Disorders of cholesterol metabolism and their unanticipated convergent mechanisms of disease.
Frances M. Platt,Christopher A. Wassif,Alexandria Colaco,Andrea Dardis,Emyr Lloyd-Evans,Bruno Bembi,Forbes D. Porter +6 more
TLDR
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.read more
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Cholesterol depletion enhances TGF-β Smad signaling by increasing c-Jun expression through a PKR-dependent mechanism.
TL;DR: It is proposed that cholesterol depletion induces overactivation of PKR, JNK, and TGF-β signaling, which together may contribute to the side effects of statins in diverse disease settings.
Fetal and Neonatal Cholesterol Metabolism
Laura A. Woollett,James E. Heubi +1 more
TL;DR: Fetuses have two sources of cholesterol, endogenous and exogenous, as do adults and children; the potential impact of maternal cholesterol on fetal cholesterol and the impact of diet on neonatal cholesterol metabolism are discussed.
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The SAGA complex, together with transcription factors and the endocytic protein Rvs167p, coordinates the reprofiling of gene expression in response to changes in sterol composition in Saccharomyces cerevisiae.
Gisele Dewhurst-Maridor,Daniel Abegg,Fabrice P. A. David,Jacques Rougemont,Cameron C. Scott,Alexander Adibekian,Howard Riezman +6 more
TL;DR: The SAGA complex, together with transcription factors and Rvs167p, coordinates sterol-dependent transcription changes in ergosterol mutants, and genes encoding stress proteins and basic amino acid synthesis are affected.
Journal ArticleDOI
Functional expression of opioid receptors and other human GPCRs in yeast engineered to produce human sterols
Jimmy Gollihar,Marker, Jeffery +1 more
TL;DR: In this paper , yeast Saccharomyces cerevisiae is used to produce cholesterol and introduce diverse mu, delta and kappa opioid receptors to create sensitive opioid biosensors that recapitulate agonist binding profiles and antagonist inhibition.
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Late Endosomal/Lysosomal Accumulation of a Neurotransmitter Receptor in a Cellular Model of Smith-Lemli-Opitz Syndrome.
TL;DR: In this paper, a cellular model of Smith-Lemli-Opitz syndrome (SLOS) was generated in HEK-293 cells stably expressing the human serotonin1A receptor (an important neurotransmitter G-protein coupled receptor) using AY 9944, an inhibitor for the enzyme 3β-hydroxy-steroid-∆7 -reductase (7-DHCR).
References
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Journal ArticleDOI
Principles of bioactive lipid signalling: lessons from sphingolipids
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.
Journal ArticleDOI
CNS synaptogenesis promoted by glia-derived cholesterol
Daniela H. Mauch,Karl Nägler,Stefan Schumacher,Christian Göritz,Eva-Christina Müller,Albrecht Otto,Frank W. Pfrieger +6 more
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.
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Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1
Stephan Rust,Rosier M,Harald Funke,Real J,Amoura Z,Piette Jc,Deleuze Jf,Brewer Hb,Nicolas Duverger,Patrice Denefle,Gerd Assmann +10 more
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).
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The mechanisms of Hedgehog signalling and its roles in development and disease.
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.
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Binding and Degradation of Low Density Lipoproteins by Cultured Human Fibroblasts COMPARISON OF CELLS FROM A NORMAL SUBJECT AND FROM A PATIENT WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
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.