Home LiteratureArticle Details
PMID: 19286647 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

ABCA1 plays no role in the centripetal movement of cholesterol from peripheral tissues to the liver and intestine in the mouse.

Journal of lipid research ·Vol. 50 ·No. 7 ·2009-07-00 ·Pages 1316-29

Xie C, Turley SD, Dietschy JM

Abstract

This study uses the mouse to explore the role of ABCA1 in the movement of this cholesterol from the peripheral organs to the endocrine glands for hormone synthesis and liver for excretion. The sterol pool in all peripheral organs was constant and equaled 2,218 and 2,269 mg/kg, respectively, in abca1(+/+) and abca1(-/-) mice. Flux of cholesterol from these tissues equaled the rate of synthesis plus the rate of LDL-cholesterol uptake and was 49.9 mg/day/kg in control animals and 62.0 mg/day/kg in abca1(-/-) mice. In the abca1(+/+) animals, this amount of cholesterol moved from HDL into the liver for excretion. In the abca1(-/-) mice, the cholesterol from the periphery also reached the liver but did not use HDL. Fecal excretion of cholesterol was just as high in abac1(-/-) mice (198 mg/day/kg) as in the abac1(+/+) animals (163 mg/day/kg), although the abac1(-/-) mice excreted relatively more neutral than acidic sterols. This study established that ABCA1 plays essentially no role in the turnover of cholesterol in peripheral organs or in the centripetal movement of this sterol to the endocrine glands, liver, and intestinal tract for excretion.

MeSH Terms
ATP Binding Cassette Transporter 1 ATP-Binding Cassette Transporters/genetics,metabolism Animals Cholesterol/metabolism Cholesterol, Dietary Cholesterol, HDL/metabolism Cholesterol, LDL/metabolism Feces/chemistry Female Hormones/biosynthesis,chemistry Intestinal Mucosa/metabolism Lipid Metabolism Liver/metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Organ Size Tissue Distribution
Chemicals
ATP Binding Cassette Transporter 1 ATP-Binding Cassette Transporters Cholesterol, Dietary Cholesterol, HDL Cholesterol, LDL Hormones Cholesterol
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Xie Chonglun
Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX 75390-9151, USA.
Turley Stephen D
Dietschy John M
References (67)
67 references, click to expand
  1. 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 U S A. 1996 Apr 30;93(9):4114-9 PMID: 8633025
  2. Kinetic parameters for high density lipoprotein apoprotein AI and cholesteryl ester transport in the hamster.
    J Clin Invest. 1997 Apr 1;99(7):1704-13 PMID: 9120015
  3. High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1.
    Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4245-50 PMID: 10760292
  4. Rates of receptor-dependent and -independent low density lipoprotein uptake in the hamster.
    Proc Natl Acad Sci U S A. 1983 Jun;80(11):3499-503 PMID: 6304713
  5. Cholesterol accumulation in tissues of the Niemann-pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coated-pit pathway in each organ.
    Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):11992-7 PMID: 10518564
  6. Liver X receptor activation enhances cholesterol loss from the brain, decreases neuroinflammation, and increases survival of the NPC1 mouse.
    J Neurosci. 2007 Dec 26;27(52):14470-80 PMID: 18160655
  7. Reevaluation and application of the dual-isotope plasma ratio method for the measurement of intestinal cholesterol absorption in the hamster.
    J Lipid Res. 1994 Feb;35(2):328-39 PMID: 8169536
  8. Measurement of rates of cholesterol synthesis using tritiated water.
    J Lipid Res. 1984 Dec 15;25(13):1469-76 PMID: 6530597
  9. A receptor-mediated pathway for cholesterol homeostasis.
    Science. 1986 Apr 4;232(4746):34-47 PMID: 3513311
  10. Degradation of surfactant lipids and surfactant protein A by alveolar macrophages in vitro.
    Am J Physiol. 1995 May;268(5 Pt 1):L772-80 PMID: 7762680
  11. Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein.
    Am J Physiol. 1999 Feb;276(2):E336-44 PMID: 9950794
  12. GM2/GD2 and GM3 gangliosides have no effect on cellular cholesterol pools or turnover in normal or NPC1 mice.
    J Lipid Res. 2008 Aug;49(8):1816-28 PMID: 18450647
  13. Role of liver in the synthesis of cholesterol and the clearance of low density lipoproteins in the cynomolgus monkey.
    J Lipid Res. 1995 Jan;36(1):67-79 PMID: 7706949
  14. Intestinal ABCA1 directly contributes to HDL biogenesis in vivo.
    J Clin Invest. 2006 Apr;116(4):1052-62 PMID: 16543947
  15. Comparison of various methods for in vitro cholesteryl ester labeling of lipoproteins from hypercholesterolemic rabbits.
    Biochim Biophys Acta. 1984 Mar 7;792(3):338-47 PMID: 6696939
  16. ATP-binding cassette transporter A1 (ABCA1) affects total body sterol metabolism.
    Gastroenterology. 2001 Apr;120(5):1203-11 PMID: 11266384
  17. The ins and outs of reverse cholesterol transport.
    Ann Med. 2004;36(2):135-45 PMID: 15119833
  18. The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway.
    J Clin Invest. 1999 Oct;104(8):R25-31 PMID: 10525055
  19. Cellular localization and trafficking of the human ABCA1 transporter.
    J Biol Chem. 2001 Jul 20;276(29):27584-90 PMID: 11349133
  20. Relation between hepatic expression of ATP-binding cassette transporters G5 and G8 and biliary cholesterol secretion in mice.
    J Hepatol. 2003 Jun;38(6):710-6 PMID: 12763362
  21. Quantitative analysis of total macrophage content in adult mouse tissues. Immunochemical studies with monoclonal antibody F4/80.
    J Exp Med. 1985 Mar 1;161(3):475-89 PMID: 3973536
  22. Dissociation of tissue uptake of cholesterol ester from that of apoprotein A-I of rat plasma high density lipoprotein: selective delivery of cholesterol ester to liver, adrenal, and gonad.
    Proc Natl Acad Sci U S A. 1983 Sep;80(17):5435-9 PMID: 6412229
  23. Cutaneous cholesterol ester deposition in Tangier disease.
    Arch Dermatol. 1967 Feb;95(2):161-5 PMID: 6018991
  24. Early embryonic lethality caused by targeted disruption of the 3-hydroxy-3-methylglutaryl-CoA reductase gene.
    J Biol Chem. 2003 Oct 31;278(44):42936-41 PMID: 12920113
  25. A PEST deletion mutant of ABCA1 shows impaired internalization and defective cholesterol efflux from late endosomes.
    J Biol Chem. 2005 Aug 12;280(32):29277-81 PMID: 15951431
  26. Central nervous system: cholesterol turnover, brain development and neurodegeneration.
    Biol Chem. 2009 Apr;390(4):287-93 PMID: 19166320
  27. Receptor-mediated and bulk-phase endocytosis cause macrophage and cholesterol accumulation in Niemann-Pick C disease.
    J Lipid Res. 2007 Aug;48(8):1710-23 PMID: 17476031
  28. Cholesterol synthesis in vivo and in vitro in the WHHL rabbit, an animal with defective low density lipoprotein receptors.
    J Lipid Res. 1983 Apr;24(4):469-80 PMID: 6304219
  29. The correlation of ATP-binding cassette 1 mRNA levels with cholesterol efflux from various cell lines.
    J Biol Chem. 2000 Sep 15;275(37):28634-40 PMID: 10893411
  30. Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels.
    J Clin Invest. 2001 Nov;108(9):1315-20 PMID: 11696576
  31. Targeted disruption of the mouse lysosomal acid lipase gene: long-term survival with massive cholesteryl ester and triglyceride storage.
    Hum Mol Genet. 1998 Sep;7(9):1347-54 PMID: 9700186
  32. Abnormal cholesterol metabolism in the Smith-Lemli-Opitz syndrome: report of clinical and biochemical findings in four patients and treatment in one patient.
    Am J Med Genet. 1994 May 1;50(4):347-52 PMID: 8209913
  33. Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1-/- mouse.
    Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2377-82 PMID: 19171898
  34. The intestine as a source of apolipoprotein A1.
    Proc Natl Acad Sci U S A. 1977 Jun;74(6):2569-73 PMID: 196292
  35. Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I.
    J Clin Invest. 2005 May;115(5):1333-42 PMID: 15841208
  36. NPC1/NPC2 function as a tag team duo to mobilize cholesterol.
    Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15223-4 PMID: 18832164
  37. Subfractionation of human high density lipoproteins by heparin-Sepharose affinity chromatography.
    J Lipid Res. 1980 Mar;21(3):316-25 PMID: 7381326
  38. Marked reduction in bile acid synthesis in cholesterol 7alpha-hydroxylase-deficient mice does not lead to diminished tissue cholesterol turnover or to hypercholesterolemia.
    J Lipid Res. 1998 Sep;39(9):1833-43 PMID: 9741696
  39. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease.
    Nat Genet. 1999 Aug;22(4):347-51 PMID: 10431237
  40. Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages.
    J Biol Chem. 2008 Aug 22;283(34):22930-41 PMID: 18552351
  41. How cells handle cholesterol.
    Science. 2000 Dec 1;290(5497):1721-6 PMID: 11099405
  42. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.
    Nat Genet. 1999 Aug;22(4):336-45 PMID: 10431236
  43. Alteration of biliary ursodeoxycholic acid in guinea pig during early stages of cholestyramine feeding.
    Steroids. 1979;34(6 Spec no):705-15 PMID: 538776
  44. A nonendocytotic mechanism for the selective uptake of high density lipoprotein-associated cholesterol esters.
    J Biol Chem. 1987 Feb 25;262(6):2443-50 PMID: 2434485
  45. Relative contributions by liver and intestine to individual plasma apolipoproteins in the rat.
    J Biol Chem. 1979 Aug 10;254(15):7316-22 PMID: 457683
  46. Is it time to modify the reverse cholesterol transport model?
    J Clin Invest. 2001 Nov;108(9):1273-5 PMID: 11696569
  47. Identification of a metabolic difference accounting for the hyper- and hyporesponder phenotypes of cynomolgus monkey.
    J Lipid Res. 1997 Aug;38(8):1598-611 PMID: 9300782
  48. Identification of HE1 as the second gene of Niemann-Pick C disease.
    Science. 2000 Dec 22;290(5500):2298-301 PMID: 11125141
  49. Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis.
    J Lipid Res. 2001 Nov;42(11):1717-26 PMID: 11714841
  50. Sterol synthesis in vivo in 18 tissues of the squirrel monkey, guinea pig, rabbit, hamster, and rat.
    J Lipid Res. 1983 Mar;24(3):303-15 PMID: 6842086
  51. Increased plasma and renal clearance of an exchangeable pool of apolipoprotein A-I in subjects with low levels of high density lipoprotein cholesterol.
    J Clin Invest. 1993 Apr;91(4):1743-52 PMID: 8473514
  52. Characterization of high density lipoproteins in patients heterozygous for Tangier disease.
    J Clin Invest. 1977 Nov;60(5):1025-35 PMID: 198431
  53. Comparative analysis of mammalian plasma lipoproteins.
    Methods Enzymol. 1986;128:70-143 PMID: 3523143
  54. 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 Mar;95(3):1124-32 PMID: 7883961
  55. Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high-density lipoprotein cholesterol deficiency.
    Am J Pathol. 2000 Sep;157(3):1017-29 PMID: 10980140
  56. Rates of sterol synthesis and uptake in the major organs of the rat in vivo.
    J Lipid Res. 1981 May;22(4):551-69 PMID: 7276735
  57. Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL.
    J Clin Invest. 2001 Sep;108(6):843-50 PMID: 11560953
  58. Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome.
    J Lipid Res. 1996 Jun;37(6):1169-80 PMID: 8808751
  59. Delineation of molecular changes in intrahepatic cholesterol metabolism resulting from diminished cholesterol absorption.
    J Lipid Res. 2005 Apr;46(4):779-89 PMID: 15654122
  60. Massive omental reticuloendothelial cell lipid uptake in Tangier disease after splenectomy.
    Am J Med. 1983 Sep;75(3):521-6 PMID: 6614036
  61. NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes.
    Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15287-92 PMID: 18772377
  62. Sterol synthesis and low density lipoprotein clearance in vivo in the pregnant rat, placenta, and fetus. Sources for tissue cholesterol during fetal development.
    J Clin Invest. 1988 Dec;82(6):2077-85 PMID: 3198766
  63. Ontogenesis and regulation of cholesterol metabolism in the central nervous system of the mouse.
    Brain Res Dev Brain Res. 2003 Dec 19;146(1-2):87-98 PMID: 14643015
  64. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1.
    Nat Genet. 1999 Aug;22(4):352-5 PMID: 10431238
  65. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.
    Science. 1997 Jul 11;277(5323):228-31 PMID: 9211849
  66. Centripetal cholesterol flux to the liver is dictated by events in the peripheral organs and not by the plasma high density lipoprotein or apolipoprotein A-I concentration.
    J Lipid Res. 1998 Nov;39(11):2143-9 PMID: 9799800
  67. ABC1: connecting yellow tonsils, neuropathy, and very low HDL.
    J Clin Invest. 1999 Oct;104(8):1015-7 PMID: 10525038
Article Info
Journal
Journal of lipid research
Abbr.
J Lipid Res
ISSN
1539-7262
Published
2009-07-00
Epub
2009-00-12
Pages
1316-29
Language
English
Region
United States
NLM ID
0376606
PMCID
PMC2694331
Subset
IM
Grants
NHLBI NIH HHS · R01 HL09610 · United States
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]