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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01 Jan 2011
TL;DR: Clinical and basic science aspects of Smith-Lemli-Opitz syndrome, desmosterolosis, lathosterolosis), HEM dysplasia, X-linked dominant chondrodysplasia punctata, Congenital Hemidyspl Asia with Ichthyosiform erythroderma and Limb Defects Syndrome, sterol-C-4 methyloxidase-like deficiency, and Antley-Bixler syndrome are reviewed.
Abstract: Cholesterol homeostasis is critical for normal growth and development. In addition to being a major mem- brane lipid, cholesterol has multiple biological functions. These roles include being a precursor molecule for the syn- thesis of steroid hormones, neuroactive steroids, oxysterols, and bile acids. Cholesterol is also essential for the proper maturation and signaling of hedgehog proteins, and thus cholesterol is critical for embryonic development. After birth, most tissues can obtain cholesterol from either en- dogenous synthesis or exogenous dietary sources, but prior to birth, the human fetal tissues are dependent on endoge- nous synthesis. Due to the blood-brain barrier, brain tissue cannot utilize dietary or peripherally produced cholesterol. Generally, inborn errors of cholesterol synthesis lead to both a defi ciency of cholesterol and increased levels of po- tentially bioactive or toxic precursor sterols. Over the past couple of decades, a number of human malformation syn- dromes have been shown to be due to inborn errors of cho- lesterol synthesis. Herein, we will review clinical and basic science aspects of Smith-Lemli-Opitz syndrome, desmo- sterolosis, lathosterolosis, HEM dysplasia, X-linked domi- nant chondrodysplasia punctata, Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects Syndrome, sterol-C-4 methyloxidase-like defi ciency, and Antley-Bixler syndrome. —Porter, F. D., and G. E. Herman. Malformation syndromes caused by disorders of cholesterol synthesis. J. Lipid Res . 2011. 52: 6-34.
321 citations
TL;DR: The data demonstrate that desmosterolosis is a cholesterol-biosynthesis disorder caused by mutations in DHCR24, a recently defined family of flavin adenine dinucleotide (FAD)–dependent oxidoreductases.
Abstract: Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies. Patients with desmosterolosis have elevated levels of the cholesterol precursor desmosterol, in plasma, tissue, and cultured cells; this abnormality suggests a deficiency of the enzyme 3β-hydroxysterol Δ24-reductase (DHCR24), which, in cholesterol biosynthesis, catalyzes the reduction of the Δ24 double bond of sterol intermediates. We identified the human DHCR24 cDNA, by the similarity between the encoded protein and a recently characterized plant enzyme—DWF1/DIM, from Arabidopsis thaliana—catalyzing a different but partially similar reaction in steroid/sterol biosynthesis in plants. Heterologous expression, in the yeast Saccharomyces cerevisiae, of the DHCR24 cDNA, followed by enzyme-activity measurements, confirmed that it encodes DHCR24. The encoded DHCR24 protein has a calculated molecular weight of 60.1 kD, contains a potential N-terminal secretory-signal sequence as well as at least one putative transmembrane helix, and is a member of a recently defined family of flavin adenine dinucleotide (FAD)–dependent oxidoreductases. Conversion of desmosterol to cholesterol by DHCR24 in vitro is strictly dependent on reduced nicotinamide adenine dinucleotide phosphate and is increased twofold by the addition of FAD to the assay. The corresponding gene, DHCR24, was identified by database searching, spans ∼46.4 kb, is localized to chromosome 1p31.1-p33, and comprises nine exons and eight introns. Sequence analysis of DHCR24 in two patients with desmosterolosis revealed four different missense mutations, which were shown, by functional expression, in yeast, of the patient alleles, to be disease causing. Our data demonstrate that desmosterolosis is a cholesterol-biosynthesis disorder caused by mutations in DHCR24.
321 citations
TL;DR: A review of the current state of knowledge surrounding the oxygen requirement for steroid biosynthesis and phylogenetic patterns in the distribution of steroid and triterpenoid biosynthetic pathways indicates that an ancestral anaerobic pathway is highly unlikely.
Abstract: There is a close connection between modern-day biosynthesis of particular triterpenoid biomarkers and presence of molecular oxygen in the environment. Thus, the detection of steroid and triterpenoi...
317 citations
TL;DR: Animals treated with N-butyldeoxynojirimycin (NB-DNJ), an inhibitor of glucosylceramide synthase, a pivotal enzyme in the early GSL synthetic pathway showed delayed onset of neurological dysfunction, increased average life span, and reduced ganglioside accumulation and accompanying neuropathological changes, suggesting that drugs inhibiting GSL synthesis could have a similar ameliorating effect on the human disorder.
315 citations
TL;DR: It is now apparent that cargo transport by members of the LDL receptor family is closely associated with regulation of cellular physiology and cellular signaling events.
Abstract: The low-density lipoprotein (LDL) receptor family consists of several related scavenger receptors that not only function as important cargo transporters, but also inform the cell of changes in its environment by mediating signaling responses. The LDL receptor was the first family member to be characterized and its function seems to be restricted to lipoprotein metabolism. By contrast, lipoprotein metabolism does not appear to be the exclusive function of the other characterized LDL receptor family members. It is now apparent that cargo transport by members of the LDL receptor family is closely associated with regulation of cellular physiology and cellular signaling events. Here, we focus on the diverse biological activities of certain members of this family.
314 citations