Impaired ABCA1-dependent Lipid Efflux and Hypoalphalipoproteinemia in Human Niemann-Pick type C Disease

The cholesterol trafficking defect in Niemann-Pick type C (NPC) disease leads to impaired regulation of cholesterol esterification, cholesterol synthesis, and low density lipoprotein receptor activity. The ATP-binding cassette transporter A1 (ABCA1), which mediates the rate-limiting step in high density lipoprotein (HDL) particle formation, is also regulated by cell cholesterol content. To determine whether the Niemann-Pick C1 protein alters the expression and activity of ABCA1, we determined the ability of apolipoprotein A-I (apoA-I) to deplete pools of cellular cholesterol and phospholipids in human fibroblasts derived from NPC1 +/+ , NPC1 +/–, and NPC1 –/– subjects. Efflux of low density lipoprotein-derived, non-lipoprotein, plasma membrane, and newly synthesized pools of cell cholesterol by apoA-I was diminished in NPC1 –/– cells, as was efflux of phosphatidylcholine and sphingomyelin. NPC1 +/– cells showed intermediate levels of lipid efflux compared with NPC1 +/+ and NPC1 –/– cells. Binding of apoA-I to cholesterol-loaded and non-cholesterol-loaded cells was highest for NPC1 +/– cells, with NPC1 +/+ and NPC1 –/– cells showing similar levels of binding. ABCA1 mRNA and protein levels increased in response to cholesterol loading in NPC1 +/+ and NPC1 +/– cells but showed low levels at base line and in response to cholesterol loading in NPC1 –/– cells. Consistent with impaired ABCA1-dependent lipid mobilization to apoA-I for HDL particle formation, we demonstrate for the first time decreased plasma HDL-cholesterol levels in 17 of 21 (81%) NPC1 –/– subjects studied. These results indicate that the cholesterol trafficking defect in NPC disease results in reduced activity of ABCA1, which we suggest is responsible for the low HDL-cholesterol in the majority of NPC subjects and partially responsible for the overaccumulation of cellular lipids in this disorder. The cholesterol trafficking defect in Niemann-Pick type C (NPC) disease leads to impaired regulation of cholesterol esterification, cholesterol synthesis, and low density lipoprotein receptor activity. The ATP-binding cassette transporter A1 (ABCA1), which mediates the rate-limiting step in high density lipoprotein (HDL) particle formation, is also regulated by cell cholesterol content. To determine whether the Niemann-Pick C1 protein alters the expression and activity of ABCA1, we determined the ability of apolipoprotein A-I (apoA-I) to deplete pools of cellular cholesterol and phospholipids in human fibroblasts derived from NPC1 +/+ , NPC1 +/–, and NPC1 –/– subjects. Efflux of low density lipoprotein-derived, non-lipoprotein, plasma membrane, and newly synthesized pools of cell cholesterol by apoA-I was diminished in NPC1 –/– cells, as was efflux of phosphatidylcholine and sphingomyelin. NPC1 +/– cells showed intermediate levels of lipid efflux compared with NPC1 +/+ and NPC1 –/– cells. Binding of apoA-I to cholesterol-loaded and non-cholesterol-loaded cells was highest for NPC1 +/– cells, with NPC1 +/+ and NPC1 –/– cells showing similar levels of binding. ABCA1 mRNA and protein levels increased in response to cholesterol loading in NPC1 +/+ and NPC1 +/– cells but showed low levels at base line and in response to cholesterol loading in NPC1 –/– cells. Consistent with impaired ABCA1-dependent lipid mobilization to apoA-I for HDL particle formation, we demonstrate for the first time decreased plasma HDL-cholesterol levels in 17 of 21 (81%) NPC1 –/– subjects studied. These results indicate that the cholesterol trafficking defect in NPC disease results in reduced activity of ABCA1, which we suggest is responsible for the low HDL-cholesterol in the majority of NPC subjects and partially responsible for the overaccumulation of cellular lipids in this disorder. Niemann-Pick type C (NPC) 1The abbreviations used are: NPC, Niemann-Pick type C; apo, apolipoprotein; ABCA1, ATP-binding cassette transporter A1; BSA, bovine serum albumin; CE, cholesteryl ester; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; HDL, high density lipoprotein; LXR, liver X receptor; LDL, low density lipoprotein; PBS, phosphate-buffered saline; PC, phosphatidylcholine; SM, sphingomyelin; MOPS, morpholinepropansulfonic acid. disease is a neurodegenerative disorder characterized by a variable phenotype but that frequently leads to premature death in childhood or adolescence (1Patterson M.C. Vanier M.T. Suzuki K. Morris J.E. Carstea E.D. Neufeld E.B. Blanchette-Mackie E.J. Pentchev P.G. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic & Molecular Bases of Inherited Disease. 8th Ed. McGraw-Hill Inc., New York2001: 3611-3633Google Scholar). Biochemically, the disorder is characterized by impaired intracellular lipid trafficking, with accumulation of unesterified cholesterol in late endosomes/lysosomes (2Pentchev P.G. Kruth H.S. Comly M.E. Butler J.D. Vanier M.T. Wenger D.A. Patel S. J. Biol. Chem. 1986; 261: 16775-16780Abstract Full Text PDF PubMed Google Scholar, 3Kruth H.S. Comly M.E. Butler J.D. Vanier M.T. Fink J.K. Wenger D.A. Patel S. Pentchev P.G. J. Biol. Chem. 1986; 261: 16769-16774Abstract Full Text PDF PubMed Google Scholar). Recent studies (4Neufeld 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. J. Biol. Chem. 1999; 274: 9627-9635Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar, 5Garver W.S. Heidenreich R.A. Erickson R.P. Thomas M.A. Wilson J.M. J. Lipid Res. 2000; 41: 673-687Abstract Full Text Full Text PDF PubMed Google Scholar) have indicated the NPC1 protein resides in a unique late endosomal compartment that becomes enriched with low density lipoprotein (LDL)-derived cholesterol. Although the exact function of the NPC1 protein remains unknown, it is believed to facilitate the transport of lipids, particularly cholesterol, from late/endosomes lysosomes to the Golgi apparatus, endoplasmic reticulum, and plasma membrane (6Liscum L. Ruggiero R.M. Faust J.R. J. Cell Biol. 1989; 108: 1625-1636Crossref PubMed Scopus (241) Google Scholar, 7Garver W.S. Krishnan K. Gallagos J.R. Michikawa M. Francis G.A. Heidenreich R.A. J. Lipid Res. 2002; 43: 579-589Abstract Full Text Full Text PDF PubMed Google Scholar, 8Wojtanik K.M. Liscum L. J. Biol. Chem. 2003; 278: 14850-14856Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). Impaired cholesterol trafficking in NPC1-deficient cells results in blunted regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and LDL receptor activity, and a defect in the delivery of unesterified cholesterol to the endoplasmic reticulum for by P.G. Comly M.E. Kruth H.S. Vanier M.T. Wenger D.A. Patel S. Brady R.O. S. PubMed Scopus Google Scholar, P.G. Comly M.E. Kruth H.S. Butler J. J. M. J.M. Patel S. Vanier M.T. Brady R.O. J. PubMed Scopus Google Scholar, L. Faust J.R. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The membrane protein for of apolipoprotein A-I the ATP-binding cassette transporter A1 (ABCA1), is also in response to increased cell cholesterol, to high density lipoprotein (HDL) particle and with the of cell cholesterol in J.F. 2002; PubMed Scopus Google Scholar). ABCA1 mediates the rate-limiting step for the of HDL and is to function by cellular phospholipids cholesterol to or apoA-I J.F. 2002; PubMed Scopus Google Scholar). in ABCA1 in a of of increased intracellular cholesterol, and low HDL levels in the disease Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. 8th Ed. Inc., New York2001: Scholar). cell cholesterol and as in in ABCA1 expression of the liver X receptor S. 2000; PubMed Scopus Google Scholar, J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Although HDL levels in human subjects with NPC disease have the to cholesterol in NPC disease ABCA1 function also impaired in this in decreased HDL particle studies from NPC1-deficient a defect in cholesterol, but to apoA-I and regulation of ABCA1 activity by and J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). HDL-cholesterol levels in NPC1-deficient have to J.M. S. 1999; PubMed Scopus Google Scholar, L. J. J.F. S. 2002; PubMed Google Scholar). the studies we characterized efflux of phospholipids and cholesterol from cellular of and regulation of ABCA1 expression in NPC1 +/–, and NPC1 –/– human and we with the plasma lipid of NPC results suggest in NPC1 the regulation and activity of ABCA1, in decreased efflux of cell phospholipids and cholesterol and of HDL in and low plasma HDL levels in the majority of NPC phosphatidylcholine and bovine serum from and from and and from was from and serum and fetal bovine serum from of and and LDL by from the plasma of J.P. J. Lipid Res. Full Text PDF PubMed Google Scholar). HDL to to and J. Lipid Res. Full Text PDF PubMed Google Scholar). The protein of HDL was by HDL and apoA-I as S. S. J. PubMed Scopus Google Scholar). LDL was with by the of and J. PubMed Scopus Google Scholar) to a activity of LDL apoA-I apoA-I was with by to a activity of Cell human fibroblasts from the NPC1 human fibroblasts the by J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). NPC1 human fibroblasts the NPC1 M.A. Morris J.A. Pentchev P.G. Ohno K. Wenger D.A. Vanier M.T. J. 1999; Full Text Full Text PDF PubMed Scopus Google and the from the Cell These cells from and have to have a defect in cholesterol J.F. Patterson M.C. K. J. Full Text Full Text PDF PubMed Scopus Google Scholar). at or and to in Dulbecco's modified Eagle's To cells with cholesterol, with phosphate-buffered and for in with cholesterol from a in To of cholesterol, cell with and for in of and cellular cholesterol cells in serum the of to to LDL receptor expression and for with with to of To cellular cholesterol cells the of to by of to loading with cholesterol G.A. J.F. PubMed Scopus Google Scholar). To plasma membrane cholesterol pools G.A. J.F. PubMed Scopus Google cholesterol-loaded cells for with the step J.F. J. Biol. Chem. Full Text PDF PubMed Google Scholar). To newly synthesized cholesterol, cells with the of to with in and with to of phospholipids in cholesterol-loaded cells by of to the the with to of apoA-I J.P. J.F. J. PubMed Scopus Google Scholar). and the cells for in the of the indicated cell with and with at lipid Efflux and for to cell in the was cells with or the was for of phospholipids J. M. J. Biol. Chem. Full Text PDF PubMed Google Scholar). lipids by and for as G.A. J.F. PubMed Scopus Google Scholar). Cell determined as A.L. J. Biol. Chem. Full Text PDF PubMed Google Scholar). Binding of of to cells was determined as M. S. PubMed Scopus Google Scholar). cells or cells with cholesterol in for at in and of with and with Cell in and for of and of was from cells by PubMed Scopus Google Scholar). The of was at a of and of was with the was of and of first BSA, and of The at for by at for and of ABCA1 and was in to of for and and to of and and was to of and of and or to the ABCA1 was by at for was at for at for and at for for a of with a of was similar the was with a of a with and The used as human ABCA1, human C of was from cells as PubMed Scopus Google Scholar). of was a in MOPS, and a membrane by The for ABCA1 was by a and by the with with the with The was by of cellular by cells in and The was by for at and the was for at The was in and and protein of membrane by and to was to a ABCA1 of K. S. K. S. PubMed Scopus Google and a was by the Lipid of NPC lipid for 21 NPC1-deficient subjects and and NPC and from with the of the as the and in the levels of HDL in NPC compared with determined the J.F. The and of in & New Scholar). Efflux of Impaired in NPC1 –/– trafficking of cholesterol in fibroblasts or is a of NPC disease (1Patterson M.C. Vanier M.T. Suzuki K. Morris J.E. Carstea E.D. Neufeld E.B. Blanchette-Mackie E.J. Pentchev P.G. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic & Molecular Bases of Inherited Disease. 8th Ed. McGraw-Hill Inc., New York2001: 3611-3633Google Scholar). To the of cholesterol by apoA-I in human NPC1-deficient cells, fibroblasts from a and or for in NPC1 to in The cells with LDL for to with of was in NPC1 –/– in NPC1 +/+ or NPC1 +/– cells with accumulation of cholesterol in late endosomes/lysosomes and a to LDL receptor activity in NPC1 –/– cells P.G. Comly M.E. Kruth H.S. Butler J. J. M. J.M. Patel S. Vanier M.T. Brady R.O. J. PubMed Scopus Google Scholar, L. Faust J.R. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of cells with apoA-I for in efflux of of to the from NPC1 +/+ cells NPC1 +/– cells showed a decreased ability to cholesterol to NPC1 –/– cells showed diminished efflux levels of efflux to to apoA-I compared with cell of cellular cholesterol to the was by a in cellular cholesteryl in NPC +/+ and NPC +/– cells NPC –/– cells showed a in cellular levels and a accumulation of and with of but to cholesterol in the endoplasmic reticulum in NPC –/– cells (1Patterson M.C. Vanier M.T. Suzuki K. Morris J.E. Carstea E.D. Neufeld E.B. Blanchette-Mackie E.J. Pentchev P.G. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic & Molecular Bases of Inherited Disease. 8th Ed. McGraw-Hill Inc., New York2001: 3611-3633Google Scholar). Efflux of and Impaired in NPC1 –/– of cholesterol in late endosomes/lysosomes in NPC1-deficient fibroblasts that the of NPC1 protein function W.S. Heidenreich R.A. Erickson R.P. Thomas M.A. Wilson J.M. J. Lipid Res. 2000; 41: 673-687Abstract Full Text Full Text PDF PubMed Google Scholar, M.E. J.P. 1999; PubMed Scopus Google Scholar). To whether efflux of cholesterol derived from is also impaired in human NPC1-deficient cells with the of to cellular cholesterol cells with to plasma membrane cholesterol G.A. J.F. PubMed Scopus Google Scholar). have that a of cholesterol-loaded human fibroblasts with results in of cholesterol cholesteryl G.A. J.F. PubMed Scopus Google Scholar). Although cholesterol we used this to the plasma membrane cholesterol also with to newly synthesized cholesterol. Consistent with the defect in of cholesterol, as as cholesterol, in NPC1 –/– cells P.G. Comly M.E. Kruth H.S. Vanier M.T. Wenger D.A. Patel S. Brady R.O. S. PubMed Scopus Google cells of cell to cells compared with and in NPC1 +/+ and NPC1 +/– cells, in efflux of cholesterol to apoA-I from cells by of was diminished from NPC1 –/– fibroblasts compared with NPC1 +/+ cells. efflux from NPC1 –/– cells increased levels of and by cells of the NPC1 +/– cells showed intermediate levels of efflux of this of cholesterol to apoA-I compared with NPC1 +/+ and NPC1 –/– cells and intermediate levels of efflux of cell and newly synthesized cholesterol of in NPC1-deficient ability of apoA-I to as a cholesterol is to apoA-I first or in a that ABCA1 J.F. 2002; PubMed Scopus Google Scholar). NPC1 –/– cells showed a diminished ability to and to apoA-I NPC1 +/– cells showed intermediate levels of efflux from NPC1 +/– cells was similar to NPC1 +/+ cells at time but to levels similar to from NPC1 –/– cells at time Impaired efflux of phospholipids by NPC1-deficient cells the decreased ability of apoA-I to cholesterol from of the cellular cholesterol pools and ABCA1 in NPC1 –/– efflux of phospholipids and pools of cellular cholesterol to apoA-I from NPC1 –/– fibroblasts ABCA1 regulation and activity is also impaired in cells. of ABCA1 mRNA and protein determined non-cholesterol-loaded and cholesterol-loaded of ABCA1 mRNA was with results by ABCA1 mRNA and protein levels increased in NPC1 +/+ fibroblasts in response to cholesterol NPC1 +/– cells showed ABCA1 mRNA levels by and ABCA1 protein levels in response to cholesterol loading compared with NPC1 +/+ cells. NPC1 –/– fibroblasts showed diminished and ABCA1 mRNA and protein levels compared with NPC1 +/+ and NPC +/– cells. Although loading with cholesterol increased ABCA1 expression in cells, the of ABCA1 mRNA and protein was in NPC1 –/– cells, the that of and cholesterol was in cells and A similar of ABCA1 protein levels was in of cells. NPC1 –/– cells showed ABCA1 protein levels NPC1 +/+ cells and loading with cholesterol ABCA1 expression in NPC –/– cells is with the decreased ability of cells to phospholipids and cholesterol to The results suggest that NPC1 protein function is for the regulation and activity of ABCA1 and that the accumulation of cellular lipids in NPC1 –/– cells disease results in from diminished function of ABCA1 Binding of to efflux to apoA-I to with of apoA-I to cells J.F. S. J. Lipid Res. Full Text PDF PubMed Google Scholar) and with levels of ABCA1 expression in J.F. 2002; PubMed Scopus Google Scholar). studies have a apoA-I and ABCA1 J.F. R.M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Morris A.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google and apoA-I to ABCA1 activity by by a S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J. 2003; PubMed Scopus Google Scholar). To of apoA-I to NPC1-deficient cells, fibroblasts to in in the or of cholesterol and with from J.F. S. J. Lipid Res. Full Text PDF PubMed Google of apoA-I was to cholesterol-loaded to non-cholesterol-loaded cells of NPC1 of cholesterol NPC1 +/– cells showed the highest levels of apoA-I binding. in ABCA1 protein levels in cholesterol-loaded and NPC1 +/+ and NPC1 –/– cells showed similar levels of apoA-I binding. The results with of cell suggest that in to the of ABCA1 determine apoA-I to cells. HDL in NPC1 –/– results human fibroblasts indicate impaired ABCA1-dependent HDL particle by NPC1-deficient cells in Although the lipid of have to (1Patterson M.C. Vanier M.T. Suzuki K. Morris J.E. Carstea E.D. Neufeld E.B. Blanchette-Mackie E.J. Pentchev P.G. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic & Molecular Bases of Inherited Disease. 8th Ed. McGraw-Hill Inc., New York2001: 3611-3633Google Scholar, Pentchev P.G. Blanchette-Mackie J. Carstea E.D. J.M. Neufeld E.B. Brady R.O. J. Lipid Res. Full Text PDF PubMed Google the in the for plasma cholesterol levels M.C. A.M. R.P. K. Pentchev P.G. Brady R.O. 43: PubMed Google Scholar). the of the we the lipid of 21 NPC1 –/– The majority of NPC for NPC1 2000; PubMed Scopus Google Scholar). Consistent with the of impaired ABCA1 expression in human NPC1 –/– we that of and of subjects HDL-cholesterol levels the of for and or of Scholar, of of the and of in of Scholar). The high of low HDL levels in NPC1 –/– subjects is that have HDL levels HDL-cholesterol levels by of in and in J. PubMed Scopus Google Scholar). The of HDL levels in of for and for J. PubMed Scopus Google Scholar). HDL levels for in for and for for and compared with in this low in the plasma lipid of NPC1 –/– subjects Although of the 21 subjects plasma the low of this the of and the low HDL-cholesterol of human NPC lipid in NPC1 –/– HDL in a lipid also for of NPC subjects in this of and of low HDL-cholesterol and the lipid in the NPC with low HDL Niemann-Pick type C disease is characterized by the accumulation of cholesterol in late endosomes/lysosomes and to of cholesterol delivery of unesterified cholesterol to the endoplasmic reticulum for by regulation of cholesterol by 3-hydroxy-3-methylglutaryl-coenzyme A and regulation of LDL receptor activity (1Patterson M.C. Vanier M.T. Suzuki K. Morris J.E. Carstea E.D. Neufeld E.B. Blanchette-Mackie E.J. Pentchev P.G. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic & Molecular Bases of Inherited Disease. 8th Ed. McGraw-Hill Inc., New York2001: 3611-3633Google Scholar, P.G. Comly M.E. Kruth H.S. Vanier M.T. Wenger D.A. Patel S. Brady R.O. S. PubMed Scopus Google Scholar, P.G. Comly M.E. Kruth H.S. Butler J. J. M. J.M. Patel S. Vanier M.T. Brady R.O. J. PubMed Scopus Google Scholar, L. Faust J.R. J. Biol. Chem. Full Text PDF PubMed Google Scholar). the studies we demonstrate that regulation of of cholesterol ABCA1, is also impaired in human NPC1-deficient showed a diminished ability to cholesterol in NPC1 –/– cells from and cholesterol and to cellular phosphatidylcholine and sphingomyelin. ABCA1 mRNA and protein levels in NPC1 –/– cells diminished at levels of cell cholesterol and loading of cells with or cholesterol, compared with NPC +/+ and NPC +/– cells. Consistent with impaired regulation of ABCA1 at the cellular we a high of of and of in the lipid of 21 NPC1 –/– subjects. Impaired activity of ABCA1 in cells is by the diminished and levels of ABCA1 mRNA and and decreased levels of and cholesterol efflux to apoA-I from cells. The of accumulation of cell cholesterol in NPC disease and of the NPC1 protein to the that the of of NPC1 is in late endosomes/lysosomes W.S. Heidenreich R.A. Erickson R.P. Thomas M.A. Wilson J.M. J. Lipid Res. 2000; 41: 673-687Abstract Full Text Full Text PDF PubMed Google Scholar, M.E. J.P. 1999; PubMed Scopus Google Scholar). ABCA1 cellular lipids to apoA-I at the plasma membrane J.F. 2002; PubMed Scopus Google Scholar, S. K. M. M. S. K. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar) and also facilitate the delivery of intracellular lipids to or cell from late endosomes/lysosomes J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, E.B. J.A. Cooney A.M. Comly M. Dwyer N.K. M. Blanchette-Mackie J. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J.D. S. 1999; PubMed Scopus Google Scholar). in NPC1 the function of ABCA1 in the of late cholesterol. the of of cholesterol mobilization from NPC1 –/– cells from cholesterol which in late endosomes/lysosomes in cells J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). also a in cholesterol mobilization to apoA-I from cholesterol newly synthesized cholesterol, in NPC1 –/– cells Although the delivery of newly synthesized cholesterol to the plasma membrane is in NPC cells (6Liscum L. Ruggiero R.M. Faust J.R. J. Cell Biol. 1989; 108: 1625-1636Crossref PubMed Scopus (241) Google Scholar, J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, E.B. Cooney A.M. J. Dwyer N.K. Pentchev P.G. Blanchette-Mackie E.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google trafficking of this cholesterol to intracellular and mobilization to apoA-I impaired in the of NPC1 the cholesterol efflux to apoA-I of cholesterol from cells with the as NPC1 is to function in the plasma ABCA1, the is to at in at the cell to lipids to Impaired efflux of cholesterol from NPC1 –/– cells this for decreased ABCA1 activity in NPC1 –/– cells, and for ABCA1 cholesterol from plasma membrane as as late levels of of cholesterol have H.S. Comly M.E. Butler J.D. Vanier M.T. Fink J.K. Wenger D.A. Patel S. Pentchev P.G. J. Biol. Chem. 1986; 261: 16769-16774Abstract Full Text PDF PubMed Google Scholar) in NPC1 cells the first of with LDL, with levels of in cells with similar levels of and efflux to apoA-I of in NPC1 +/– and NPC1 +/+ cells a with LDL Efflux of plasma membrane, and newly synthesized from NPC1 +/– cells intermediate NPC1 +/+ and NPC1 –/– cells as was efflux of phosphatidylcholine indicated a in levels of ABCA1 mRNA in NPC1 +/– to NPC1 +/+ cells, ABCA1 protein levels in response to cholesterol and LDL loading similar NPC1 +/+ and NPC1 +/– cells we of low HDL in the NPC1 lipid studied. The cell results in NPC1 +/– cells, in showing intermediate levels of lipid efflux in to of the NPC1 and in low HDL or plasma levels of HDL in NPC The decreased ABCA1 expression and decreased ABCA1-dependent lipid efflux to apoA-I in the NPC1 –/– phenotype cells and the low HDL levels in the majority of NPC1 –/– indicate the of impaired ABCA1 regulation in NPC disease subjects with the studies to determine whether the low HDL in NPC is the of impaired ABCA1 regulation in NPC1 –/– NPC1 +/– fibroblasts showed the highest levels of in non-cholesterol-loaded and cholesterol-loaded cells in ABCA1 levels of apoA-I to NPC1 +/+ and NPC1 –/– cells similar The for this suggest ABCA1, S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google in the These results suggest NPC cells to of apoA-I binding. results showing impaired efflux and cholesterol efflux from cholesterol pools in to results J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) for from a of NPC J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) levels of efflux to apoA-I from cells and that ABCA1 function was levels of of mRNA and protein for –/– and type in response to with levels of expression indicated J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of in –/– cells by is with the ability of to the in cholesterol esterification, cholesterol synthesis, LDL receptor activity, and cholesterol accumulation in NPC cells L. Faust J.R. J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google and for that ABCA1 regulation is also impaired in this disorder. The decreased ability of cell cholesterol to cholesterol in human NPC1 –/– and –/– cells a defect in synthesis, or trafficking in cells. A by and J.R. J.E. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar) of and is impaired in human NPC1-deficient cells, to the to expression and to of impaired ABCA1 regulation in NPC1 –/– cells is with this The of impaired ABCA1-dependent efflux of lipids to apoA-I from human NPC1 –/– cells and cells have to in the expression of this defect in the human and cell used in To determine whether impaired ABCA1 function in human NPC1 –/– fibroblasts is of impaired HDL particle in we the lipid of NPC1 –/– subjects. The results in and low HDL-cholesterol levels in the majority (81%) of NPC lipid high of results by Although the of ABCA1 in the is unknown, to a of low HDL-cholesterol J. Lipid Res. 2003; Full Text Full Text PDF PubMed Scopus Google and results also this of apoA-I is to the rate-limiting step in HDL particle and a of HDL levels J.F. 2002; PubMed Scopus Google Scholar, J.P. J. Lipid Res. Full Text Full Text PDF PubMed Google Scholar). Impaired efflux of cholesterol from NPC1 –/– cells as apoA-I as of cholesterol G.A. J.F. J. PubMed Scopus Google Scholar, J. Lipid Res. Full Text PDF PubMed Google Scholar). Impaired regulation of ABCA1 activity, as indicated by the lipid efflux results and ABCA1 expression levels in human NPC1 –/– cells, is the for a high of low HDL-cholesterol in NPC The of low HDL in the NPC lipid is of the of and in this disorder M.T. Wenger D.A. Comly M.E. Brady R.O. Pentchev P.G. PubMed Scopus Google Scholar, Comly M.E. Blanchette-Mackie J. Kruth H.S. Vanier M.T. Brady R.O. Pentchev P.G. PubMed Scopus Google which variable regulation of ABCA1 The high of low HDL in NPC disease this used as to in or C disease in which is frequently a to The for the in cell results and HDL levels human NPC1 disease and the of this disease HDL levels in –/– J.M. S. 1999; PubMed Scopus Google Scholar, L. J. J.F. S. 2002; PubMed Google Scholar) with expression of in Although the and in –/– similar to in P.G. Kruth H.S. J. Brady R.O. J. Biol. Chem. Full Text PDF PubMed Google Scholar, S. Pentchev P.G. Suzuki K. PubMed Scopus Google lipoprotein and PubMed Scopus Google Scholar). The suggest in the of NPC HDL in compared with low HDL-cholesterol levels have also in with the Niemann-Pick disease L. J. J. M. 2003; PubMed Scopus Google Scholar). to the defect in ABCA1-dependent lipid mobilization in human NPC cholesterol mobilization was in fibroblasts of Niemann-Pick was that the low HDL in subjects to impaired cholesterol activity L. J. J. M. 2003; PubMed Scopus Google Scholar). to whether the of disease in NPC with of ABCA1 HDL-cholesterol levels of ABCA1 expression in the Wilson J.E. 2002; PubMed Scopus Google Scholar, R.P. J. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google the that in this disease to impaired regulation of ABCA1 in the trafficking in J.E. J. 2002; PubMed Scopus Google Scholar, J.E. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar) and S. J. Lipid Res. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) suggest that ABCA1 expression is reduced in cells in the as we have in NPC1 –/– the results demonstrate defect in regulation of a ABCA1, in NPC suggest that this is responsible for the in the majority of NPC disease studied. studies at the of ABCA1 in the and in the of this Francis for with and and for in the lipid

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