Influence of genetic hyperlipemia in the zucker rat upon the lipemic response to graded estradiol exposure

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


      The present investigation was designed to examine the influence of genetic Type IV hyperlipoproteinemia on the metabolism of lipids in response to estrogen exposure.
      The influence of 17-β-estradiol was examined in a dose-response study over a range of hormone concentration from 10 to 100 pg/ml in genetic hyperlipidemic Zucker rats. In oophorectomized female rats, replacement levels of plasma estradiol of 40 pg/ml resulted in maximal hypertriglyceridemia of approximately 500 mg/dl representing a 5-fold exaggeration of that observed in control genetically normo-lipemic animals. This hypertriglyceridemia was associated with an increased production of triglyceride (TG) in excess of clearance, with a resulting production : clearance ratio of approximately 1.5. Exposure to maximum blood levels of estradiol, approximately 100 pg/ml, resulted in subnormal levels of plasma TG (∼145 mg/dl) in association with a reduced production: clearance ratio of approximately 0.36.
      In contrast to the marked hypocholesterolemic response to maximum estrogen exposure seen in normolipemic animals, the genetic Type IV hyperlipemic animal failed to demonstrate reduced plasma cholesterol concentration. This phenomenon was related to a rise in plasma LDL concentration in conjunction with parallel reduction in plasma HDL2 levels. Thus, an abnormal ratio of excessive LDL : HDL emerged in response to estrogen exposure in this model of human Type IV lipemia. This observation suggests that the genetic predisposition of the host may be critical to both the quantitative as well as the qualitative response to estrogen.


      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


        • Simonelli C.
        • Eaton R.P.
        Reduced triglyceride secretion — A metabolic consequence of chronic exercise.
        Amer. J. Physiol. 1978; 234: E221
        • Simonelli C.
        • Eaton R.P.
        Effect of clofibrate on in vivo triglyceride production and clearance in genetically hyperlipemic rats.
        Atherosclerosis. 1978; 29: 269
        • Engelken S.F.
        • Eaton R.P.
        The effects of altered thyroid status on lipid metabolism in the genetic hyperlipemic Zucker rat.
        Atherosclerosis. 1981; 38: 177
        • Schillinger E.
        • Gerhards E.
        Influence of hormonal contraceptives on carbohydrate and lipid metabolism in the rat.
        Biochem. Pharm. 1973; 22: 1835
        • Kim H.-J.
        • Kalkhoff R.
        Sex steroid influence on triglyceride metabolism.
        J. Clin. Invest. 1975; 56: 888
        • Kelner K.
        • Malinov R.
        • Anderson W.
        Effects of estradiol-17β on cholesterol metabolism in the rat.
        Steroids. 1977; 29: 1
        • Ferreri L.F.
        • Naito H.
        Stimulation of hepatic cholesterol 7α-hydroxylase activity by administration of an estrogen (17β-eatradiol-3-benzoate) to female rats.
        Steroids. 1977; 29: 229
        • Weinstein I.
        • Turner F.
        • Argilaga C.
        • Heimberg M.
        Effects of ethynyl estradiol on serum lipoprotein lipids in male and female rats.
        Biochim. Biophys. Acta. 1978; 530: 394
        • Kim H.-J.
        • Kalkhoff R.
        Altered apolipoproteins in sex steroid-treated rats.
        Metabolism. 1978; 27: 571
        • Fewster M.
        • Pirrie R.
        • Turner D.
        Effect of estradiol benzoate on lipid metabolism in the rat.
        Endocrinology. 1967; 80: 263
        • Aftergood L.
        • Alfin-Slater R.
        Further studies of the effects of an anovulatory drug on lipid metabolism in the rat.
        J. Lipid Res. 1971; 12: 306
        • Davis R.
        • Showalter R.
        • Kern Jr., F.
        Reversal by Triton of ethynyl-oestradiol-induced hepatic cholesterol esterification.
        Biochem. J. 1978; 174: 45
        • Davis R.
        • Roheim P.
        Pharmacologically induced hypolipidemia — The ethynyl-estradiol-treated rat.
        Atherosclerosis. 1978; 30: 293
        • Chao Y.
        • Windier E.
        • Chen G.
        • Havel R.
        Hepatic catabolism of rat and human lipoproteins in rats treated with 17α-ethinyl estradiol.
        J. Biol. Chem. 1979; 254: 11360
        • Winstein I.
        • Belitsky R.
        • Seedman S.
        • Fregly M.
        • Thrasher T.
        Effect of long-term therapy with oral contraceptive on some aspects of hepatic lipid metabolism in vitro.
        Biochem. Pharmacol. 1975; 24: 1583
        • Patsch W.
        • Kim K.
        • Weist W.
        • Schonfeld G.
        Effects of sex hormones on rat lipoproteins.
        Endocrinology. 1980; 107: 1085
        • Ferreri L.
        • Naito H.
        Effect of estrogens on rat serum cholesterol concentrations — Consideration of dose, type of estrogen, and treatment duration.
        Endocrinology. 1978; 102: 1621
        • Schweppe J.
        • Jungmann R.
        The effect of hormones on hepatic cholesterol ester synthesis in vitro.
        in: Proc. Soc. Exp. Biol. Med.131. 1969: 868
        • Loriaur D.L.
        • Ruder H.J.
        • Lipsett M.B.
        The measurement of estrone sulfate in plasma.
        Steroids. 1971; 18: 463
        • Brown-Grant K.
        • Exley D.
        • Naftolin F.
        Peripheral plasma oestradiol and lutenizing hormone concentrations during the oestrus cycle of the rat.
        J. Endocrinol. 1970; 48: 295
        • Grasso P.
        • Lansdown A.B.G.
        Long-term toxicity of propylene glycol in rats.
        Fd. Cosmet. Toxicol. 1972; 10: 151
        • Robertson R.P.
        • Gavareski D.J.
        • Henderson J.D.
        • Porte Jr., D.
        • Bierman E.L.
        Accelerated triglyceride secretion — A metabolic consequence of obesity.
        J. Clin Invest. 1973; 52: 1620
        • Ishikawa T.
        • Fidge N.
        Changes in the concentration of plasma lipoproteins and apoproteins following the administration of Triton WR-1339 to rats.
        J. Lipid Res. 1979; 20: 254
        • Baculo G.
        • David H.
        Quantitative determination of serum triglyceride.
        Clin. Chem. 1973; 19: 476
        • Carlson L.A.
        • Rossner S.
        A methodological study of an intravenous fat tolerance test with Intralipid emulsion.
        Scand. J. Clin. Lab. Invest. 1972; 29: 271
        • Allain C.C.
        • et al.
        Enzymatic determination of total serum cholesterol.
        Clin. Chem. 1974; 20: 270
        • Lopes-Virella M.F.
        • Stone P.
        • Ellis S.
        • Colwell J.A.
        Cholesterol determination in high-density lipoprotein separated by three different methods.
        Clin. Chem. 1977; 23: 882
        • Schonfeld G.
        • Frick M.S.
        • Bailey A.P.
        Measurement of apolipoprotein A-1 in rat high density lipoprotein and in rat plasma by radioimmunoassay.
        J. Lipid Res. 1976; 17: 25
        • Friedewald W.T.
        • Levy R.I.
        • Fredrickson D.S.
        Estimation of the concentration of low density cholesterol in plasma without the use of the preparative ultracentrifuge.
        Clin. Chem. 1972; 18: 499
        • Schonfeld G.
        • Felski C.
        • Howard M.A.
        Characterization of the plasma lipoprotein of the genetically obese hyperlipoproteinemia Zucker fatty rat.
        J. Lipid Res. 1974; 15: 457
        • Davidoff F.
        • Tishler S.
        • Rosoff C.
        Marked hyperlipidemia and pancreatitis associated with oral contraceptive therapy.
        N. Engl. J. Med. 1973; 289: 552
        • Hill P.
        • Martin W.G.
        Effect of estrogens on rat serum lipoproteins.
        Canad. J. Biochem. 1972; 50: 474
        • Chan L.
        • Jackson R.
        • O'Malley B.
        • Means A.
        Synthesis of very-low-density lipoproteins in the cockerel, effects of estrogen.
        J. Clin. Invest. 1976; 58: 368
        • Witztum J.
        • Schonfeld G.
        High density lipoproteins.
        Diabetes. 1979; : 326
        • Kovanen P.T.
        • Brown M.S.
        • Goldstein J.L.
        Increased binding of low density lipoprotein to liver membrane from rats treated with 17α-ethinyl estradiol.
        J. Biol. Chem. 1979; 254: 11367
        • Hay R.V.
        • Pottenger L.A.
        • Reingold A.L.
        • Getz G.S.
        • Wissler R.W.
        Degradation of I125labeled serum low density lipoprotein in normal and estrogen treated male rats.
        Biochem. Biophys. Res. Comm. 1971; 44: 1471
        • Kritchevsky D.
        • Tepper S.A.
        • Whitehouse M.M.
        Influence of sex and sex hormones on the oxidation of cholesterol-26-C14 by rat liver mitochondria.
        J. Lipid Res. 1963; 4: 188
        • Kraemer F.B.
        • Chen D.I.
        • Cheung R.M.C.
        • Reaven G.M.
        Lipoprotein binding in sucrose induced hypertriglyceridemia in the rat.
        Clin. Res. 1981; 29 (Abstr.): 56A
        • Mahley R.W.
        • Weisgraber K.H.
        • Melchior G.W.
        • Innerarity T.L.
        • Holcombe K.S.
        Inhibition of receptor-mediated clearance of lipemic and arginine-modified lipoproteins from the plasma of rats and monkeys.
        in: Proc. Nat. Acad. Sci.77. 1980: 225
        • Witztum J.L.
        • Branks M.J.
        • Steinberg D.
        Non-enzymatic glycosylation of low density lipoprotein (LDL) interferes with its high affinity receptor uptake by fibroblasts.
        Clin. Res. 1981; 29 (Abstr.): 61A
        • Russ E.M.
        • Eder H.A.
        • Barr D.P.
        Influence of gonadal hormones on protein-lipid relationships in human plasma.
        Amer. J. Med. 1955; 19: 4
        • Oliver M.F.
        • Boyd G.S.
        The influence of the sex hormones on the circulating lipids and lipoproteins in coronary sclerosis.
        Circulation. 1956; 13: 82
        • The Coronary Drug Project Research Group
        The Coronary Drug Project — Findings leading to discontinuation of the 0.5 mg/day estrogen group.
        J. Amer. Med. Ass. 1973; 226: 652
        • Tikkanen M.J.
        • Nikkilä E.A.
        • Vartiainen
        Natural oestrogen as an effective treatment for Type II hyperlipoproteinemia in postmenopausal women.
        The Lancet. 1978; ii (Sept.): 490
        • Wallentin L.
        • Larsson-Cohn U.
        Metabolic and hormonal effects of post-menopausal oestrogen replacement treatment.
        Acta Endocrinol. (Copenh.). 1977; 86: 597
        • Gordon T.
        • Castelli W.P.
        • Hjørtland M.C.
        • Kannel W.B.
        • Dawber T.R.
        High density lipoprotein as a protective factor against coronary heart disease.
        Amer. J. Med. 1977; 62: 707