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• W2109538419 abstract "Niemann-Pick type C (NPC) protein functions to move unesterified cholesterol from the lysosomal compartment to other intracellular sites for further metabolism and/or excretion. This cholesterol is brought into the cell through the coated-pit pathway and accumulates in the lysosomes when NPC protein is mutated. The present study quantitated the alternative uptake process that brings cholesterol into the cell through the scavenger receptor, class B, type I (SR-BI) pathway in animals with this mutation. In homozygous NPC mice, the tissues of the extrahepatic compartment accumulated an excess of 14 mg of cholesterol each day per kg body weight, and synthesis increased by a similar amount (to 111 mg/day per kg) to compensate for this functional loss of sterol through lysosomal sequestration. An amount of cholesterol (108 mg/day per kg) nearly equal to that synthesized in the extrahepatic compartment was carried through the circulation by high density lipoprotein (HDL) and taken up by the liver. The rate of hepatic cholesterol excretion from the NPC mice as fecal acidic (65 mg/day per kg) and neutral (85 mg/day per kg) sterols was elevated 61% above control values and was accounted for by the total amount of cholesterol brought to the liver in HDL and synthesized in the hepatocytes. These studies demonstrated that while cholesterol entering tissues of the NPC animals through the coated-pit pathway became sequestered in the lysosomal compartment and was metabolically inactive, cholesterol that was newly synthesized or that entered cells through the SR-BI pathway was metabolized and excreted normally. —Xie, C., S. D. Turley, and J. M. Dietschy. Centripetal cholesterol flow from the extrahepatic organs through the liver is normal in mice with mutated Niemann-Pick type C protein (NPC1). J. Lipid Res. 2000. 41: 1278–1289. Niemann-Pick type C (NPC) protein functions to move unesterified cholesterol from the lysosomal compartment to other intracellular sites for further metabolism and/or excretion. This cholesterol is brought into the cell through the coated-pit pathway and accumulates in the lysosomes when NPC protein is mutated. The present study quantitated the alternative uptake process that brings cholesterol into the cell through the scavenger receptor, class B, type I (SR-BI) pathway in animals with this mutation. In homozygous NPC mice, the tissues of the extrahepatic compartment accumulated an excess of 14 mg of cholesterol each day per kg body weight, and synthesis increased by a similar amount (to 111 mg/day per kg) to compensate for this functional loss of sterol through lysosomal sequestration. An amount of cholesterol (108 mg/day per kg) nearly equal to that synthesized in the extrahepatic compartment was carried through the circulation by high density lipoprotein (HDL) and taken up by the liver. The rate of hepatic cholesterol excretion from the NPC mice as fecal acidic (65 mg/day per kg) and neutral (85 mg/day per kg) sterols was elevated 61% above control values and was accounted for by the total amount of cholesterol brought to the liver in HDL and synthesized in the hepatocytes. These studies demonstrated that while cholesterol entering tissues of the NPC animals through the coated-pit pathway became sequestered in the lysosomal compartment and was metabolically inactive, cholesterol that was newly synthesized or that entered cells through the SR-BI pathway was metabolized and excreted normally. —Xie, C., S. D. Turley, and J. M. Dietschy. Centripetal cholesterol flow from the extrahepatic organs through the liver is normal in mice with mutated Niemann-Pick type C protein (NPC1). J. Lipid Res. 2000. 41: 1278–1289. The integrity of cells in virtually every tissue of the body, including neurons of the central nervous system, apparently depends on access to a continuous supply of cholesterol cycling through the cystosol to the plasma membrane. While several steps in this cycling process have been elucidated, only recently has the protein been identified and cloned that functions to move unesterified cholesterol from the lysosomal compartment to a metabolically active pool of sterol in the cell that can regulate cholesterol and bile acid synthesis, act as substrate for several biosynthetic pathways and be excreted from the cell into the plasma or bile (1Pentchev P.G. Comly M.E. Kruth H.S. Vanier M.T. Wenger D.A. Patel S. Brady R.O. A defect in cholesterol esterification in Niemann-Pick disease (type C) patients.Proc. Natl. Acad. Sci. USA. 1985; 82: 8247-8251Google Scholar, 2Liscum L. Faust J.R. Low density lipoprotein (LDL)-mediated suppression of cholesterol synthesis and LDL uptake is defective in Niemann-Pick type C fibroblasts.J. Biol. Chem. 1987; 262: 17002-17008Google Scholar, 3Sokol J. Blanchette-Mackie E.J. Kruth H.S. Dwyer N.K. Amende L.M. Butler J.D. Robinson E. Patel S. Brady R.O. Comly M.E. Vanier M.T. Pentchev P.G. Type C Niemann-Pick disease. Lysosomal accumulation and defective intracellular mobilization of low density lipoprotein cholesterol.J. Biol. Chem. 1988; 263: 3411-3417Google Scholar, 4Loftus S.K. Morris J.A. Carstea E.D. Gu J.Z. Cummings C. Brown A. Ellison J. Ohno K. Rosenfeld M.A. Tagle D.A. Pentchev P.G. Pavan W.J. Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene.Science. 1997; 277: 232-235Google Scholar, 5Carstea E.D. Morris J.A. Coleman K.G. Loftus S.K. Zhang D. Cummings C. Gu J. Rosenfeld M.A. Pavan W.J. Krizman D.B. Nagle J. Polymeropoulos M.H. Sturley S.L. Ioannou Y.A. Higgins M.E. Comly M. Cooney A. Brown A. Kaneski C.R. Blanchette-Mackie E.J. Dwyer N.K. Neufeld E.B. Chang T-Y. Liscum L. Strauss III, J.F. Ohno K. Zeigler M. Carmi R. Sokol J. Markie D. O'Neill R.R. van Diggelen O.P. Elleder M. Patterson M.C. Brady R.O. Vanier M.T. Pentchev P.G. Tagle D.A. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.Science. 1997; 277: 228-231Google Scholar). Because mutational inactivation of this molecule leads to the clinical syndrome of Niemann-Pick type C (NPC) disease, this protein has been designated NPC1. This molecule has an endoplasmic reticulum signal peptide, 13–16 potential membrane-spanning regions, and a possible lysosomal targeting motif (4Loftus S.K. Morris J.A. Carstea E.D. Gu J.Z. Cummings C. Brown A. Ellison J. Ohno K. Rosenfeld M.A. Tagle D.A. Pentchev P.G. Pavan W.J. Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene.Science. 1997; 277: 232-235Google Scholar, 5Carstea E.D. Morris J.A. Coleman K.G. Loftus S.K. Zhang D. Cummings C. Gu J. Rosenfeld M.A. Pavan W.J. Krizman D.B. Nagle J. Polymeropoulos M.H. Sturley S.L. Ioannou Y.A. Higgins M.E. Comly M. Cooney A. Brown A. Kaneski C.R. Blanchette-Mackie E.J. Dwyer N.K. Neufeld E.B. Chang T-Y. Liscum L. Strauss III, J.F. Ohno K. Zeigler M. Carmi R. Sokol J. Markie D. O'Neill R.R. van Diggelen O.P. Elleder M. Patterson M.C. Brady R.O. Vanier M.T. Pentchev P.G. Tagle D.A. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.Science. 1997; 277: 228-231Google Scholar, 6Liscum L. Klansek J.J. Niemann-Pick disease type C.Curr. Opin. Lipidol. 1998; 9: 131-135Google Scholar). It manifests significant sequence homology to other cellular proteins such as PATCHED, SCAP, and HMG-CoA reductase that are also known to play important roles in maintaining intracellular cholesterol homeostasis (6Liscum L. Klansek J.J. Niemann-Pick disease type C.Curr. Opin. Lipidol. 1998; 9: 131-135Google Scholar, 7Gil G. Faust J.R. Chin D.J. Goldstein J.L. Brown M.S. Membrane-bound domain of HMG-CoA reductase is required for sterol-enhanced degradation of the enzyme.Cell. 1985; 41: 249-258Google Scholar, 8Kumagai H. Chun K.R. Simoni R.D. Molecular dissection of the role of the membrane domain in the regulated degradation of 3-hydroxy-3-methylglutaryl coenzyme A reductase.J. Biol. Chem. 1995; 270: 19107-19113Google Scholar, 9Brown M.S. Goldstein J.L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor.Cell. 1997; 89: 331-340Google Scholar). NPC1 is synthesized in the endoplasmic reticulum, moves through prelysosomal vesicles, and eventually enters the lysosomal compartment (10Watari H. Blanchette-Mackie E.J. Dwyer N.K. Glick J.M. Patel S. Neufeld E.B. Brady R.O. Pentchev P.G. Strauss III, J.F. Niemann-Pick C1 protein: obligatory roles for N-terminal domains and lysosomal targeting in cholesterol mobilization.Proc. Natl. Acad. Sci. USA. 1999; 96: 805-810Google Scholar). There it is apparently crucial for transporting unesterified cholesterol, and probably other lipids, to sites within the cytosol where the sterol can be further metabolized and/or transported out of the cell (11Neufeld E.B. Wastney M. Patel S. Suresh S. Cooney A.M. Dwyer N.K. Roff C.F. Ohno K. Morris J.A. Carstea E.D. Incardona J.P. Strauss III, J.F. Vanier M.T. Patterson M.C. Brady R.O. Pentchev P.G. Blanchette-Mackie E.J. The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo.J. Biol. Chem. 1999; 274: 9627-9635Google Scholar). Mutations that inactivate NPC1 have been described not only in humans, but also in mice, dogs, cats, and other species (4Loftus S.K. Morris J.A. Carstea E.D. Gu J.Z. Cummings C. Brown A. Ellison J. Ohno K. Rosenfeld M.A. Tagle D.A. Pentchev P.G. Pavan W.J. Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene.Science. 1997; 277: 232-235Google Scholar, 12Morris M.D. Bhuvaneswaran C. Shio H. Fowler S. Lysosome lipid storage disorder in NCTR-BALB/c mice. I. Description of the disease and genetics.Am. J. Pathol. 1982; 108: 140-149Google Scholar, 13Higashi Y. Murayama S. Pentchev P.G. Suzuki K. Cerebellar degeneration in the Niemann-Pick type C mouse.Acta Neuropathol. 1993; 85: 175-184Scopus (178) Google Scholar, 14Kuwamura M. Awakura T. Shimada A. Umemura T. Kagota K. Kawamura N. Naiki M. Type C Niemann-Pick disease in a boxer dog.Acta Neuropathol. 1993; 85: 345-348Google Scholar, 15Muñana K.R. Luttgen P.J. Thrall M.A. Mitchell T.W. Wenger D.A. Neurological manifestations of Niemann-Pick disease type C in cats.J. Vet. Intern. Med. 1994; 8: 117-121Google Scholar). The phenotype is similar in all of these groups. Fetal growth and development, including development of the brain, apparently take place normally. However, shortly after birth progressive enlargement of organs such as the liver and spleen occurs, liver dysfunction becomes manifest, and progressive neurological degeneration supervenes (12Morris M.D. Bhuvaneswaran C. Shio H. Fowler S. Lysosome lipid storage disorder in NCTR-BALB/c mice. I. Description of the disease and genetics.Am. J. Pathol. 1982; 108: 140-149Google Scholar, 15Muñana K.R. Luttgen P.J. Thrall M.A. Mitchell T.W. Wenger D.A. Neurological manifestations of Niemann-Pick disease type C in cats.J. Vet. Intern. Med. 1994; 8: 117-121Google Scholar, 16Pentchev P.G. Vanier M.T. Suzuki K. Patterson M.C. Niemann-Pick disease type C: a cellular cholesterol lipidosis.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. Stanbury J.B. Wyngaarden J.B. Fredrickson D.S. The Metabolic and Molecular Bases of Inherited Diseases. 2. McGraw-Hill, New York1995: 2625-2639Google Scholar, 17Xie C. Turley S.D. Pentchev P.G. Dietschy J.M. Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein.Am. J. Physiol. 1999; 276: E336-E344Google Scholar). This sequence of events takes place over a few years in the affected child but over only 5–10 weeks in the homozygous NPC mouse (16Pentchev P.G. Vanier M.T. Suzuki K. Patterson M.C. Niemann-Pick disease type C: a cellular cholesterol lipidosis.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. Stanbury J.B. Wyngaarden J.B. Fredrickson D.S. The Metabolic and Molecular Bases of Inherited Diseases. 2. McGraw-Hill, New York1995: 2625-2639Google Scholar, 17Xie C. Turley S.D. Pentchev P.G. Dietschy J.M. Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein.Am. J. Physiol. 1999; 276: E336-E344Google Scholar). The availability of these animal models and, particularly, the mouse model, has provided a powerful tool for exploring the role of NPC1 in cholesterol homeostasis in the live animal, for dissecting the relative importance of different pathways for cholesterol movement across the cells of the different tissues, and for elucidating the mechanisms of how cholesterol accumulation may lead to cell death in organs like the liver and central nervous system. The hallmark of the NPC mouse is the time-dependent accumulation of cholesterol in virtually every organ. While the newborn pup homozygous for this mutation has a whole-body cholesterol pool (2377 mg/kg body weight) that is barely elevated above that of control animals (1833 mg/kg), this pool progressively expands with age until at 7 weeks it is elevated 2.5-fold above the normal value (17Xie C. Turley S.D. Pentchev P.G. Dietschy J.M. Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein.Am. J. Physiol. 1999; 276: E336-E344Google Scholar). Every tissue, except the central nervous system, participates in this expansion, although there are marked differences in the level of sterol sequestration in different organs. For example, the concentration of cholesterol is elevated 10-fold in the liver but only 1.3-fold in striated muscle (17Xie C. Turley S.D. Pentchev P.G. Dietschy J.M. Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein.Am. J. Physiol. 1999; 276: E336-E344Google Scholar). A series of observations supports the conclusion that in the whole animal in vivo, as in the fibroblast in vitro, this pool of sequestered unesterified cholesterol is derived from sterol entering the cells through the clathrin-coatedpit pathway. First, the rate of cholesterol accumulation in each tissue is proportional to the rate of uptake of sterol carried in either chylomicrons (CM-C) or low density lipoprotein (LDL-C) (17Xie C. Turley S.D. Pentchev P.G. Dietschy J.M. Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein.Am. J. Physiol. 1999; 276: E336-E344Google Scholar). Second, abrogation of LDL receptor (LDLR) activity alters the rate of cholesterol accumulation in each organ in a manner that parallels the observed change in uptake of LDL-C by that same tissue (18Xie C. Turley S.D. Dietschy J.M. Cholesterol accumulation in tissues of the Niemann-Pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coatedpit pathway in each organ.Proc. Natl. Acad. Sci. USA. 1999; 96: 11992-11997Google Scholar). Third, when the rate of CM-C cleared from the plasma is altered, there is a similar change in the rate of sterol accumulation in the liver, but not in other organs (17Xie C. Turley S.D. Pentchev P.G. Dietschy J.M. Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein.Am. J. Physiol. 1999; 276: E336-E344Google Scholar). Finally, the rate of uptake of CM-C and LDL-C from the plasma (86 mg/day per kg) is sufficient to account fully for the rate of cholesterol sequestration (67 mg/day per kg) observed in the whole animal (17Xie C. Turley S.D. Pentchev P.G. Dietschy J.M. Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein.Am. J. Physiol. 1999; 276: E336-E344Google Scholar, 18Xie C. Turley S.D. Dietschy J.M. Cholesterol accumulation in tissues of the Niemann-Pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coatedpit pathway in each organ.Proc. Natl. Acad. Sci. USA. 1999; 96: 11992-11997Google Scholar). Taken together, these quantitative findings are consistent with the view that in NPC disease unesterified and esterified cholesterol carried in CM and LDL is taken up into the various organs through interaction with either the LDL receptor (LDLR) or LDL-related protein (LPR) and then processed through the coated-pit pathway. The unesterified cholesterol that results from this processing, however, is unable to move out of the lysosomal compartment and provide sterol to meet the normal metabolic needs of the cells. However, despite this major block in the flow of cholesterol through the coated-pit pathway, fetal development apparently occurs normally. The sterol required for such tissue growth and maintenance, therefore, must come from a source other than CM-C and LDL-C. Presumably, this second source is the cholesterol that is continuously synthesized in each cell and that moves out of the tissues of the extrahepatic compartment, through the plasma to the liver, and, ultimately, is excreted in the feces. Quantitatively, this centripetal flow of sterol from the sites of synthesis in the periphery to the intestinal lumen is the largest net flux of cholesterol found in every animal and equals about 11, 35, and 100 mg/day per kg, respectively, in species like the monkey, rabbit, and mouse (19Dietschy J.M. Kita T. Suckling K.E. Goldstein J.L. Brown M.S. Cholesterol synthesis in vivo and in vitro in the WHHL rabbit, an animal with defective low density lipoprotein receptors.J. Lipid Res. 1983; 24: 469-480Google Scholar, 20Dietschy J.M. Turley S.D. Spady D.K. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans.J. Lipid Res. 1993; 34: 1637-1659Google Scholar, 21Turley S.D. Spady D.K. Dietschy J.M. Role of liver in the synthesis of cholesterol and the clearance of low density lipoproteins in the cynomolgus monkey.J. Lipid Res. 1995; 36: 67-79Google Scholar, 22Osono Y. Woollett L.A. Herz J. Dietschy J.M. Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse.J. Clin. Invest. 1995; 95: 1124-1132Google Scholar, 23Osono Y. Woollett L.A. Marotti K.R. Melchior G.W. Dietschy J.M. Centripetal cholesterol flux from extrahepatic organs to the liver is independent of the concentration of high density lipoprotein-cholesterol in plasma.Proc. Natl. Acad. Sci. USA. 1996; 93: 4114-4119Google Scholar). This flux begins with the movement of unesterified cholesterol from the cells of the extrahepatic organs to acceptors in the plasma such as apolipoprotein A-I (apoA-I), a process that may be facilitated by a specific transporter located in the plasma membrane or in the caveolae of these membranes (24Fielding C.J. Fielding P.E. Molecular physiology of reverse cholesterol transport.J. Lipid Res. 1995; 36: 211-228Google Scholar, 25Ji Y. Jian B. Wang N. Sun Y. de la Llera Moya M. Phillips M.C. Rothblat G.H. Swaney J.B. Tall A.R. Scavenger receptor BI promotes high density lipoprotein-mediated cellular cholesterol efflux.J. Biol. Chem. 1997; 272: 20982-20985Google Scholar, 26Jian B. de la Llera-Moya M. Ji Y. Wang N. Phillips M.C. Swaney J.B. Tall A.R. Rothblat G.H. Scavenger receptor class B type I as a mediator of cellular cholesterol efflux to lipoproteins and phospholipid acceptors.J. Biol. Chem. 1998; 273: 5599-5606Google Scholar, 27Remaley A.T. Rust S. Rosier M. Knapper C. Naudin L. Broccardo C. Peterson K.M. Koch C. Arnould I. Prades C. Duverger N. Funke H. Assman G. Dinger M. Dean M. Chimini G. Santamarina-Fojo S. Frederickson D.S. Denefle P. Brewer Jr., H.B. Human ATP-binding cassette transporter 1 (ABC1): genomic organization and identification of the genetic defect in the original Tangier disease kindred.Proc. Natl. Acad. Sci. USA. 1999; 96: 12685-12690Google Scholar, 28De la Llera-Moya M. Rothblat G.H. Connelly M.A. Kellner-Weibel G. Sakr S.W. Phillips M.C. Williams D.L. Scavenger receptor BI (SR-BI) mediates free cholesterol flux independently of HDL tethering to the cell surface.J. Lipid Res. 1999; 40: 575-580Google Scholar, 29Klucken J. Büchler C. Orsó E. Kaminski W.E. PorschÖzcürümez M. Liebisch G. Kapinsky M. Diederich W. Drobnik W. Dean M. Allikmets R. Schmitz G. ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport.Proc. Natl. Acad. Soc. USA. 2000; 97: 817-822Google Scholar). Once associated with apoA-I, the sterol is esterified by the enzyme lecithin:cholesterol acyltransferase and, in the rodent, this cholesteryl ester ultimately is selectively taken up into the liver and endocrine glands through interaction with the scavenger receptor, class B, type 1 (SR-BI) (30Acton S. Rigotti A. Landschulz K.T. Xu S. Hobbs H.H. Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor.Science. 1996; 271: 518-520Google Scholar, 31Xu S. Laccotripe M. Huang X. Rigotti A. Zannis V.I. Krieger M. Apolipoproteins of HDL can directly mediate binding to the scavenger receptor SR-BI, an HDL receptor that mediates selective lipid uptake.J. Lipid Res. 1997; 38: 1289-1298Google Scholar, 32Fluiter K. van der Westhuijzen D.R. van Berkel T.J.C. In vivo regulation of scavenger receptor BI and the selective uptake of high density lipoprotein cholesteryl esters in rat liver parenchymal and Kupffer cells.J. Biol. Chem. 1998; 273: 8434-8438Google Scholar, 33Stangl H. Cao G. Wyne K.L. Hobbs H.H. Scavenger receptor, class B, type I-dependent stimulation of cholesterol esterification by high density lipoproteins, low density lipoproteins, and nonlipoprotein cholesterol.J. Biol. Chem. 1998; 273: 31002-31008Google Scholar, 34Rodrigueza W.V. Thuahnai S.T. Temel R.E. Lund-Klatz S. Mechanism of scavenger receptor class B type I-mediated selective uptake of cholesteryl esters from high density lipoprotein to adrenal cells.J. Biol. Chem. 1999; 274: 20344-20350Google Scholar). The present studies were undertaken to establish whether this HDL/SR-BI pathway is, in fact, functionally normal in animals with mutated NPC1. The first set of studies quantitated the rate of cholesterol acquisition in the tissues of the extrahepatic compartment. In a second set of investigations these rates were compared with independent measurements of the rate at which sterol moves through the plasma in HDL and is taken up by the liver and adrenal gland. Finally, a third set of experiments quantitated the utilization of this sterol for excretion as fecal acidic and neutral sterols. These quantitative measurements of the flow of cholesterol through the HDL/SR-BI pathway in normal and NPC mice, along with similar measurements of the flow of sterol through the coatedpit pathway (18Xie C. Turley S.D. Dietschy J.M. Cholesterol accumulation in tissues of the Niemann-Pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coatedpit pathway in each organ.Proc. Natl. Acad. Sci. USA. 1999; 96: 11992-11997Google Scholar), provide the first detailed description of cholesterol balance in an animal with mutation of NPC1. Heterozygous NPC mice (NPC+/−) with a BALB/c background were crossbred with homozygous LDLR knockout (LDLR−/−) animals (18Xie C. Turley S.D. Dietschy J.M. Cholesterol accumulation in tissues of the Niemann-Pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coatedpit pathway in each organ.Proc. Natl. Acad. Sci. USA. 1999; 96: 11992-11997Google Scholar, 22Osono Y. Woollett L.A. Herz J. Dietschy J.M. Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse.J. Clin. Invest. 1995; 95: 1124-1132Google Scholar). Three groups were ultimately generated that included mice that were NPC+/+/LDLR+/+, NPC−/−/LDLR+/+, and NPC−/−/LDLR−/−. The genotypes of these mice were identified by using either polymerase chain reaction (PCR) or Southern blot analysis (4Loftus S.K. Morris J.A. Carstea E.D. Gu J.Z. Cummings C. Brown A. Ellison J. Ohno K. Rosenfeld M.A. Tagle D.A. Pentchev P.G. Pavan W.J. Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene.Science. 1997; 277: 232-235Google Scholar, 17Xie C. Turley S.D. Pentchev P.G. Dietschy J.M. Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein.Am. J. Physiol. 1999; 276: E336-E344Google Scholar, 22Osono Y. Woollett L.A. Herz J. Dietschy J.M. Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse.J. Clin. Invest. 1995; 95: 1124-1132Google Scholar, 35Ishibashi S. Brown M.S. Goldstein J.L. Gerard R.D. Hammer R.E. Herz J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.J. Clin. Invest. 1993; 92: 883-893Google Scholar). After weaning, all animals were housed in plastic colony cages in rooms with alternating 12-h periods of light and dark. All mice were fed a basal rodent diet (No. 7001; Harlan Teklad, Madison, WI) containing 0.016% (w/w) cholesterol until they were studied at 7 weeks of age. In one experiment, either cholesterol (1%, w/w) or cholestyramine (2%, w/w) was added to the meal form of this basal diet. These supplemented diets were begun at the 6th week of age and were fed for 1 week. Most studies were carried out in the fed state during the final hour of the dark phase of the light cycle. In one preliminary experiment, rates of cholesterol synthesis were also measured in vivo at the mid-dark and mid-light points of the light cycle. All experimental groups contained nearly equal numbers of males and females, except for the experiment dealing with cholesterol balance in the adrenal, which was carried out using only male animals. All experimental protocols were approved by the Institutional Animal Care and Research Advisory Committee. Mouse plasma was harvested from both male and female NPC+/+/LDLR−/− mice maintained on the low-cholesterol basal rodent diet (22Osono Y. Woollett L.A. Herz J. Dietschy J.M. Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse.J. Clin. Invest. 1995; 95: 1124-1132Google Scholar). The LDL and HDL fractions were isolated by preparative ultracentrifugation in the density ranges of 1.020–1.055 and 1.063–1.21 g/mL, respectively. LDL was then radiolabeled with either 125I-labeled tyramine cellobiose or 131I (21Turley S.D. Spady D.K. Dietschy J.M. Role of liver in the synthesis of cholesterol and the clearance of low density lipoproteins in the cynomolgus monkey.J. Lipid Res. 1995; 36: 67-79Google Scholar, 22Osono Y. Woollett L.A. Herz J. Dietschy J.M. Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse.J. Clin. Invest. 1995; 95: 1124-1132Google Scholar). The apoE-containing HDL that contaminated these LDL fractions was removed by passing the lipoprotein solutions over a heparin Sepharose CL-6B column (Pharmacia Biotech, Uppsala, Sweden) (36Weisgraber K.H. Mahley R.W. Subfraction of human high density lipoprotein by heparin-Sepharose affinity chromatography.J. Lipid Res. 1980; 21: 316-325Google Scholar). After dialysis, these radiolabeled LDL preparations were passed through a 0.45-μm pore size Millex-HA filter immediately prior to injection into the recipient animal. HDL was labeled with either [1α, 2α(n)-3H]cholesteryl oleyl ether or [4-14C]cholesteryl oleate by exchange from donor liposomes (37Hough J.L. Zilversmit D.B. Comparison of various methods for in vitro cholesteryl ester labeling of lipoproteins from hypercholesterolemic rabbits.Biochim. Biophys. Acta. 1984; 792: 338-347Google Scholar, 38Pittman R.C. Knecht T.P. Rosenbaum M.S. Taylor Jr., C.A. A nonendocytotic mechanism for the selective uptake of high density lipoprotein-associated cholesterol esters.J. Biol. Chem. 1987; 262: 2443-2450Google Scholar, 39Woollett L.A. Spady D.K. Kinetic parameters for high density lipoprotein apoprotein AI and cholesteryl ester transport in the hamster.J. Clin. Invest. 1997; 99: 1704-1713Google Scholar). Freshly collected rabbit plasma was used as the source for cholesteryl ester transfer protein. Rabbit HDL accounted for <5% of the HDL in the reaction mixture. The labeled HDL was then reisolated by ultracentrifugation in the density range of 1.070–1.21 g/mL and dialyzed against isotonic saline. All four of these radiolabeled LDL and HDL fractions were used within 48 h of preparation. Mice were anesthetized with diethyl ether and xylazine, and a catheter was inserted into a jugular vein. After awakening, each animal was given a bolus of 125I-labeled tyramine cellobiose-labeled LDL followed by a continuous infusion of the same preparation at a rate determined to maintain a constant specific activity in the plasma (22Osono Y. Woollett L.A. Herz J. Dietschy J.M. Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse.J. Clin. Invest. 1995; 95: 1124-1132Google Scholar, 40Spady D.K. Bilheimer D.W. Dietschy J.M. Rates of receptor-dependent and -independent low density lipoprotein uptake in the hamster.Proc. Natl. Acad. Sci. USA. 1983; 80: 3499-3503Google Scholar, 41Spady D.K. Meddings J.B. Dietschy J.M. Kinetic constants for receptor-dependent and receptor-independent low density lipoprotein transport in the tissues of the rat and hamster.J. Clin. Invest. 1986; 77: 1474-1481Google Scholar). Ten minutes before the termination of the 4-h infusion period, a bolus of 131I-labeled LDL was administered to each animal. The animals were exsanguinated at 4 h and tissue and plasma samples were then assayed for their content of 125I and 131I. A similar procedure was used for determining HDL clearance. Animals were administered a priming dose of [3H]cholesteryl oleyl ether-labeled HDL followed by the continuous infusion of the same radiolabeled lipoprotein at a rate demonstrated to maintain a constant specific activity in the plasma over the next 4" @default.
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• W2109538419 title "Centripetal cholesterol flow from the extrahepatic organs through the liver is normal in mice with mutated Niemann-Pick type C protein (NPC1)" @default.
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