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.
Abstract: Cholesterol 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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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".
213 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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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.
181 citations
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.
115 citations
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.
105 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)....
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..., 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....
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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.
73 citations
References
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TL;DR: A model in which Sre1 and Scp1 monitor oxygen-dependent sterol synthesis as an indirect measure of oxygen supply and mediate a hypoxic response in fission yeast is proposed and tested.
301 citations
TL;DR: The present ultrastructural data are consistent with previous biochemical and genetic evidence indicating that LDL exerts its regulatory action on cellular cholesterol metabolism in fibroblasts through an interaction with a specific cell surface receptor and that this receptor is defective in homozygous familial hypercholesterolemia fibro Blasts.
Abstract: Monolayers of normal human fibroblasts were observed to bind ferritin-labeled low density lipoprotein (LDL-ferritin) at specific receptor sites on the cell surface membrane. When fibroblasts were incubated with LDL-ferritin at 4 degrees, more than 70% of the surface-bound ferritin cores were localized by electron microscopy to short segments of the plasma membrane where the membrane appeared indented and coated on both of its sides by a fuzzy material. These membrane segments corresponded to "coated regions" previously described in other cell types. Unver the conditions of these experiments, an average of 55 LDL-ferritin particles were bound to each millimeter of plasma membrane in normal cells. In the presence of a 15-fold excess of native LDL, the number of bound ferritin cores was reduced by 75%, suggesting that the LDL-ferritin was binding to specific LDL receptor sites. Although fibroblasts from a patient with the homozygous form of familial hypercholesterolemia contained the same number of indented, coated membrane regions per millimeter of cell surface as did normal cells, no LDL-ferritin was observed to bind to the cell membrane in these mutant cells. The present ultrastructural data are consistent with previous biochemical and genetic evidence indicating that LDL exerts its regulatory action on cellular cholesterol metabolism in fibroblasts through an interaction with a specific cell surface receptor and that this receptor is defective in homozygous familial hypercholesterolemia fibroblasts. Moreover, the data suggest that the LDL receptor is localized to indented, coated regions of the plasma membrane that appear to participate in the adsorptive endocytosis of proteins.
298 citations
TL;DR: This review will present evidence that the previous studies by the authors and other researchers established a framework for subsequent transmission, scanning and high-voltage electron microscopic (HVEM) investigations concerning ultrastructural, ultracytochemical and immunoultra-structural alterations of the cerebral ECs and the mechanisms of the BBB transport that occurs after CNS injury.
Abstract: This review presents an overview of the highlights of major concepts involving the anatomical routes for the transport of macromolecules and the transmigration of cellular elements across the blood-brain barrier (BBB) during inflammation The particular focus will include inflammatory leukocytes, neoplastic cells and pathogenic microorganisms including specific types of viruses, bacteria and yeasts The experimental animal models presented here have been employed successfully by the authors in several independent experiments during the past twenty-five years for investigations of pathologic alterations of the BBB after a variety of experimentally induced injuries and inflammatory conditions in mammalian and non-mammalian animal species The initial descriptions of endothelial cell (EC) vesicles or caveolae serving as mini-transporters of fluid substances essentially served as a springboard for many subsequent discoveries during the past half century related to mechanisms of uptake of materials into ECs and whether or not pinocytosis is related to the transport of these materials across EC barriers under normal physiologic conditions and after tissue injury In the mid-1970's, the authors of this review independently applied morphologic techniques (transmission electron microscopy-TEM), in conjunction with the plant protein tracer horseradish peroxidase (HRP) to investigate macromolecular transport structures that increased after the brain and spinal cord had been subjected to a variety of injuries Based on morphologic evidence from these studies of BBB injury, the authors elaborated a unique EC system of modified caveolae that purportedly fused together forming transendothelial cell channels, and later similar EC profiles defined as vesiculo-canalicular or vesiculo-tubular structures (VTS, Lossinsky, et al, 1999) These EC structures were observed in association with increased BBB permeability of tracers including exogenously injected HRP, normally excluded from the intercellular milieu of the CNS Subsequent studies of non-BBB-type tumor ECs determined that the EC VTS and other vesicular structures were defined by others as vesiculo-vacuolar organelles (VVOs, Kohn et al, 1992; Dvorak et al, 1996) Collectively, these structures appear to represent a type of anatomical gateway to the CNS likely serving as conduits However, these CNS conduits become patent only in damaged ECs for the passage of macromolecules, and purportedly for inflammatory and neoplastic cells as well (Lossinsky et al, 1999) In this review, we focus attention on the similarities and differences between caveolae, fused racemic vesicular bundles, endothelial tubules and channels (VTS and the VVOs) that are manifest in normal, non-BBB-type blood vessels, and in the BBB after injury This review will present evidence that the previous studies by the authors and other researchers established a framework for subsequent transmission (TEM), scanning (SEM) and high-voltage electron microscopic (HVEM) investigations concerning ultrastructural, ultracytochemical and immunoultra-structural alterations of the cerebral ECs and the mechanisms of the BBB transport that occurs after CNS injury This review is not intended to include all of the many observations that might be included in a general historical overview of the development of the EC channel hypothesis, but it will discuss several of the major contributions We have attempted to present some of the structural evidence that supports our early contributions and those made by other investigators by highlighting major features of these EC structures that are manifest in the injured BBB We have focused on currently established concepts and principles related to mechanisms for the transendothelial transport of macromolecules after CNS injury and also offer a critical appraisal of some of this literature Finally, we describe more recent concepts of transBBB avenues for viruses, including HIV-1, bacterial and mycotic organisms, as well as inflammatory and neoplastic cell adhesion and migration across the injured mammalian BBB Data from studies of EC-related adhesion molecules, both from the literature and from the author's experimental results and observations made in other laboratories, as well as from personal communications underscore the importance of the adhesion molecules in facilitating the movement of leukocytic, neoplastic cell and human pathogens across the BBB during inflammatory and neoplastic events Exciting, ongoing clinical trials are addressing possible therapeutic intervention in neuroinflammatory diseases, including multiple sclerosis, by blocking certain glycoprotein adhesion molecules before cells have the ability to adhere to the ECs and migrate across the BBB Approaches whereby inflammation may be reduced or arrested using anti-adhesion molecules, by restructuring EC cytoskeletal, filamentous proteins, as well as remodeling cholesterol components of the modified VTS are discussed in the context of developing future therapies for BBB injury and inflammation Understanding new concepts about the mechanism(s) by which inflammatory cells and a variety of pathogenic microorganisms are transported across the BBB can be expected to advance our understanding of fundamental disease processes Taken together, the literature and the author's experiences during the past quarter of a century, will hopefully provide new clues related to the mechanisms of transendothelial cell adhesion and emigration across the injured BBB, issues that have been receiving considerable attention in the clinical arena Learning how to chemically modulate the opening and/or closure of EC VTS and VVO structural pathways, or junctional complexes prior to cellular or microorganism adhesion and breaching the BBB presents challenging new questions in modern medicine Future studies will be critically important for the development of therapeutic intervention in several human afflictions including traumatic brain and spinal cord injuries, stroke, cancer, multiple sclerosis and conditions where the immune system may be compromised including HIV infection, infantile and adult meningitis
292 citations
TL;DR: All sterol accumulation in brain during the period of rapidMyelination can be explained by local synthesis; neither diet nor production of cholesterol by other organs plays a direct role in supplying cholesterol for myelination in brain.
Abstract: We examined whether cholesterol needed for myelin formation is locally synthesized or whether it comes from the circulation. The experimental design was to inject [3H]water and to use incorporation of label into brain cholesterol as a measure of the rate of accumulation of newly synthesized cholesterol in brain. The contribution of the circulation to this labeled cholesterol pool was minimized by repressing liver synthesis of cholesterol with a high cholesterol diet. The rate of accumulation of total cholesterol was calculated from the increasing amounts of sterol in brain regions at successive time intervals during development. Thus, accumulating cholesterol not explained as being newly synthesized (radioactive) could be assumed to have come from the circulation. Long-Evans rats, ranging in age from birth to 35 days, were injected intraperitoneally with [3H]water (0.3-1.0 mCi/g of body weight) and killed 2 h later. The brain was dissected into brainstem, cerebellum, and cerebral hemispheres, and total lipids were extracted. Cholesterol and its precursors were quantified by HPLC. The radioactivity associated with the sterol fractions and the specific activity of body water determined from serum were used to calculate the absolute amount of newly synthesized sterol. The rates of cholesterol synthesis were compared with the rates of accumulation of total cholesterol in each brain region. The rate of accumulation of total sterol (cholesterol and desmosterol) closely followed that of newly synthesized total sterol in all brain regions from the second through the fifth postnatal weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
290 citations
TL;DR: A new kind of job-sharing between neurons and astrocytes is proposed to improve the still insufficient understanding of brain cholesterol metabolism and its role in neurodegeneration.
Abstract: Brain function depends on the cooperation between highly specialized cells. Neurons generate electrical signals and glial cells provide structural and metabolic support. Here, I propose a new kind of job-sharing between neurons and astrocytes. Recent studies on primary cultures of highly purified neurons from the rodent central nervous system (CNS) suggest that, during development, neurons reduce or even abandon cholesterol synthesis to save energy and import cholesterol from astrocytes via lipoproteins. The cholesterol shuttle may be restricted to compartments distant from the soma including synapses and may be regulated by electrical activity. Testing these hypotheses will help to improve our still insufficient understanding of brain cholesterol metabolism and its role in neurodegeneration.
290 citations