Mechanisms for Cellular Cholesterol Transport: Defects and Human Disease

2006 ◽  
Vol 86 (4) ◽  
pp. 1237-1261 ◽  
Author(s):  
Elina Ikonen
Keyword(s):  
Mouse Models ◽  
Human Disease ◽  
Human Diseases ◽  
Cholesterol Transport ◽  
Cholesterol Trafficking ◽  
Cellular Cholesterol ◽  
Intracellular Cholesterol

This review summarizes the mechanisms of cellular cholesterol transport and monogenic human diseases caused by defects in intracellular cholesterol processing. In addition, selected mouse models of disturbed cholesterol trafficking are discussed. Current pharmacological strategies to prevent atherosclerosis are largely based on altering cellular cholesterol balance and are introduced in this context. Finally, because of the organizing potential of cholesterol in membranes, disturbances in cellular cholesterol transport have implications for a wide variety of human diseases, of which selected examples are given.

Apolipoprotein A-I stimulates the transport of intracellular cholesterol to cell-surface cholesterol-rich domains (caveolae)

2001 ◽  
Vol 358 (1) ◽  
pp. 79-86 ◽  
Author(s):  
Dmitri SVIRIDOV ◽  
Noel FIDGE ◽  
Gabrielle BEAUMIER-GALLON ◽  
Christopher FIELDING
Keyword(s):  
Cell Surface ◽  
Cholesterol Efflux ◽  
Partial Purification ◽  
Cholesterol Transport ◽  
Dependent Manner ◽  
Cholesterol Trafficking ◽  
Apolipoprotein A ◽  
Intracellular Cholesterol ◽  
Plasma Apolipoprotein ◽  
Stimulation Of

We have studied the effect of lipid-free human plasma apolipoprotein A-I (apoA-I) on the transport of newly synthesized cholesterol to cell-surface cholesterol-rich domains, which in human skin fibroblasts are mainly represented by caveolae. Changes in transport of newly synthesized cholesterol were assessed after labelling cells with [14C]acetate at 15°C and warming cells to permit the transfer of cholesterol, followed by the selective oxidation of cholesterol in cholesterol-rich domains (caveolae) in the plasma membrane before their partial purification. ApoA-I, but not BSA added in an equimolar concentration, enhanced the transport of cholesterol to the caveolae up to 5-fold in a dose- and time-dependent manner. The effect of apoA-I on cholesterol transport exceeded its effect on cholesterol efflux, resulting in an accumulation of intracellular cholesterol in caveolae. Methyl-β-cyclodextrin, added at a concentration promoting cholesterol efflux to the same extent as apoA-I, also stimulated cholesterol trafficking, but was 3-fold less effective than apoA-I. Progesterone inhibited the transport of newly synthesized cholesterol to the caveolae. Treatment of cells with apoA-I stimulated the expression of caveolin, increasing the amount of caveolin protein and mRNA by approx. 2-fold. We conclude that apoA-I induces the transport of intracellular cholesterol to cell-surface caveolae, possibly in part through the stimulation of caveolin expression.

scholarly journals TarGo: network based target gene selection system for human disease related mouse models

2019 ◽  
Vol 35 (1) ◽  
Author(s):  
Daejin Hyung ◽  
Ann-Marie Mallon ◽  
Dong Soo Kyung ◽  
Soo Young Cho ◽  
Je Kyung Seong
Keyword(s):  
Mouse Models ◽  
Network Topology ◽  
Human Disease ◽  
Target Gene ◽  
Gene Selection ◽  
Genetically Engineered ◽  
Human Diseases ◽  
Selection System ◽  
Genetically Engineered Mouse Models ◽  
Disease Signatures

Abstract Genetically engineered mouse models are used in high-throughput phenotyping screens to understand genotype-phenotype associations and their relevance to human diseases. However, not all mutant mouse lines with detectable phenotypes are associated with human diseases. Here, we propose the “Target gene selection system for Genetically engineered mouse models” (TarGo). Using a combination of human disease descriptions, network topology, and genotype-phenotype correlations, novel genes that are potentially related to human diseases are suggested. We constructed a gene interaction network using protein-protein interactions, molecular pathways, and co-expression data. Several repositories for human disease signatures were used to obtain information on human disease-related genes. We calculated disease- or phenotype-specific gene ranks using network topology and disease signatures. In conclusion, TarGo provides many novel features for gene function prediction.

scholarly journals Interaction of NPC2 protein with Lysobisphosphatidic Acid is required for normal endolysosomal cholesterol trafficking

2019 ◽  
Author(s):  
Leslie A. McCauliff ◽  
Annette Langan ◽  
Ran Li ◽  
Olga Ilnytska ◽  
Debosreeta Bose ◽  
...  
Keyword(s):  
Functional Relationship ◽  
Cholesterol Transport ◽  
Unesterified Cholesterol ◽  
Cholesterol Trafficking ◽  
Cholesterol Accumulation ◽  
Genes Encoding ◽  
Lysobisphosphatidic Acid ◽  
Intracellular Cholesterol ◽  
Niemann Pick ◽  
Stimulation Of

AbstractUnesterified cholesterol accumulation in the late endosomal/lysosomal (LE/LY) compartment is the cellular hallmark of Niemann-Pick C (NPC) disease, caused by defects in the genes encoding NPC1 or NPC2. We previously reported the dramatic stimulation of NPC2 cholesterol transport rates by the LE/LY phospholipid lysobisphosphatidic acid (LBPA) and in these studies sought to determine their functional relationship in normal LE/LY cholesterol egress. Here we demonstrate that NPC2 interacts directly with LBPA and identify the NPC2 hydrophobic knob domain as the site of interaction. Using its precursor phosphatidylglycerol (PG), we show that PG-induced LBPA enrichment results in clearance of accumulated cholesterol from NPC1-deficient cells but is ineffective in cells lacking functional NPC2. Together these studies reveal a heretofore unknown aspect of intracellular cholesterol trafficking, in which NPC2 and LBPA function together in an obligate step of sterol egress from the LE/LY compartment, which appears to be independent of NPC1.

scholarly journals Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acid

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Leslie A McCauliff ◽  
Annette Langan ◽  
Ran Li ◽  
Olga Ilnytska ◽  
Debosreeta Bose ◽  
...  
Keyword(s):  
Cholesterol Transport ◽  
Unesterified Cholesterol ◽  
Cholesterol Trafficking ◽  
Cholesterol Accumulation ◽  
Functional Interaction ◽  
Genes Encoding ◽  
Lysobisphosphatidic Acid ◽  
Intracellular Cholesterol ◽  
Niemann Pick ◽  
Stimulation Of

Unesterified cholesterol accumulation in the late endosomal/lysosomal (LE/LY) compartment is the cellular hallmark of Niemann-Pick C (NPC) disease, caused by defects in the genes encoding NPC1 or NPC2. We previously reported the dramatic stimulation of NPC2 cholesterol transport rates to and from model membranes by the LE/LY phospholipid lysobisphosphatidic acid (LBPA). It had been previously shown that enrichment of NPC1-deficient cells with LBPA results in cholesterol clearance. Here we demonstrate that LBPA enrichment in human NPC2-deficient cells, either directly or via its biosynthetic precursor phosphtidylglycerol (PG), is entirely ineffective, indicating an obligate functional interaction between NPC2 and LBPA in cholesterol trafficking. We further demonstrate that NPC2 interacts directly with LBPA and identify the NPC2 hydrophobic knob domain as the site of interaction. Together these studies reveal a heretofore unknown step of intracellular cholesterol trafficking which is critically dependent upon the interaction of LBPA with functional NPC2 protein.

scholarly journals NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Paige B. Martin ◽  
Yu Kigoshi-Tansho ◽  
Roger B. Sher ◽  
Gianina Ravenscroft ◽  
Jennifer E. Stauffer ◽  
...  
Keyword(s):  
Quality Control ◽  
Nervous System ◽  
Mouse Models ◽  
Human Disease ◽  
Neuromuscular Disease ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Ribosome Stalling

Abstract A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway—Ribosome-associated Quality Control (RQC)—by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF’s role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.

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