humans. In this report, drugs aimed at lowering plasma cholesterol and triglycerides in hyperlipidemic individuals are reviewed. Studies analyzing the hypolipidemic effect of HMG-CoA reductase inhibitors, acyl CoA cholesterol acyltransferase inhibitors, fibrates, bile acid resins, apical sodium bile acid transporter inhibitors, and others show that guinea pigs and humans have comparable responses to drug therapy. In addition, results from the limited clinical reports addressing specific effects of drugs on LDL catabolism or VLDL synthesis are in agreement with observations in guinea pigs. From the review of these studies, it is apparent that the guinea pig is a useful animal model to further explore the mechanisms of action of lipid lowering drugs including effects on specific receptors and regulatory enzymes involved in cholesterol metabolism and on early atherosclerosis development. Abbreviations: ACAT, acyl-CoA:cholesterol acyltransferase; ASBT, apical sodium co-dependent bile acid transporter; ApoB, apolipoprotein B; CHD, coronary heart disease; CYP7, cholesterol 7alpha-hydroxylase; HDL, high density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; FCR, free catabolic rate; LDL, low density lipoprotein; PPAR, peroxisome proliferators-activated receptor; TC, total cholesterol; TG, triglycerides; VLDL, very low density lipoprotein.     

The Hypolipidemic Activity of l-N-3-Methylphthalimido-butan-3-semicarbazone in Rodents

l-N-(3-Methylphthalimido)butan-3-one semicarbazone demonstrated potent hypolipidemic activity in normal rats and mice and hyperlipidemic diet-induced mice. The compound decreased tissue lipid levels and increased the fecal excretion of cholesterol and triglycerides. After 2 weeks of administration, serum lipoprotein levels were modulated so that very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) cholesterol concentrations were reduced and high-density lipoprotein (HDL) cholesterol concentrations were elevated to levels unprecedented by the cyclic imide derivatives previously tested. The VLDL triglyceride content was also reduced. Hepatic in vitro enzymatic studies demonstrated that the compound suppressed the activity of enzymes in the early synthesis of fatty acids and cholesterol and the regulatory enzymes for the de novo synthesis of triglycerides.