title: Lysosomal acid lipase deficiency impairs regulation of ABCA1 gene and formation of high density lipoproteins in cholesteryl ester storage disease.
abstract: ATP-binding cassette transporter A1 (ABCA1) mediates the rate-limiting step in high density lipoprotein (HDL) particle formation, and its expression is regulated primarily by oxysterol-dependent activation of liver X receptors. We previously reported that ABCA1 expression and HDL formation are impaired in the lysosomal cholesterol storage disorder Niemann-Pick disease type C1 and that plasma HDL-C is low in the majority of Niemann-Pick disease type C patients. Here, we show that ABCA1 regulation and activity are also impaired in cholesteryl ester storage disease (CESD), caused by mutations in the LIPA gene that result in less than 5% of normal lysosomal acid lipase (LAL) activity. Fibroblasts from patients with CESD showed impaired up-regulation of ABCA1 in response to low density lipoprotein (LDL) loading, reduced phospholipid and cholesterol efflux to apolipoprotein A-I, and reduced α-HDL particle formation. Treatment of normal fibroblasts with chloroquine to inhibit LAL activity reduced ABCA1 expression and activity, similar to that of CESD cells. Liver X receptor agonist treatment of CESD cells corrected ABCA1 expression but failed to correct LDL cholesteryl ester hydrolysis and cholesterol efflux to apoA-I. LDL-induced production of 27-hydroxycholesterol was reduced in CESD compared with normal fibroblasts. Treatment with conditioned medium containing LAL from normal fibroblasts or with recombinant human LAL rescued ABCA1 expression, apoA-I-mediated cholesterol efflux, HDL particle formation, and production of 27-hydroxycholesterol by CESD cells. These results provide further evidence that the rate of release of cholesterol from late endosomes/lysosomes is a critical regulator of ABCA1 expression and activity, and an explanation for the hypoalphalipoproteinemia seen in CESD patients.
authors.affiliation: Department of Medicine, Institute for Heart and Lung Health, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6, Canada.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Bowden
authors.affiliation: Department of Medicine, Institute for Heart and Lung Health, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6, Canada.
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Bilbey
authors.affiliation: Department of Medicine, Institute for Heart and Lung Health, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6, Canada.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Bilawchuk
authors.affiliation: Department of Medicine, Institute for Heart and Lung Health, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Boadu
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Rohini
authors.initials: R
authors.lastname: Sidhu
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.affiliation: Department of Medicine, Institute for Heart and Lung Health, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6, Canada.
authors.forename: Teddy
authors.initials: T
authors.lastname: Chan
authors.affiliation: Department of Medicine, Institute for Heart and Lung Health, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6, Canada. Electronic address: gordon.francis@hli.ubc.ca.
authors.forename: Gordon A
authors.initials: GA
authors.lastname: Francis
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D002738:Chloroquine / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D015217:Cholesterol Ester Storage Disease / Q000235:genetics* / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism*; D009154:Mutation; D010743:Phospholipids / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D013261:Sterols / Q000737:chemistry; D015223:Wolman Disease / Q000235:genetics* / Q000378:metabolism
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D017077:Culture Media, Conditioned; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D010743:Phospholipids; D011994:Recombinant Proteins; D013261:Sterols; D002738:Chloroquine; D002784:Cholesterol