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Journal ArticleDOI

Disorders of cholesterol metabolism and their unanticipated convergent mechanisms of disease.

03 Sep 2014-Annual Review of Genomics and Human Genetics (Annu Rev Genomics Hum Genet)-Vol. 15, Iss: 1, pp 173-194

TL;DR: A surprising finding is not only shedding light on details of cellular cholesterol homeostasis but also suggesting novel approaches to therapy.

AbstractCholesterol plays a key role in many cellular processes, and is generated by cells through de novo biosynthesis or acquired from exogenous sources through the uptake of low-density lipoproteins. Cholesterol biosynthesis is a complex, multienzyme-catalyzed pathway involving a series of sequentially acting enzymes. Inherited defects in genes encoding cholesterol biosynthetic enzymes or other regulators of cholesterol homeostasis result in severe metabolic diseases, many of which are rare in the general population and currently without effective therapy. Historically, these diseases have been viewed as discrete disorders, each with its own genetic cause and distinct pathogenic cascades that lead to its specific clinical features. However, studies have recently shown that three of these diseases have an unanticipated mechanistic convergence. This surprising finding is not only shedding light on details of cellular cholesterol homeostasis but also suggesting novel approaches to therapy.

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Citations
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Journal ArticleDOI
TL;DR: A reappraisal of lipid storage and lysosomal enzymes activities in tissues/cells from NPC patients and animal models is provided, with emphasis on differences between systemic organs and the brain.
Abstract: Niemann-Pick disease type C (NPC) is an atypical lysosomal storage disease resulting from mutations in one of two genes, either NPC1 or NPC2. Although a neurovisceral disorder, it is above all a neurodegenerative disease in the vast majority of patients. Not an enzyme deficiency, it is currently conceived as a lipid trafficking disorder. Impaired egress of cholesterol from the late endosomal/lysosomal (LE/L) compartment is a specific and key element of the pathogenesis, but other lipids, more specially sphingolipids, are also involved, and there are indications for further abnormalities. The full function of the NPC1 and NPC2 proteins is still unclear. This review provides a reappraisal of lipid storage and lysosomal enzymes activities in tissues/cells from NPC patients and animal models. It summarizes the current knowledge on the NPC1 and NPC2 proteins and their function in transport of cholesterol within the late endosomal-lysosomal compartment, with emphasis on differences between systemic organs and the brain; it also discusses regulation by membrane lipids of the NPC2-mediated cholesterol trafficking, interplay between cholesterol and sphingomyelin, the metabolic origin of glycosphingolipids stored in brain, and the putative role of free sphingoid bases in pathogenesis. Brief mention is finally made of diseases affecting other genes that were very recently shown to impact the "NPC pathway".

178 citations


Cites background from "Disorders of cholesterol metabolism..."

  • ...This is a significant finding, as failure to release sufficient calcium could lead to a block in trafficking/fusion events essential for late endosomal/lysosomal function (Platt et al 2014), and there are indeed many indications of impaired fusion/fission in NPC cells....

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  • ...The mechanism by which loss of function of ABCA1 interacts with the NPC pathway is still unknown, but considering the fine homeostatic network regulating choleterol trafficking and levels in cells, perturbation in one element is likely to have an impact on other pathways (Platt et al 2014)....

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  • ...Other disorders affecting the "NPC pathway" Very recently, unexpected links were found between SmithLemli-Opitz syndrome (SLOS), a disorder of cholesterol biosynthesis, NPC, and Tangier disease (a reverse cholesterol transport disorder) (Platt et al 2014)....

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  • ...Molecular mechanisms leading to NPC disease have also been discussed (Vance and Karten 2014; Platt et al 2014)....

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Journal ArticleDOI
TL;DR: Despite ongoing challenges, various therapeutic strategies for LSDs now exist, with many agents approved, undergoing clinical trials or in preclinical development.
Abstract: Lysosomal storage disorders (LSDs) - designated as 'orphan' diseases - are inborn errors of metabolism caused by defects in genes that encode proteins involved in various aspects of lysosomal homeostasis. For many years, LSDs were viewed as unattractive targets for the development of therapies owing to their low prevalence. However, the development and success of the first commercial biologic therapy for an LSD - enzyme replacement therapy for type 1 Gaucher disease - coupled with regulatory incentives rapidly catalysed commercial interest in therapeutically targeting LSDs. Despite ongoing challenges, various therapeutic strategies for LSDs now exist, with many agents approved, undergoing clinical trials or in preclinical development.

120 citations


Journal ArticleDOI
TL;DR: Advances in mass spectrometry has allowed identification of several sensitive plasma biomarkers elevated in NP-C, which, together with the concomitant progress in molecular genetic technology, have greatly impacted the strategy of laboratory testing.
Abstract: Niemann-Pick disease type C (NP-C) is a neurovisceral lysosomal cholesterol trafficking and lipid storage disorder caused by mutations in one of the two genes, NPC1 or NPC2. Diagnosis has often been a difficult task, due to the wide range in age of onset of NP-C and clinical presentation of the disease, combined with the complexity of the cell biology (filipin) laboratory testing, even in combination with genetic testing. This has led to substantial delays in diagnosis, largely depending on the access to specialist centres and the level of knowledge about NP-C of the physician in the area. In recent years, advances in mass spectrometry has allowed identification of several sensitive plasma biomarkers elevated in NP-C (e.g. cholestane-3β,5α,6β-triol, lysosphingomyelin isoforms and bile acid metabolites), which, together with the concomitant progress in molecular genetic technology, have greatly impacted the strategy of laboratory testing. Specificity of the biomarkers is currently under investigation and other pathologies are being found to also result in elevations. Molecular genetic testing also has its limitations, notably with unidentified mutations and the classification of new variants. This review is intended to increase awareness on the currently available approaches to laboratory diagnosis of NP-C, to provide an up to date, comprehensive and critical evaluation of the various techniques (cell biology, biochemical biomarkers and molecular genetics), and to briefly discuss ongoing/future developments. The use of current tests in proper combination enables a rapid and correct diagnosis in a large majority of cases. However, even with recent progress, definitive diagnosis remains challenging in some patients, for whom combined genetic/biochemical/cytochemical markers do not provide a clear answer. Expertise and reference laboratories thus remain essential, and further work is still required to fulfill unmet needs.

96 citations


Book ChapterDOI
TL;DR: Methodological caveats and variability of patterns encountered in patients with proven Niemann-Pick C disease (typical "classic" or "intermediate," atypical "variant") are described, leading to a proposed algorithm for interpretation of results in the filipin test.
Abstract: Niemann-Pick disease type C (NPC) is an atypical neurovisceral lysosomal storage disorder resulting from mutations in either the NPC1 or the NPC2 gene, currently conceived as a lipid trafficking disorder. Impaired egress of cholesterol from the late endosomal/lysosomal (LE/L) compartment is a key element of the pathogenesis. The resulting accumulation of unesterified cholesterol in the LE/L compartment can be visualized by fluorescence microscopy after staining with filipin. The "filipin test," performed on cultured fibroblasts, is the historical gold standard method to establish the diagnosis in patients. The authors provide methodological details of the protocol developed and used in their laboratory since 1988, in which two sources of low-density lipoproteins (LDL) (total serum and pure LDL) are used in parallel to facilitate the final interpretation. Methodological caveats and variability of patterns encountered in patients with proven Niemann-Pick C disease (typical "classic" or "intermediate," atypical "variant") are described. An overview of the past 5 years referrals (533 subjects tested, 57 NPC cases, but also 74 mildly/weakly positive tests not due to NPC) is discussed, leading to a proposed algorithm for interpretation of results in the filipin test. This tool takes into account the limits of the method. In up to 15% of all referrals, the filipin test was inconclusive in absence of molecular analysis. Patients diagnosed in the adult age preferentially showed an "intermediate" or "variant" pattern. Well conducted, the filipin test remains an efficient approach for diagnosing NPC, and it is a good functional test to study the pathogenicity of novel mutations.

79 citations


Cites background from "Disorders of cholesterol metabolism..."

  • ...ABCA1 is an important player in the network regulating cholesterol trafficking and levels in cells, and it has been suggested that perturbation in one element of the network might impact other pathways (Platt et al., 2014)....

    [...]

  • ..., 1991) and confounding profiles described in diseases other than NPC (Platt et al., 2014; Wortmann et al., 2012) render interpretation of such profiles difficult in clinical laboratory practice....

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  • ...Smith-Lemli-Opitz syndrome has also been reported as associated with an abnormal filipin test (Platt et al., 2014)....

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  • ...NPB: NiemannePick disease type B; NPA: NiemannePick disease type A. (See color plate) (Platt et al., 2014; Sechi et al., 2014)....

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  • ...…obtained for 85% of the NPC cases, a variant pattern observed in a subset of NPC patients (Vanier et al., 1991) and confounding profiles described in diseases other than NPC (Platt et al., 2014; Wortmann et al., 2012) render interpretation of such profiles difficult in clinical laboratory practice....

    [...]


Journal ArticleDOI
TL;DR: Different fluorescent lipid analogs are compared for their performance in cellular assays and their applicability in fluorescence correlation spectroscopy (FCS)-based and super-resolution stimulated emission depletion-FCS-based measurements of membrane diffusion dynamics.
Abstract: Cholesterol (Chol) is a crucial component of cellular membranes, but knowledge of its intracellular dynamics is scarce. Thus, it is of utmost interest to develop tools for visualization of Chol organization and dynamics in cells and tissues. For this purpose, many studies make use of fluorescently labeled Chol analogs. Unfortunately, the introduction of the label may influence the characteristics of the analog, such as its localization, interaction, and trafficking in cells; hence, it is important to get knowledge of such bias. In this report, we compared different fluorescent lipid analogs for their performance in cellular assays: 1) plasma membrane incorporation, specifically the preference for more ordered membrane environments in phase-separated giant unilamellar vesicles and giant plasma membrane vesicles; 2) cellular trafficking, specifically subcellular localization in Niemann-Pick type C disease cells; and 3) applicability in fluorescence correlation spectroscopy (FCS)-based and super-resolution stimulated emission depletion-FCS-based measurements of membrane diffusion dynamics. The analogs exhibited strong differences, with some indicating positive performance in the membrane-based experiments and others in the intracellular trafficking assay. However, none showed positive performance in all assays. Our results constitute a concise guide for the careful use of fluorescent Chol analogs in visualizing cellular Chol dynamics.

61 citations


References
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Abstract: It has become increasingly difficult to find an area of cell biology in which lipids do not have important, if not key, roles as signalling and regulatory molecules. The rapidly expanding field of bioactive lipids is exemplified by many sphingolipids, such as ceramide, sphingosine, sphingosine-1-phosphate (S1P), ceramide-1-phosphate and lyso-sphingomyelin, which have roles in the regulation of cell growth, death, senescence, adhesion, migration, inflammation, angiogenesis and intracellular trafficking. Deciphering the mechanisms of these varied cell functions necessitates an understanding of the complex pathways of sphingolipid metabolism and the mechanisms that regulate lipid generation and lipid action.

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09 Nov 2001-Science
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Abstract: The molecular mechanisms controlling synaptogenesis in the central nervous system (CNS) are poorly understood. Previous reports showed that a glia-derived factor strongly promotes synapse development in cultures of purified CNS neurons. Here, we identify this factor as cholesterol complexed to apolipoprotein E-containing lipoproteins. CNS neurons produce enough cholesterol to survive and grow, but the formation of numerous mature synapses demands additional amounts that must be provided by glia. Thus, the availability of cholesterol appears to limit synapse development. This may explain the delayed onset of CNS synaptogenesis after glia differentiation and neurobehavioral manifestations of defects in cholesterol or lipoprotein homeostasis.

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Journal ArticleDOI
Abstract: Tangier disease (TD) was first discovered nearly 40 years ago in two siblings living on Tangier Island This autosomal co-dominant condition is characterized in the homozygous state by the absence of HDL-cholesterol (HDL-C) from plasma, hepatosplenomegaly, peripheral neuropathy and frequently premature coronary artery disease (CAD) In heterozygotes, HDL-C levels are about one-half those of normal individuals Impaired cholesterol efflux from macrophages leads to the presence of foam cells throughout the body, which may explain the increased risk of coronary heart disease in some TD families We report here refining of our previous linkage of the TD gene to a 1-cM region between markers D9S271 and D9S1866 on chromosome 9q31, in which we found the gene encoding human ATP cassette-binding transporter 1 (ABC1) We also found a change in ABC1 expression level on cholesterol loading of phorbol ester-treated THP1 macrophages, substantiating the role of ABC1 in cholesterol efflux We cloned the full-length cDNA and sequenced the gene in two unrelated families with four TD homozygotes In the first pedigree, a 1-bp deletion in exon 13, resulting in truncation of the predicted protein to approximately one-fourth of its normal size, co-segregated with the disease phenotype An in-frame insertion-deletion in exon 12 was found in the second family Our findings indicate that defects in ABC1, encoding a member of the ABC transporter superfamily, are the cause of TD

1,430 citations


Journal ArticleDOI
TL;DR: It is raised that a prerequisite for the regulation of cholestero-genesis in cultured fibroblasts is the initial binding of low density lipoproteins to the high affinity surface receptor sites and that a defect in this process represents the primary genetic abnormality in the disorder familial hypercholesterolemia.
Abstract: 125I-Labeled low density lipoproteins were found to associate with monolayers of cultured normal fibroblasts by two processes—one of high affinity and one of low affinity. The high affinity association appeared to represent binding of the low density lipoprotein to specific receptor sites on the cell surface. This binding process exhibited saturation kinetics at low concentrations of the lipoprotein and competition by related molecules such as very low density lipoproteins. In addition, this process was stimulated by the presence of calcium in the culture medium and could be destroyed by limited treatment of the cells with pronase. The other process, designated low affinity uptake, may represent nonspecific endocytosis since the uptake was proportional to the lipoprotein concentration in the medium with no apparent saturation and because it showed no competition by very low density lipoproteins, no stimulation by calcium, and no destruction by pronase treatment. The 125I-labeled low density lipoproteins associated with normal cells by either the high or low affinity process were degraded by proteolysis to trichloroacetic acid-soluble material, most of which was 125I-tyrosine. In normal cells, binding of low density lipoproteins to the high affinity membrane receptor sites appears to serve two functions: (a) it results in suppression of the synthesis of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-controlling enzyme in cholesterol biosynthesis, and (b) it facilitates the degradation of low density lipoproteins when they are present in the culture medium at low concentrations (i.e. high affinity degradation). Cultured cells from subjects with the homozygous form of familial hypercholesterolemia, which were found to lack the high affinity binding process, were resistant to suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity by low density lipoproteins and were also deficient in high affinity degradation. On the other hand, these mutant cells showed a normal low affinity uptake of low density lipoproteins and were able to degrade these lipoproteins when they were present in the culture medium at high concentrations. The possibility is raised, therefore, that a prerequisite for the regulation of cholestero-genesis in cultured fibroblasts is the initial binding of low density lipoproteins to the high affinity surface receptor sites and that a defect in this process represents the primary genetic abnormality in the disorder familial hypercholesterolemia.

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Journal ArticleDOI
14 Nov 2003-Cell
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1,366 citations