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 ␣-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.

Protective role of n6/n3 PUFA supplementation with varying DHA/EPA ratios against atherosclerosis in mice

“…On the other hand, to prevent the accumulation of excess cholesterol, the esterification of cholesterol is mediated by the microsomal enzyme acyl-coenzyme A: cholesterol acyltransferase (ACAT) [26] and the efflux of cholesterol or reverse cholesterol transport is regulated by the transporters ATP binding cassette transporter A1 (ABCA1), ATP binding cassette transporter G1 (ABCG1) [27,28]. Lysosomal acid lipase (LAL) not only contributes to the hydrolysis of the cholesteryl ester and triglycerides for cholesterol efflux [29], but also regulates the expression of ABCA1 and high-density lipoprotein formation [30].…”

Regulation of High-Density Lipoprotein Metabolism

“…72,73 The ability of ABCA1 to efflux cholesterol to apoA-I and generate discoidal HDLs is also impaired in people with lysosomal acid lipase deficiency. 60 This effect has been attributed to reduced release of cholesterol from late endosomes/lysosomes. 60 Localization of ABCA1 in the plasma membrane and the efflux of cellular phospholipids and cholesterol to apoA-I in the extracellular space can also be enhanced by the palmitoylation of ABCA1 cysteine residues 74 as well as by increased expression of the GTPase, Rab8.…”

“…60 This effect has been attributed to reduced release of cholesterol from late endosomes/lysosomes. 60 Localization of ABCA1 in the plasma membrane and the efflux of cellular phospholipids and cholesterol to apoA-I in the extracellular space can also be enhanced by the palmitoylation of ABCA1 cysteine residues 74 as well as by increased expression of the GTPase, Rab8. 75 Inhibition of cathepsin D, by contrast, is associated with retention of ABCA1 in lysosomes and reduced efflux of cholesterol from both macrophages and hepatocytes.…”

“…59 ABCA1 gene transcription as well as cholesterol efflux to apoA-I and the generation of discoidal HDLs are also impaired in people with lysosomal acid lipase deficiency. 60 Inhibition of extracellular signalregulated protein kinases 1 and 2 and overexpression of the brefeldin A-inhibited guanine nucleotide-exchange protein-1, however, increase macrophage ABCA1 mRNA levels, ABCA1 protein stability, and cholesterol efflux to apoA-I. 61,62 Posttranscriptional Regulation of ABCA1 Protein Levels Compelling evidence of posttranscriptional regulation of ABCA1 protein levels comes from studies showing that microRNA-33 (miR-33) represses ABCA1 protein levels, decreases cholesterol efflux to apoA-I, and reduces HDL cholesterol levels.…”

Regulation of Lipid Droplet Cholesterol Efflux From Macrophage Foam Cells

“…46,47 Consequently, enhancing LAL activity has been proposed as a promising antiatherogenic therapy, similar to overexpression of neutral cholesterol ester hydrolases. Interestingly, recent results show that LAL activity contributes to the regulation of ABCA1 expression and high-density lipoprotein formation, 48 which could explain why low plasma high-density lipoprotein cholesterol and premature atherosclerosis often occur in CESD patients. 49,50 On the other hand, 2 recent genome-wide association studies report links of a gain-of-function LAL mutation with enhanced susceptibility to coronary artery disease.…”