| Lysosomal acid lipase deficiency impairs regulation of ABCA1 and formation of high density lipoproteins in Cholesteryl Ester Storage Disease. | |
| | |
MedLine Citation:
|
PMID: 21757691 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
|
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 (LXRs). We previously reported that ABCA1 expression and HDL formation are impaired in the lysosomal cholesterol storage disorder Niemann Pick disease type C1 (NPC1), and that plasma HDL-C is low in the majority of NPC patients. Here we show that ABCA1 regulation and activity is 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 upregulation 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. LXR 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 (27-HC) was reduced in CESD compared to 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-HC 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:
|
Kristin L Bowden; Nicolas J Bilbey; Leanne M Bilawchuk; Emmanuel Boadu; Rohini Sidhu; Daniel S Ory; Hong Du; Teddy Chan; Gordon A Francis |
Publication Detail:
|
Type: JOURNAL ARTICLE Date: 2011-7-10 |
Journal Detail:
|
Title: The Journal of biological chemistry Volume: - ISSN: 1083-351X ISO Abbreviation: - Publication Date: 2011 Jul |
Date Detail:
|
Created Date: 2011-7-15 Completed Date: - Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: - |
Other Details:
|
Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
|
University of British Columbia, Canada; |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Nuclear orphan receptor NR4A2 modulates fatty acid oxidation pathways in colorectal cancer.
Next Document: Characterization of the Deoxynucleotide Triphosphate Triphosphohydrolase (dNTPase) Activity of the E...