Effects of ciprofibrate and fenofibrate on liver lipids and lipoprotein synthesis in normo- and hyperlipidemic rats

      This paper is only available as a PDF. To read, Please Download here.


      The plasma lipoprotein and liver lipid composition, and the lipid, cholesterol and apolipoprotein synthesis have been studied in normal and diet-induced hyperlipidemic rats, receiving ciprofibrate (2.5 mg/kg body weight) or fenofibrate (50 mg/kg b.w.) for 8 days. Ciprofibrate is about 25-fold more active than fenofibrate in reducing plasma triglyceride and cholesterol concentrations both in normolipemic and in hyperlipemic rats. In normolipemic rats ciprofibrate reduced the concentration and the lipid content of all lipoprotein classes. The incorporation of [14C]palmitate and [3H]leucine into the lipoproteins was reduced by ciprofibrate and fenofibrate. The reduction in lipoprotein production was confirmed by prevention of Triton-induced hyperlipemia. Liver and plasma cholesterol synthesis estimated by 3H2O and [14C]mevalonate incorporation indicated an inhibitory effect on HMG-CoA reductase. Administration of ciprofibrate or fenofibrate to rats fed a fat and cholesterol-rich diet partially prevented liver steatosis and hyperlipemia. Both drugs reduced the overproduction of lower density lipoproteins. The ratio of (VLDL + LDL)-cholesterol/HDL-cholesterol which was increased by the diet alone from 0.4 (normal) to 11 remained close to the normal value in the animals receiving ciprofibrate. In the hyperlipemic animals, ciprofibrate reduced the incorporation of [3H]oleate into the liver and plasma glycerolipid and increased cholesterol esterification. Ciprofibrate efficiently reduces plasma levels of cholesterol, triglyceride and phospholipid. Cholesterol and glycerolipid synthesis in the liver were significantly reduced leading to a lower lipoprotein secretion rate in both normolipidemic and diet-induced hyperlipidemic rats.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Thorp J.M.
        • Waring W.S.
        Modification of metabolism and distribution of lipids by ethyl-chlorophenoxy-isobutyrate.
        Nature. 1962; 194: 948
        • Arnold A.
        • McAuliff J.P.
        • Beyler A.L.
        Metabolic effects of a new hypolipidemic agent, Ciprofibrate.
        Pharm. Sci. 1979; 68: 1557
        • Arnold A.
        • McAuliff J.P.
        • Powers L.G.
        • Phillips D.K.
        • Beyler A.L.
        The results of animal studies with Ciprofibrate, a new orally effective hypolipidemic drug.
        Atherosclerosis. 1979; 32: 155
        • Davignon J.
        • Gascon B.
        • Brossard D.
        • Quidoz S.
        • Leboeuf N.
        • Lelorier J.
        The use of Ciprofibrate in the treatment of familial hyperlipidaemias.
        in: Lipoproteins and Coronary Athersoclerosis. Elsevier Biomedical Press B.V, Montreal1982: 213
        • Brown D.F.
        • Beyler A.
        • Daudiss K.
        Effective therapy in type II hyperlipoproteinemia with a new long acting drug, Ciprofibrate.
        Am. J. Cardiol. 1979; 43: 409
        • Angelin B.
        • Einarssonn K.
        • Leidj B.
        Effect of ciprofibrate treatment on biliary lipids in patients with hyperlipoproteinaemia.
        Eur. J. Clin. Invest. 1984; 14: 73
        • Harvengt C.
        • Heller F.
        • Desager J.P.
        Hypolipidemic and hypouricemic action of fenofibrate in various types of hyperlipoproteinemia.
        Artery. 1980; 7: 73
        • Rossner S.
        • Orö L.
        Fenofibrate therapy of hyperlipoproteinemia. A dose-response study and a comparison with clofibrate.
        Atherosclerosis. 1981; 38: 273
        • Edelson J.
        • Benziger D.
        • Arnold A.
        • Beyler A.L.
        Blood levels, tissue distribution and the duration of action in rats of ciprofibrate, a new hypolipidemic agent.
        Atherosclerosis. 1979; 33: 351
        • Davison C.
        • Benziger D.
        • Fritz A.
        • Edelson J.
        Absorption and disposition of 2-[4-(2,2-dichlorocyclopropyl) phenoxy]-2-methyl propanoic acid, WN 35833, in rats, monkeys and men.
        Drug Metab. Dispos. 1975; 3: 520
        • Dole V.P.
        A relation between non esterified fatty acids in plasma and the metabolism of glucose.
        J. Clin. Invest. 1956; 35: 150
        • Lindemann R.
        • Gjessing L.R.
        • Merton B.
        • Loken A.C.
        • Halvorsen S.
        Amino acid metabolism in hereditary fructosemia.
        Acta Paediatr. Scand. 1970; 59: 141
        • Havel R.J.
        • Eder H.A.
        • Bragdon J.H.
        The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum.
        J. Clin. Invest. 1955; 34: 1345
        • Folch H.
        • Less M.
        • Sloane-Stanley G.H.
        A simple method for the isolation and purification of total lipids from animal tissues.
        J. Biol. Chem. 1957; 226: 497
        • Lowry O.H.
        • Rosebrough N.J.
        • Farr A.L.
        • Randall R.J.
        Protein measurement with the Folin phenol reagent.
        J. Biol. Chem. 1951; 193: 265
        • Mans R.J.
        • Novelli G.D.
        Measurement of the incorporation of radioactive amino acids into protein by a filter paper disk method.
        Arch. Biochem. Biophys. 1961; 94: 48
        • Kritchevsky D.
        • Tepper S.A.
        • Story J.A.
        Influence of procetofen on lipid metabolism in normocholesteremic rats.
        Pharmacol. Res. Commun. 1979; 11: 635
        • Castelli W.P.
        • Doyle J.T.
        • Gordon T.
        • Hames C.G.
        • Hjoftland M.C.
        • Hulley S.B.
        • Kagan A.
        • Zukel W.J.
        HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study.
        Circulation. 1977; 55: 767
        • Miller N.E.
        • Førde O.H.
        • Thelle D.S.
        • Mjøs O.D.
        The Tromsø heart study. High density lipoprotein and coronary heart disease: a prospective case-control study.
        Lancet. 1977; i: 965
        • Timms A.R.
        • Kelly L.A.
        • Ho R.S.
        • Trapold J.H.
        Laboratory of 1-methyl-4-piperidyl bis(p-chlorophenoxy) acetate (SaH42-348). A new hypolipidemic agent.
        Biochem. Pharmacol. 1969; 18: 1861
        • Olsson A.G.
        • Oro L.
        Dose response study of the effect of ciprofibrate on serum lipoprotein concentrations in hyperlipoproteinaemia.
        Atherosclerosis. 1982; 42: 229
        • Illingworth D.R.
        • Olsen G.D.
        • Cook S.F.
        • Sexton G.J.
        • Wendel H.A.
        • Connor W.E.
        Ciprofibrate in the therapy of type II hypercholesterolema. A double-blind trial.
        Atherosclerosis. 1982; 44: 211
        • Brindley D.N.
        • Bowley M.
        Drugs affecting the synthesis of glycerides and phospholipids in rat liver: the effects of clofibrate, fenfluramine, amphetamine, cinchocaine, demethylimipramine, imipyramine and some of their derivatives.
        Biochem. J. 1975; 148: 461
        • Brindley D.N.
        Some aspects of the physiological and pharmacological control of the synthesis of triacylglycerols and phospholipids.
        Int. J. Obesity. 1978; 2: 7
        • Skrede S.
        • Halvorsen O.
        Increased biosynthesis of CoA in the liver of rats treated with clofibrate.
        Eur. J. Biochem. 1979; 98: 223
        • Lamb R.G.
        • Fallon H.J.
        Inhibition of monoacylglycerophosphate formation by chlorophenoxyisobutyrate and β-benzalbutyrate.
        J. Biol. Chem. 1972; 247: 1281
        • Christiansen R.J.
        The effect of clofibrate on hepatic fatty acid metabolism.
        Biochim. Biophys. Acta. 1978; 530: 314
        • Burch R.E.
        • Curran G.L.
        Hepatic aceto acetyl-CoA deacylase activity in rats fed ethyl chlorophenoxyisobutyrate.
        J. Lipid Res. 1969; 10: 668
        • Bourdeaux A.M.
        • Paris R.M.
        Influence de produits normolipémiants (clofibrate et procétofène) sur le m'etabolisme des chylomicrons chez le rat.
        Arch. Int. Physiol. Biochim. 1980; 88: 75
        • Reddy J.K.
        • Osumi T.
        • Hashimoto T.
        • Nemali M.
        • Lalwani N.D.
        • Reddy M.K.
        Tissue specific induction of peroxisomal fatty acyl-CoA oxidase and peroxisomal bifunctional proteins messenger RNA levels by ciprofibrate.
        J. Cell Biol. 1985; 101: 66A
        • Kawashima Y.
        • Katoh H.
        • Watanuki H.
        • Takegishi M.
        • Kozuka H.
        Effects of long-term administration of clofibric acid on peroxisomal beta-oxidation, fatty acid binding protein and cytosolic long-chain acyl-CoA hydrolases in rat liver.
        Biochem. Pharmacol. 1985; 34: 325
        • Harrison E.H.
        Action of clofibrate and its analogs in rats. Dissociation of hypolipidemic effects and the induction of peroxisomal beta-oxidation.
        Biochim. Biophys. Acta. 1984; 796: 163
        • Khosla P.
        • Rogers M.P.
        • Cunningham V.J.
        Hypolipoproteinaemic effects of ciprofibrate.
        Biochem. Soc. Trans. 1985; 16: 144
        • Foster D.W.
        • Srere P.A.
        Citrate cleavage enzyme and fatty acid synthesis.
        J. Biol. Chem. 1968; 243: 1926
        • Cenedella R.J.
        Clofibrate and nafenopin: effects on plasma clearance and tissue distribution of chylomicron triglyceride in the dog.
        Lipids. 1972; 7: 644