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: The desmosterol data demonstrate the importance of steric configuration of the triphenylethyl portion of the clomiphene molecule as a determinant of potency of Δ24-reductase inhibition.
20 citations
TL;DR: It is suggested that desmosterol may be able to replace cholesterol in the retina, both structurally and functionally, in the context of “sterol synergism.”
Abstract: Desmosterolosis is a rare, autosomal recessive, human disease characterized by multiple congenital anomalies in conjunction with grossly elevated levels of desmosterol and markedly reduced levels of cholesterol in all bodily tissues. Herein, we evaluated retinal sterol composition, histology, and electrophysiological function in an animal model that exhibited the biochemical features of desmosterolosis, produced by treating pregnant rats and their progeny with U18666A, an inhibitor of desmosterol reductase. Treated rats had cataracts, were substantially smaller, and had markedly high levels of desmosterol and profoundly low levels of cholesterol in their retinas and other tissues compared to age-matched controls. However, their retinas were histologically normal and electrophysiologically functional. These results suggest that desmosterol may be able to replace cholesterol in the retina, both structurally and functionally. These findings are discussed in the context of "sterol synergism".
19 citations
TL;DR: There were no significant differences in the craniofacial pattern profile between the sexes or clinical severity as measured by either plasma cholesterol level at the time of diagnosis or the physical severity score, suggesting that the degree of deviation from cranioFacial norms is a function of the overall physical severity.
Abstract: Smith-Lemli-Opitz syndrome (SLOS), is an autosomal recessive condition caused by cholesterol synthesis deficiency which results in a wide phenotypic spectrum which includes multiple malformations, distinctive facial appearance, and intellectual disability. This anthropometric and observational study was carried out to define the key facial characteristics of individuals with SLOS and to evaluate evolution of the facial phenotype with age. Clinical photographs were obtained on 51 subjects with SLOS and standardized facial anthropometry was performed on 42; the ages ranged from 6 months to 20 years. For each individual, 22 standardized cranial and facial measurements were obtained and compared to published age- and sex-matched controls. Craniofacial pattern profiles were compared between sexes, various age groups, plasma cholesterol concentration at the time of diagnosis, and physical severity score. Mean-Z, a measurement of overall facial size, and craniofacial variability index (CVI), a summary anthropometric measure of craniofacial deviation from the norm, were calculated and compared according to methods published previously. A characteristic craniofacial pattern profile was universally present: narrow forehead, brachycephaly, short palpebral fissures, short nasal ridge, anteverted nares, flat face, normal jaw width, and retrognathia. The facial measurements of subjects with SLOS had higher deviations from the norm with mean CVI of 2.11; SD = 0.47 (controls: Mean = 0.76, SD = 0.19; <0.0001) than age- and sex-matched controls. Their faces were also smaller than controls: 70% of subjects had mean-Z values 2 SD below the mean for controls; average Z-score was -1.64; SD = 0.85 (controls: mean = 0, SD = 0.64; <0.0001). There were no significant differences in the craniofacial pattern profile between the sexes or clinical severity as measured by either plasma cholesterol level at the time of diagnosis or the physical severity score. Patients with a lower weight at the time of assessment and patients with higher physical severity score had higher CVI measures (P < 0.001 and P < 0.002, respectively), suggesting that the degree of deviation from craniofacial norms is a function of the overall physical severity.
18 citations
TL;DR: Novel data demonstrate that the cholesterol-deficient SLOS fetus is able to obtain cholesterol from trophoblasts at a time when cholesterol is playing a critical role in development, and has implications for design of treatments for cholesterol deficiency syndromes as well as understanding of prenatal cholesterol transport in humans.
16 citations
TL;DR: Based on recent high resolution structures of several NBDs and an intact transporter, a model of how dimers of these important proteins function will be discussed, with particular attention to HlyB, the ABC transporter from E. coli.
Abstract: The general properties of ABC transporters, from bacteria to humans, including a brief history of their initial discovery, are considered. ABC transporters, one of the largest protein super families and vital for human health, are in toto responsible for the transport of an enormous range of molecules from ions (CFTR) or anti-tumour drugs (Pgp/MDR) to large polypeptides. Nevertheless, all ABC transporters are powered by a conserved ATPase the ABC or NBD domain, using in all probability the same basic mechanism of action for the hydrolysis of ATP and its coupling to the transport process. Based on recent high resolution structures of several NBDs and an intact transporter, a model of how dimers of these important proteins function will be discussed, with particular attention to HlyB, the ABC transporter from E. coli.
14 citations