Lysosomal acid lipase deficiency impairs regulation of ABCA1 gene and formation of high density lipoproteins in cholesteryl ester storage disease.

TitleLysosomal acid lipase deficiency impairs regulation of ABCA1 gene and formation of high density lipoproteins in cholesteryl ester storage disease.
Publication TypeJournal Article
Year of Publication2011
AuthorsBowden, KL, Bilbey, NJ, Bilawchuk, LM, Boadu, E, Sidhu, R, Ory, DS, Du, H, Chan, T, Francis, GA
JournalJ Biol Chem
Date Published2011 Sep 2
KeywordsATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters, Chloroquine, Cholesterol, Cholesterol Ester Storage Disease, Culture Media, Conditioned, Fibroblasts, Humans, Lipoproteins, Lipoproteins, HDL, Mutation, Phospholipids, Recombinant Proteins, Skin, Sterols, Wolman Disease

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.

Alternate JournalJ. Biol. Chem.
PubMed ID21757691
PubMed Central IDPMC3162423
Grant ListHL067773 / HL / NHLBI NIH HHS / United States
HL087001 / HL / NHLBI NIH HHS / United States
MOP-79532 / / Canadian Institutes of Health Research / Canada