Short and long-term effects of streptozotocin on dietary cholesterol absorption, plasma lipoproteins and liver lipoprotein receptors in RICO rats

Summary:

Adult male genetically hypercholesterolemic RICO rats were studied 6 and 28 days after streptozotocin (STZ) administration together with untreated RICO controls. The absorption coefficient of dietary cholesterol was determined using dual-isotope blood ratio method. Plasma lipoproteins as well as fecal neutral sterols and bile acids were analysed at both experimental times. Liver lipid parameters were measured and lipoprotein receptors (LDLr, SR-BI and HB2) were assayed by immunodetection. Six days after STZ administration, dietary cholesterol absorption was more efficient (+ 49%) in treated rats than in controls, and stayed higher (+ 68%) in the diabetic rats sacrificed at day 28. Fecal neutral sterol elimination decreased soon after STZ administration (by 35% at day 6), due to a higher cholesterol absorption coefficient, then increased to control level at day 28, due to installed diabetes-induced hyperphagia. Comparison of the lipoprotein profiles indicated that the concentration of HDL1, which is typically high in control Rico rats, fell significantly in diabetic rats at both experimental times, whereas that of HDL2 increased only at day 28. In diabetic rats, an early and strong enhancement of the hepatic expression of SR-BI appeared at day 6 (+ 415%) and persisted at day 28, but at a lesser extent (+ 85%). The expression of LDLr and HB2 was unchanged at day 6, but was significantly modified at day 28 (+ 140% for LDLr and - 50% for HB2). These data show that streptozotocin-induced diabetes in Rico rats results in modifications of the expression of liver lipoprotein receptors which can contribute to alterations of the lipoprotein profile.

Key words:

Genetically hypercholesterolemic RICO rats - diabetes - cholesterol absorption - lipoproteins - lipoproteins receptors

References

• 1 Acton S, Rigotti A, Landschulz K T, Shangzhe X, Hobbs H H, Krieger M. Identification of scavenger receptor SR-BI as a High Density Lipoprotein receptor.  Science. 271 518-520 1996; 
• 2 Arai T, Wang N, Bezouevski M, Welch C, Tall A R. Decreased atherosclerosis in heterozygous low density density lipoprotein receptor-deficient mice expressing the scavenger receptor BI transgene.  J Biol Chem. 274 2366-2371 1999; 
• 3 Arbeeny C M, Edelstein D, Freedman S R, Eder H A. Serum lipoproteins of diabetic rats fed a high cholesterol diet.  Diabetes. 29 774-777 1980; 
• 4 Bennion L J, Grundy S M. Effects of diabetes mellitus on cholesterol metabolism in man.  N Engl J Med. 296 1365-1371 1977; 
• 5 Cardona-Sanclemente L E, Férézou J, Lutton C. Cholesterol metabolism in the genetically hypercholesterolemic rat (RICO). II. Study of plasma lipoproteins and effect of dietary cholesterol.  Biochim Biophys Acta. 960 382-389 1988; 
• 6 Cardona-Sanclemente L E, Verneau C, Mathé D, Lutton C. Cholesterol metabolism in the genetically hypercholesterolemic rat (RICO). I. Measurement of turnover processes.  Biochim Biophys Acta. 919 205-212 1987; 
• 7 Cases S, Novack S, Zheng Y, Myers H M, Lear S R, Sande E, Welch C B, Lusis A J, Spencer T A, Crouse B R, Erickson S K, Farese R V. ACAT-2, a second mammalian acyl-CoA: cholesterol acyltransferase.  J Biol Chem. 273 26755-26764 1998; 
• 8 Chang C CY, Huh H Y, Cadigan K M, Chang T Y. Molecular cloning and functional expression of human acyl-CoA: cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells.  J Biol Chem. 268 20747-20755 1993; 
• 9 Christrieb A R. Diabetes and hypertensive vascular disease. Mechanism and treatment.  Am J Cardiol. 32 592-606 1973; 
• 10 Colca J R, Dailey C F, Palazuk B J, Hillman R M, Dinh D M, Melchior G W, Spilman C H. Pioglitazone hydrochloride inhibits cholesterol absorption and lowers plasma cholesterol concentrations in cholesterol-fed rats.  Diabetes. 40 1669-1674 1991; 
• 11 Felgines C, Sérougne C, Mazur A, Férézou J, Lutton C, Rayssiguier Y. Hepatic apolipoprotein and LDL receptor gene expression in the genetically hypercholesterolemic (RICO) rat.  Atherosclerosis. 117 15-24 1995; 
• 12 Gavish D, Oschry Y, Eisenberg S. In vivo conversion of human HDL3 to HDL2 and ApoE-rich HDL1 in the rat: effects of lipid transfer protein.  J Lipid Res. 28 257-267 1987; 
• 13 Grundy S M, Ahrens E H, Miettinen T A. Quantitative isolation and gas liquid chromatography analysis of total fecal bile acids.  J Lipid Res. 30 719-730 1965; 
• 14 Hauser H, Dyer J H, Nandy A, Vega M A, Werder M, Bieliauskaite E, Weber F E, Compassi S, Gemperli A, Boffelli D, Wehrli E, Schulthess G, Phillips M C. Identification of a receptor mediating absorption of dietary cholesterol in the intestine.  Biochemistry. 37 17843-17850 1998; 
• 15 Howard B V. Lipoprotein metabolism in diabetes mellitus.  J Lipid Res. 28 613-628 1987; 
• 16 Jiao S, Matsuzawa Y, Matsubara K, Kihara S, Nakamuna T, Tokunaga K, Kubo M, Tarui S. Increased activity of intestinal acylCoA: cholesterol acyltransferase in rats with streptozotocin-induced diabetes and restoration by insulin supplementation.  Diabetes. 37 342-346 1988; 
• 17 Khallou J, Riottot M, Parquet M, Verneau C, Lutton C. Biodynamics of cholesterol and bile acids in the lithiasic hamster.  Br J nutr. 66 479-492 1991; 
• 18 Kovanen P T, Brown M J, Goldstein J L. Increased binding of low density lipoproteins to liver membranes from rats treated with 17a-ethinyl estradiol.  J Biol Chem. 254 11367-11373 1979; 
• 19 Kozarsky K F, Donahee M H, Rigotti A, Iqbal S N, Edelman E R, Krieger M. Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels.  Nature. 387 414-417 1997; 
• 20 Krieger F B. Diabetes and lipoprotein receptors.  Diabetes Metabolism Reviews. 3 591-618 1987; 
• 21 Kusunoki J, Aragane K, Kitamine T, Kozono H, Kano K, Fujinami K, Kojima K, Chiwata T, Sekine Y. Postprandial hyperlipidemia in Streptozotocin-induced diabetics rats is due to abnormal increase in intestinal acyl coenzyme A: cholesterol acyltransferase activity.  Arterioscler Thromb Vasc Biol. 20 171-178 2000; 
• 22 Largis E E, Wang C H, De Vries V G, Schaffer S A. CL 277,082: a novel inhibitor of ACAT catalyzed cholesterol esterification and cholesterol absorption.  J Lipid Res. 30 681-690 1989; 
• 23 Lowry O H, Rosebrough H J, Farr A, Randall R J. Protein measurement with the folin phenol reagent.  J Biol Chem. 193 265-275 1951; 
• 24 Lutton C. Mesure de l'absorption du cholestérol chez le Rat. Identité des résultats obtenus par la méthode d'équilibre isotopique et la méthode de Zilversmit.  Ann Biol Anim Bioch Biophys. 19 757-761 1979; 
• 25 Lutton C. Comparison of isotopic equilibrium and dual isotope blood ratio methods for measurement of cholesterol absorption in rats.  Digestion. 20 346-350 1980; 
• 26 Lutton C. Anatomical heterogeneity of the intestinal mucosa and cholesterol homeostasis.  Digestion. 57 1-10 1996; 
• 27 Lutton C, Fidge N H. Distribution of high density lipoprotein binding proteins among various tissues of the rat.  CR Acad Sc Paris. 317 731-735 1994; 
• 28 Maechler P, Wolheim C B, Bentzenard C L, Niesor E. Role of the intestinal acylCoA: cholesterol acyltransferase activity in the hyperresponse of diabetic rats to dietary cholesterol.  J Lipid Res. 33 1475-1484 1992; 
• 29 Mamo J C, Hirano T, Sainsbury A, Fitzgerald A C, Redgrave T G. Hypertriglyceridemia is exacerbated by slow lipolysis of triaglycerol rich lipoproteins in fed but not fasted streptozotocin diabetic rats.  Biochim Biophys Acta. 1128 132-138 1992; 
• 30 Marzetta C A, Savoy Y E, Freeman A M, Long C A, Pettini J L, Hagar R E, Inskeep P B, Davis K, Stucchi A F, Nicolosi R J, Hamanaka E S. Pharmacological properties of a novel ACAT inhibitor (CP-113,818) in cholesterol-fed rats, hamsters, rabbits, and monkeys.  J Lipid Res. 35 1829-1838 1994; 
• 31 Matsumoto A, Mitchell A, Kurata H, Pyle L, Kondo K, Itakura H, Fidge N H. Cloning and characterization of HB2, a candidate high density lipoprotein receptor.  J Biol Chem. 272 16778-16782 1997; 
• 32 Matthai D, Fidge N H, Tozuka M, Mitchell A. Simvastatin and cholestyramine treatment reduces the level of expression of high density lipoprotein binding proteins in rat liver.  Arteriosclerosis. 10 1045-1050 1990; 
• 33 McLean M P, Zhao Z, Ness G C. Reduced hepatic LDLr, 3-hydroxy-methylglutaryl-CoenzymeA reductase and sterol carrier protein 2 expression is associated with pregnancy loss in the diabetic rat.  Endocrine. 3 695-703 1995; 
• 34 Meiner V L, Cases S, Myers H M, Sande E R, Bellosta S, Schambelan M, Pitas R E, McGuire J, Herz J, Farese R V. Disruption of the acyl-CoA: cholesterol acyltransferase gene in mice: evidence suggesting multiple cholesterol esterification enzymes in mammals.  Proc Natl Acad Sci USA. 93 14041-14046 1996; 
• 35 Milliat F, Sérougne C, Gripois D, Lutton C. Effects of insulin deficiency on lipoproteins and their hepatic receptors in Rico rats.  CR Acad Sc Paris. 321 999-1006 1998; 
• 36 Nakai T, Oida K, Tamai T, Kutsumi Y, Miyabo S, Takeda R. Characteristics of lipoproteins receptors of the isolated liver parenchymal cells prepared from the streptozotocin-induced diabetic rats.  Life Sci. 38 653-662 1986; 
• 37 Nervi F O, Gonzalez A, Valdivieso V D. Studies on cholesterol metabolism in experimental diabetic rat.  Metabolism. 23 495-503 1974; 
• 38 Ouguerram K, Magot T, Lutton C. Alterations in cholesterol metabolism in the genetically hypercholesterolemic RICO rat: an overview. In: Malmendier CL, Alaupovic P, Brewer HB (eds): Hypercholesterolemia, hypocholesterolemia, hypertriglyceridemia, in vivo kinetics. Advances in Experimental Medicine and Biology Plenum Press, New York, London 285 257-274 23 495-503
• 39 Riottot M, Olivier P, Huet A, Caboche J, Parquet M, Khallou J, Lutton C. Hypolipidemic effects of β-cyclodextrin in the hamster and in the genetically hypercholesterolemic Rico rat.  Lipids. 28 181-188 1994; 
• 40 Salter A M, Fisher S C, Brindley D N. Interactions of triiodothyronine, insulin and dexamethasone on the binding of human LDL to rat hepatocytes in monolayer culture.  Atherosclerosis. 71 77-80 1988; 
• 41 Schedl H P, Wilson H D. Effects of diabetes on intestinal growth in the rat.  J Exp Zool. 176 487-496 1971; 
• 42 Schneider W J, Beisiegel U, Goldstein J L, Brown M S. Purification of the low density lipoprotein receptor, an acidic glycoprotein of 164,000 molecular weight.  J Biol Chem. 257 2664-2673 1982; 
• 43 Schonfeld G. Diabetes, lipoproteins and atherosclerosis.  Metabolism. 34 5-50 1985; 
• 44 Sérougne C, Felgines C, Férézou J, Hajri T, Bertin C, Mazur A. Hypercholesterolemia induced by cholesterol or cystine enriched diets is characterized by different plasma lipoprotein and apolipoprotein levels in rats.  J Nutr. 125 35-41 1995; 
• 45 Sérougne C, Férézou J, Rukaj A. A new relationship between cholesterolemia and cholesterol synthesis determined in rats fed an excess of cystine.  Biochim Biophys Acta. 921 522-530 1987; 
• 46 Sérougne C, Feurgard C, Hajri T, Champarnaud G, Férézou J, Mathé D, Lutton C. Catabolism of HDL1 cholesteryl ester in the rat. Effect of ethinyl estradiol treatment.  CR Acad Sc Paris. 322 591-596 1999; 
• 47 Suckling K E, Stange E F. Role of acylCoA cholesterol acyltransferase in cellular cholesterol metabolism.  J Lipid Res. 26 647-671 1985; 
• 48 Swami S, Sztalryd C, Kraemer F B. Effects of streptozotocin-induced diabetes on low density lipoprotein receptor expression in rat adipose tissue.  J Lipid Res. 37 229-236 1996; 
• 49 Thomson A BR. Unidirectional flux rate of cholesterol and fatty acids into the intestine of rats with drug-induced diabetes mellitus: effect of variations in the effective resistance of the unstirred water layer and the bile acid micelle.  J Lipid Res. 21 687-698 1980; 
• 50 Tozuka W J, Fidge N H. Purification and characterization of two high density lipoproteins binding proteins from rat and human liver.  J Biochem. 261 239-244 1989; 
• 51 Trezzi E, Catapano A L. Effects of insulin deficiency on the catabolism of plasma lipoproteins and on the expression of hepatic lipoprotein receptors in rats.  Pharmacol Res Com. 16 539-548 1984; 
• 52 Wade D P, Knight B L, Soutar A K. Hormonal regulation of low-density lipoprotein (LDL) receptor activity in human hepatoma Hep G2 cells.  Eur J Biochem. 174 213-218 1988; 
• 53 Wang N, Arai T, Ji Y, Rinninger F, Tall A R. Liver-specific overexpression of scavenger receptor BI decreases levels of very low density lipoprotein apoB, low density lipoprotein apoB and high density lipoprotein in transgenic mice.  J Biol Chem. 273 32920-32926 1998; 
• 54 Young N L, Lopez D R, Mc Namara D J. Contributions of absorbed dietary cholesterol and cholesterol synthesized in small intestine to hypercholesterolemia in diabetic rats.  Diabetes. 37 1151-1156 1988; 
• 55 Young N L, McNamara D J, Saudek C D, Krasovsky J, Lopez D R, Levy G. Hyperphagia alters cholesterol dynamics in diabetic rat.  Diabetes. 32 811-819 1983; 
• 56 Zilversmit D B, Hughes L B. validation of a dual-isotope plasma ratio method for measurement of cholesterol absorption in rats.  J lipid Res. 15 465-473 1974;