In vivo model systems: the choice of the experimental animal model for analysis of lipoproteins and atherosclerosis

Overturf, M. L.; Loose-Mitchell, David S.

doi:10.1097/00041433-199206000-00004

Cited by 31 publications

(18 citation statements)

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“…For example, hamsters respond much like humans to various dietary fat [17], fibers [18] and proteins [19] with respect to changes in plasma lipids and lipoproteins. In addition, the hamster plasma cholesterol level, rate of cholesterogenesis and lipoprotein metabolism are similar to those in humans [20,21]. The results of such studies indicate that the hamster is a good model for estimating the potential efficacy of cholesterollowering agents in humans.…”

Section: Discussionmentioning

confidence: 63%

Effect of SMP-500, a Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitor, on the Cholesterol Esterification and Its Hypocholesterolemic Properties

Ioriya¹,

Noguchi²,

Muraoka³

et al. 2002

Pharmacology

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We investigated the effects of SMP-500, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activities in the liver and intestine, and in macrophages. We measured its effects on the serum cholesterol levels and hepatic cholesterol content in mice, rabbits and hamsters. SMP-500 inhibited ACAT activities in rabbit liver and small intestine microsomes with IC₅₀ values of 72 and 84 nmol/l, respectively, and acted as a competitive inhibitor of rabbit liver ACAT. SMP-500 potently inhibited cholesterol esterification in rat peritoneal macrophages (IC₅₀ = 15 nmol/l). In high-fat and high-cholesterol diet-fed mice and in high-cholesterol diet-fed rabbits, SMP-500 reduced the serum cholesterol levels and the hepatic cholesterol content. SMP-500 also reduced the serum and hepatic cholesterol in normal chow-fed hamsters in a dose-dependent manner. In all the animal models, SMP-500 reduced the hepatic free cholesterol content as well as the total and esterified cholesterol. Administered orally, SMP-500 had a direct inhibitory effect on hepatic ACAT activity. These results indicate that SMP-500 is a potent and competitive ACAT inhibitor and may have a therapeutic potential for treating hypercholesterolemia and atherosclerosis.

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Section: Discussionmentioning

confidence: 63%

Effect of SMP-500, a Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitor, on the Cholesterol Esterification and Its Hypocholesterolemic Properties

Ioriya¹,

Noguchi²,

Muraoka³

et al. 2002

Pharmacology

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“…We have employed HFD induced diabetes-dyslipidemia in hamster, which is a very suitable model for screening of drugs for the regulation of lipid and carbohydrate matabolism (29,30). Feeding with solvent ether and ethanolic fractions of T.atjuna exhibited lowering of plasma lipids and glucose, suggesting that this property of test samples is mediated through peroxisomes proliferater activated receptor-~ subtype (PPAR~) in diversified manner by catabolizing Tg, upregulating lipoprotein lipases to rid off dietary load, and improve the HDL levels for the maintenance of lipid-glucose homeostasis in hamster model (31,32).…”

Section: Discussionmentioning

confidence: 99%

Antidyslipidemic and antioxidant activities of different fractions ofTerminalia arjuna stem bark

Chander

Singh

Khanna

et al. 2004

Indian J Clin Biochem

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Terminalia aquna (T. aduna) stem bark was successively extracted with petroleum ether (A), solvent ether (B), ethanol (C) and water (D). The lipid lowering activity of these four fractions A, B, C, and D was evaluated in vivo in two models viz., triton WR-1339 induced hyperlipemia in rats as well as fructose rich high fat diet (HFD) fed diabetic-dyslipidemic hamsters. Hyperlipidemia induced by triton caused marked increase in the plasma levels of total cholesterol (-Fc), triglyceride (Tg) and phospholipids (PL) in rats. After treatment with T. a~una fractions A, B, C, and D at the doses of 250 mg/kg per oral (p.o.), only the ethanolic fraction (C) exerted significant lipid lowering effect as assessed by reversal of plasma levels of Tc, Tg and PL in hyperlipidemic rats. In another experiment, feeding with HFD produced marked dyslipidemia as observed by increased levels of plasma Tc, Tg, glucose (Glu), glycerol (Gly) and free fatty acids (FFA) in hamsters. After treatment with T. arjuna fractions at the doses of 250 mg/kg p.o. only two fractions (B and C) could exert significant lowering in the plasma levels of lipids and Glu. in dyslipidemic hamsters. In vitro experiment T. arjuna fractions at tested concentrations (50-500 pg/ml) inhibited the oxidative degradation of lipids in human low density lipoprotein and rat liver microsomes induced by metal ions. These fractions when tested against generation of oxygen free radicals at the concentrations (50-500 iglml), counteracted the formation of superoxide anions (0 2) and hydrodyl radicals (OH) in non enzymic test systems. The efficacy of T. a~una fractions as antidysiipidemic and antioxidant agents was found, fraction C> fraction B> fraction A. KEY WORDSAntidyslipidemic activity, antioxidant activity, Terminalia arjuna oxygen free radical, triton model, hamster model.

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“…The rabbit was selected for this undertaking because of its usefulness in investigating the relationship of lipoprotein and cholesterol metabolism to the development of atherosclerosis (28).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of hepatic lipase in transgenic rabbits leads to a marked reduction of plasma high density lipoproteins and intermediate density lipoproteins.

Fan

Wang

Bensadoun

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

226

160

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To elucidate the precise metabolic roles of hepatic lipase (HL), a human HL cDNA in a liver-specific expression vector was used to generate transgenic lines in the rabbit, an animal that normally expresses low levels of this enzyme. HL was detected in the plasma of all rabbits only after the aministration ofheparin; HL activity in transgenic rabbits was found at levels up to 80-fold greater than that in nontransgenic littermates. This increase in enzyme activity was associated with as much as a 5-fold decrease in total plasma cholesterol levels. Expression of the transgene resulted in a dramatic reduction in the level of large high density lipoproteins (HDL1 (6).Studies in vitro indicate that HL possesses both triglyceride hydrolase and phospholipase activities, and it has a high affinity for HDL particles (1). Administration of specific antibodies against HL in cats, rats, and monkeys indicated a role for this enzyme in the conversion of very low density lipoprotein (VLDL) remnants to low density lipoproteins (LDL) (7-9), in the metabolism of apolipoprotein (apo) B48-containing lipoproteins (10-12), and in the conversion of HDL2 to HDL3 (13,14). These findings are consistent with the phenotype of HL deficiency in human subjects. This disorder, in which the premature development of atherosclerosis is a cardinal feature, is characterized by elevated total plasma triglycerides and cholesterol corresponding to an increase in the amount of triglyceride-rich . However, the precise role of HL in lipoprotein metabolism remains unclear.To elucidate the physiological roles of HL, we generated transgenic rabbits that express human HL only in the liver, a major site of metabolic activity. The rabbit was selected as a model for studying HL functions because it has naturally decreased activity of this enzyme; it has about 1/10th as much activity as that of the rat (18, 19). Our results demonstrate that HL plays a key rate-limiting role in both IDL andThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. 8724HDL metabolism; it has dramatic effects on the distribution and composition of these particles in plasma, with concomitant effects on plasma cholesterol levels. To our knowledge, this study is the first report of transgenic rabbits that overexpress an enzyme involved in lipid metabolism. MATERIALS AND METHODSCreation of the Human HL Constructs. Vectors designed for liver-specific expression contained sequences from the human apoE gene: 3 kb (plivhHL1) or 5 kb (plivhHL2) of 5'-flanking sequence, the first exon, first intron, the first six nucleotides (a nontranslated portion) of the second exon, a polylinker for cDNA insertion, the distal 92 nucleotides in the noncoding region of the fourth exon, the proximal 114 nucleotides of 3'-flanking sequence (20), and the hepatic control region (21, 22) of the apoE/C

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In vivo model systems: the choice of the experimental animal model for analysis of lipoproteins and atherosclerosis

Cited by 31 publications

References 0 publications

Effect of SMP-500, a Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitor, on the Cholesterol Esterification and Its Hypocholesterolemic Properties

Effect of SMP-500, a Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitor, on the Cholesterol Esterification and Its Hypocholesterolemic Properties

Antidyslipidemic and antioxidant activities of different fractions ofTerminalia arjuna stem bark

Overexpression of hepatic lipase in transgenic rabbits leads to a marked reduction of plasma high density lipoproteins and intermediate density lipoproteins.

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