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: This review considers the following hypotheses: that cholesterol is integral to the function of caveolae; a mediator of Hedgehog regulation; and a ligand for the binding of cytolytic toxins to membranes.
Abstract: This review considers the following hypotheses, some well-supported and some speculative. Almost all of the sterol molecules in plasma membranes are associated with bilayer phospholipids in complexes of varied strength and stoichiometry. These complexes underlie many of the material properties of the bilayer. The small fraction of cholesterol molecules exceeding the binding capacity of the phospholipids is thermodynamically active and serves diverse functions. It circulates briskly among the cell membranes, particularly through contact sites linking the organelles. Active cholesterol provides the upstream feedback signal to multiple mechanisms governing plasma membrane homeostasis, pegging the sterol level to a threshold set by its phospholipids. Active cholesterol could also be the cargo for various inter-organelle transporters and the form excreted from cells by reverse transport. Furthermore, it is integral to the function of caveolae; a mediator of Hedgehog regulation; and a ligand for the binding of cytolytic toxins to membranes. Active cholesterol modulates a variety of plasma membrane proteins-receptors, channels and transporters-at least in vitro.
15 citations
TL;DR: Functional characterization of transmembrane protein TMEM147 is focused on, and it is found that it localizes at the ER and nuclear envelope in HeLa cells, and physically interacts with LBR and DHCR, two key sterol reductases in cholesterol biosynthesis.
Abstract: The structurally and functionally complex Endoplasmic Reticulum (ER) hosts critical processes including lipid synthesis. Here, we focus on the functional characterization of transmembrane protein TMEM147 and report that it localizes at the ER and nuclear envelope in HeLa cells. Silencing of TMEM147 drastically reduces the level of lamin B receptor (LBR) at the Inner Nuclear Membrane and results in mistargeting of LBR to the ER. LBR possesses a modular structure and corresponding bifunctionality in heterochromatin organization, via its N-terminus, and cholesterol biosynthesis, via its sterol-reductase C-terminal domain. We show that TMEM147 physically interacts with LBR and the C-terminus of LBR is essential for their functional interaction. We find that TMEM147 also physically interacts with key sterol reductase DHCR7 in cholesterol biosynthesis. Similar to LBR, TMEM147 downregulation results in sharp decline of DHCR protein levels and co-ordinate transcriptional decrease of LBR and DHCR7 expression. Consistently, lipidomic analysis upon TMEM147 silencing identified changes in cellular cholesterol levels, cholesteryl ester levels and profile, and in cellular cholesterol uptake, raising the possibility that TMEM147 is an important new regulator of cholesterol homeostasis in cells.
12 citations
TL;DR: The 5-domain NPCCSS reliability study supports the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis.
Abstract: Niemann–Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease associated with neurovisceral manifestations resulting from lysosomal dysfunction and aberrant lipid accumulation. A multicentre, prospective observational study (Clinical Trials.gov ID: NCT02435030) of individuals with genetically confirmed NPC1 or NPC2 receiving routine clinical care was conducted, to prospectively characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals. Progression was measured using the abbreviated 5-domain NPC Clinical Severity Scale (NPCCSS), 17-domain NPCCSS and NPC clinical database (NPC-cdb) score. Cholesterol esterification and heat shock protein 70 (HSP70) levels were assessed from peripheral blood mononuclear cells (PBMCs), cholestane-3β,5α-,6β-triol (cholestane-triol) from serum, and unesterified cholesterol from both PBMCs and skin biopsy samples. The inter- and intra-rater reliability of the 5-domain NPCCSS was assessed by 13 expert clinicians’ rating of four participants via video recordings, repeated after ≥ 3 weeks. Intraclass correlation coefficients (ICCs) were calculated. Of the 36 individuals with NPC (2–18 years) enrolled, 31 (86.1%) completed the 6–14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (± SD) increase in 5-domain NPCCSS scores of 1.4 (± 2.9) was observed, corresponding to an annualized progression rate of 1.5. On the 17-domain NPCCSS, a mean (± SD) progression of 2.7 (± 4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (p < 0.0001), HSP70 (p < 0.0001) and skin unesterified cholesterol (p = 0.0006). Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals (p = 0.008) and correlated with the 5-domain NPCCSS (Spearman’s correlation coefficient = 0.265, p = 0.0411). The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability (ICC = 0.995) and intra-rater reliability (ICC = 0.937). Progression rates observed were consistent with other reports on disease progression in NPC. The 5-domain NPCCSS reliability study supports its use as an abbreviated alternative to the 17-domain NPCCSS that focuses on the most relevant domains of the disease. The data support the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis. Levels of HSP70 in individuals with NPC were significantly decreased compared with healthy individuals. CT-ORZY-NPC-001: ClincalTrials.gov NCT02435030, Registered 6 May 2015, https://clinicaltrials.gov/ct2/show/NCT02435030
; EudraCT 2014–005,194-37, Registered 28 April 2015, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-005194-37/DE
. OR-REL-NPC-01: Unregistered.
12 citations
Cites background from "Disorders of cholesterol metabolism..."
...Mutations in the NPC genes either result in reduced protein function because of limited binding capacity, or reduced abundance because of a more rapid degradation of the dysfunctional protein [2, 4, 54, 55]; therefore, NPC function is not expected to change with disease progression....
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TL;DR: The sterol biosynthesis inhibitors (SBIs) are a class of lipids with essential roles in sustaining the domain structure of cell membranes and regulating biological processes as discussed by the authors, however, despite the essential role of sterols in cell functioning in eukaryotes, several organisms are not able to synthesize sterols themselves.
Abstract: Sterols are a class of lipids with essential roles in sustaining the domain structure of cell membranes and regulating biological processes [1]. Human health is affected by high cholesterol levels [2]; drugs preventing this are widely used. Also striking is the high demand for compounds classified as sterol biosynthesis inhibitors (SBIs), either as medicine to control fungal infections or as agrochemicals to combat fungal plant diseases [3,4]. Despite the essential role of sterols in cell functioning in eukaryotes, several organisms, including nematodes, insects, and plasmodia, are not able to synthesize sterols themselves. To sustain normal development, these sterol auxotrophs may have to acquire exogenous sterols from their food or environment [5,6].
12 citations
TL;DR: It is found that when ABCA1 is defective (Tangier disease) there is secondary inhibition of the NPC disease pathway, linking these two diseases at the level of cellular pathophysiology.
Abstract: Niemann-Pick disease type C (NPC) and Tangier disease are genetically and clinically distinct rare inborn errors of metabolism. NPC is caused by defects in either NPC1 or NPC2; whereas Tangier disease is caused by a defect in ABCA1. Tangier disease is currently without therapy, whereas NPC can be treated with miglustat, a small molecule inhibitor of glycosphingolipid biosynthesis that slows the neurological course of the disease. When a Tangier disease patient was misdiagnosed with NPC and treated with miglustat, her symptoms improved. This prompted us to consider whether there is mechanistic convergence between these two apparently unrelated rare inherited metabolic diseases. In this study, we found that when ABCA1 is defective (Tangier disease) there is secondary inhibition of the NPC disease pathway, linking these two diseases at the level of cellular pathophysiology. In addition, this study further supports the hypothesis that miglustat, as well as other substrate reduction therapies, may be potential therapeutic agents for treating Tangier disease as fibroblasts from multiple Tangier patients were corrected by miglustat treatment.
11 citations
Cites background from "Disorders of cholesterol metabolism..."
...As ABCA1 and the NPC1/NPC2 proteins are involved in regulating different aspects of cellular cholesterol homeostasis, this is not unexpected as it likely reflects perturbations and compensatory responses to changes in cholesterol homeostasis within diseased cells.(9) For example, increased expression of ABCA1 in NPC1 deficient cells using upstream activators, such as LXR, increases cholesterol and lipid efflux thus rescuing the cellular phenotypes characteristic of NPC disease cells....
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...Tangier disease cells as it may provide insights into the underlying pathogenic/convergent mechanisms.(9) We therefore examined the effects of 2-hydroxypropylβ-cyclodextrin (HPβCD), which reduces cholesterol and sphingolipid storage and is currently in clinical trials for NPC1,(23) as well as acetyl-DL-leucine (ADLL), which has previously been shown to improve symptoms in patients with cerebellar ataxia....
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References
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TL;DR: An understanding of the complex pathways of sphingolipid metabolism and the mechanisms that regulate lipid generation and lipid action is required to understand the mechanisms of cell growth, death, senescence, adhesion, migration, inflammation, angiogenesis and intracellular trafficking.
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.
2,856 citations
TL;DR: Cholesterol complexed to apolipoprotein E-containing lipoproteins may explain the delayed onset of CNS synaptogenesis after glia differentiation and neurobehavioral manifestations of defects in cholesterol or lipoprotein homeostasis.
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.
1,543 citations
TL;DR: 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).
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
1,463 citations
TL;DR: Novel biological insights are revealed into the function of HH lipidation in the secretion and transport of this ligand and details of the signal transduction pathway, which involves Patched 1, Smoothened and GLI proteins, as well as, in vertebrates, primary cilia.
Abstract: The cloning of the founding member of the Hedgehog (HH) family of secreted proteins two decades ago inaugurated a field that has diversified to encompass embryonic development, stem cell biology and tissue homeostasis. Interest in HH signalling increased when the pathway was implicated in several cancers and congenital syndromes. The mechanism of HH signalling is complex and remains incompletely understood. Nevertheless, studies have revealed novel biological insights into this system, including the function of HH lipidation in the secretion and transport of this ligand and details of the signal transduction pathway, which involves Patched 1, Smoothened and GLI proteins (Cubitus interruptus in Drosophila melanogaster), as well as, in vertebrates, primary cilia.
1,437 citations
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.
1,421 citations