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.

BackgroundInborn errors of metabolism (IEMs) have been anecdotally reported in the literature as presenting with features of cerebral palsy (CP) or misdiagnosed as ‘atypical CP’. A significant proportion is amenable to treatment either directly targeting the underlying pathophysiology (often with improvement of symptoms) or with the potential to halt disease progression and prevent/minimize further damage.MethodsWe performed a systematic literature review to identify all reports of IEMs presenting with CP-like symptoms before 5 years of age, and selected those for which evidence for effective treatment exists.ResultsWe identified 54 treatable IEMs reported to mimic CP, belonging to 13 different biochemical categories. A further 13 treatable IEMs were included, which can present with CP-like symptoms according to expert opinion, but for which no reports in the literature were identified. For 26 of these IEMs, a treatment is available that targets the primary underlying pathophysiology (e.g. neurotransmitter supplements), and for the remainder (n = 41) treatment exerts stabilizing/preventative effects (e.g. emergency regimen). The total number of treatments is 50, and evidence varies for the various treatments from Level 1b, c (n = 2); Level 2a, b, c (n = 16); Level 4 (n = 35); to Level 4–5 (n = 6); Level 5 (n = 8). Thirty-eight (57%) of the treatable IEMs mimicking CP can be identified by ready available metabolic screening tests in blood or urine, while the remaining IEMs require more specific and sometimes invasive tests.ConclusionsLimited by the rare nature of IEMs and incomplete information in the literature, we conclude that (1) A surprisingly large number of IEMs can present with CP symptoms, as ‘CP mimics’, (2) although individually rare, a large proportion of these diseases are treatable such that neurological damage can either be reversed or prevented, (3) clinician awareness of treatable CP mimics is important for appropriate screening, diagnosis, and early intervention, and (4) systematic studies are required to elucidate the collective frequency of treatable IEMs in CP.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0197-2) contains supplementary material, which is available to authorized users.

LXR is activated by oxysterol derivatives of cholesterol in vivo and is thus positioned to sense the cellular levels of cholesterol and regulate genes required for its elimination (7). The ABCA1-dependent efflux of cholesterol and phospholipids to extracellular apolipoprotein A1 (apoAI) to form nascent high density lipoprotein is the initial and limiting step in the reverse cholesterol transport pathway (reviewed in Ref. 8). Although transcriptional induction of ABCA1 by LXR is a key event in this process, it is now recognized that regulation of ABCA1 protein stability in the plasma membrane (PM) and endosomes is also involved. ApoAI binds and stabilizes ABCA1, resulting in increased PM localization and decreased degradation by thiol proteases (9, 10). Phosphorylation of a PEST sequence in the large cytoplasmic loop of ABCA1 mediates internalization and subsequent degradation by calpain (11-13). Phosphorylation of the PEST sequence is inhibited by apoAI, resulting in increased surface localization and stabilization. ABCA1 also interacts with ␤1-and ␣1-syntrophin, scaffolding proteins that regulate transport through linkage to the cytoskeleton, resulting in stabilization at intracellular sites and the PM (14, 15). Thus, distribution of ABCA1 between the PM and endosomes affects protein stability and efficiency of cholesterol efflux to apoA1. Other sterol-binding proteins could affect cholesterol homeostasis by sequestration or delivery of oxysterol ligands to LXR or by influencing the supply of cholesterol or phospholipids to ABCA1 for efflux to apoA1. A class of binding proteins that could fulfill these functions is the OSBP (oxysterol-binding protein) and ORP (OSBP-related) gene family, which are expressed across eukaryotic phyla and consist of 12 mammalian and seven yeast members (16,17). OSBP and ORPs are characterized by a C-terminal OSBP homology domain that binds oxysterols and cholesterol (18 -20). The majority of family members also contain pleckstrin homology (PH) and FFAT (two phenylalanines in an acidic tract) domains that mediate interaction with phosphatidylinositol phosphates (21, 22) and the resident ER protein vesicle-associated membrane protein-associated protein (VAP) (23, 24), respectively. The PH and FFAT domain of OSBP facilitate partitioning between the ER and Golgi apparatus in response to oxysterol and cholesterol binding (23,25,26). Sterol-dependent partitioning of OSBP between the Golgi and ER does not appear to be directly involved in cholesterol regulation, since depletion by RNA interference did not affect the * This work was support in part by Canadian Institutes of Health ResearchOperating Grant MOP 15284. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1

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