scholarly journals Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1

2013 ◽  
Vol 24 (21) ◽  
pp. 3309-3325 ◽  
Author(s):  
Nicholas L. Cianciola ◽  
Diane J. Greene ◽  
Richard E. Morton ◽  
Cathleen R. Carlin
Keyword(s):  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Loss Of Function ◽  
Major Pathway ◽  
Alternative Pathways ◽  
Oxysterol Binding Protein ◽  
Niemann Pick Disease ◽  
Niemann Pick ◽  
Cholesterol Storage

Niemann–Pick disease type C (NPC) is caused by mutations in NPC1 or NPC2, which coordinate egress of low-density-lipoprotein (LDL)-cholesterol from late endosomes. We previously reported that the adenovirus-encoded protein RIDα rescues the cholesterol storage phenotype in NPC1-mutant fibroblasts. We show here that RIDα reconstitutes deficient endosome-to-endoplasmic reticulum (ER) transport, allowing excess LDL-cholesterol to be esterified by acyl-CoA:cholesterol acyltransferase and stored in lipid droplets (LDs) in NPC1-deficient cells. Furthermore, the RIDα pathway is regulated by the oxysterol-binding protein ORP1L. Studies have classified ORP1L as a sterol sensor involved in LE positioning downstream of GTP-Rab7. Our data, however, suggest that ORP1L may play a role in transport of LDL-cholesterol to a specific ER pool designated for LD formation. In contrast to NPC1, which is dispensable, the RIDα/ORP1L-dependent route requires functional NPC2. Although NPC1/NPC2 constitutes the major pathway, therapies that amplify minor egress routes for LDL-cholesterol could significantly improve clinical management of patients with loss-of-function NPC1 mutations. The molecular identity of putative alternative pathways, however, is poorly characterized. We propose RIDα as a model system for understanding physiological egress routes that use ORP1L to activate ER feedback responses involved in LD formation.

Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein

1999 ◽  
Vol 276 (2) ◽  
pp. E336-E344 ◽  
Author(s):  
Chonglun Xie ◽  
Stephen D. Turley ◽  
Peter G. Pentchev ◽  
John M. Dietschy
Keyword(s):  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Protein A ◽  
Density Lipoprotein ◽  
Loss Of Function ◽  
C Protein ◽  
Niemann Pick Disease ◽  
Intracellular Cholesterol ◽  
Niemann Pick

Type C Niemann-Pick disease is due to a mutation in Niemann-Pick C (NPC) protein, a putative determinant of intracellular cholesterol transport. This study quantifies cholesterol balance in vivo across all tissues in mice with this defect. Cholesterol balance in the heterozygous animal is normal, but in the homozygous mouse the whole animal cholesterol pool expands continuously from birth, reaching 5,442 mg/kg at 7 wk. The size of this pool in each organ is proportional to the rate at which each tissue clears low-density lipoprotein-cholesterol. Despite this expansion, however, cholesterol synthesis is increased so that whole animal synthesis equals 180 mg ⋅ day−1 ⋅ kg−1. Forcing additional cholesterol into the liver through the clathrin-coated pit pathway increases the hepatic cholesterol pool in control mice, all of which is esterified, while there is a much greater increase in this pool in mutant mice, all of which is unesterified. These findings are consistent with the view that there is a block in sterol movement from the lysosome to the sites of regulation in NPC disease and have important implications for understanding the function of the NPC protein in intracellular cholesterol metabolism, in general, and in the brain, in particular.

scholarly journals Fluorescent Sterols and Cholesteryl Esters as Probes for Intracellular Cholesterol Transport

2015 ◽  
Vol 8s1 ◽  
pp. LPI.S31617 ◽  
Author(s):  
Katarzyna A. Solanko ◽  
Maciej Modzel ◽  
Lukasz M. Solanko ◽  
Daniel Wüstner
Keyword(s):  
Photophysical Properties ◽  
Low Density Lipoprotein ◽  
Chemical Properties ◽  
Density Lipoprotein ◽  
Cholesterol Transport ◽  
Sterol Esters ◽  
Niemann Pick Disease ◽  
Niemann Pick ◽  
Fluorescent Sterols ◽  
Quantitative Fluorescence

Cholesterol transport between cellular organelles comprised vesicular trafficking and nonvesicular exchange; these processes are often studied by quantitative fluorescence microscopy. A major challenge for using this approach is producing analogs of cholesterol with suitable brightness and structural and chemical properties comparable with those of cholesterol. This review surveys currently used fluorescent sterols with respect to their behavior in model membranes, their photophysical properties, as well as their transport and metabolism in cells. In the first part, several intrinsically fluorescent sterols, such as dehydroergosterol or cholestatrienol, are discussed. These polyene sterols (P-sterols) contain three conjugated double bonds in the steroid ring system, giving them slight fluorescence in ultraviolet light. We discuss the properties of P-sterols relative to cholesterol, outline their chemical synthesis, and explain how to image them in living cells and organisms. In particular, we show that P-sterol esters inserted into low-density lipoprotein can be tracked in the fibroblasts of Niemann–Pick disease using high-resolution deconvolution microscopy. We also describe fluorophore-tagged cholesterol probes, such as BODIPY-, NBD-, Dansyl-, or Pyrene-tagged cholesterol, and eventual esters of these analogs. Finally, we survey the latest developments in the synthesis and use of alkyne cholesterol analogs to be labeled with fluorophores by click chemistry and discuss the potential of all approaches for future applications.

scholarly journals Rab8-dependent Recycling Promotes Endosomal Cholesterol Removal in Normal and Sphingolipidosis Cells

2007 ◽  
Vol 18 (1) ◽  
pp. 47-56 ◽  
Author(s):  
Matts D. Linder ◽  
Riikka-Liisa Uronen ◽  
Maarit Hölttä-Vuori ◽  
Peter van der Sluijs ◽  
Johan Peränen ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Receptor Activation ◽  
Cholesterol Esterification ◽  
Rab Gtpase ◽  
Cell Periphery ◽  
Regulatory Machinery ◽  
Niemann Pick

The mechanisms by which low-density lipoprotein (LDL)-cholesterol exits the endocytic circuits are not well understood. The process is defective in Niemann–Pick type C (NPC) disease in which cholesterol and sphingolipids accumulate in late endosomal compartments. This is accompanied by defective cholesterol esterification in the endoplasmic reticulum and impaired ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux. We show here that overexpression of the recycling/exocytic Rab GTPase Rab8 rescued the late endosomal cholesterol deposition and sphingolipid mistrafficking in NPC fibroblasts. Rab8 redistributed cholesterol from late endosomes to the cell periphery and stimulated cholesterol efflux to the ABCA1-ligand apolipoprotein A-I (apoA-I) without increasing cholesterol esterification. Depletion of Rab8 from wild-type fibroblasts resulted in cholesterol deposition within late endosomal compartments. This cholesterol accumulation was accompanied by impaired clearance of LDL-cholesterol from endocytic circuits to apoA-I and could not be bypassed by liver X receptor activation. Our findings establish Rab8 as a key component of the regulatory machinery that leads to ABCA1-dependent removal of cholesterol from endocytic circuits.

scholarly journals Changes in PCSK 9 and apolipoprotein B100 in Niemann–Pick disease after enzyme replacement therapy with olipudase alfa

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Bethanie Garside ◽  
Jan Hoong Ho ◽  
See Kwok ◽  
Yifen Liu ◽  
Shaishav Dhage ◽  
...  
Keyword(s):  
Reference Group ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Enzyme Replacement ◽  
Niemann Pick Disease ◽  
Tnf Α ◽  
Niemann Pick ◽  
Lipid Parameters

Abstract Background Enzyme replacement therapy (ERT) with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is being developed to treat patients with ASM deficiency (ASMD), commonly known as Niemann–Pick disease (NPD) types A or B. This study assessed the effect of ERT on lipid parameters and inflammatory markers. Methods Serum and plasma samples from five adults with NPD type B (NPD-B) who received olipudase alfa ERT for 26 weeks were analysed. We also collected fasting blood samples from fifteen age- and sex-matched participants as reference and comparison group. We measured fasting lipid profile, apolipoproteins B48 and B100 (apoB48 and apoB100), apolipoprotein A1 (apoA1), proprotein convertase subtilisin/klexin type 9 (PCSK9) mass, oxidised low-density lipoprotein (oxLDL), small dense low-density lipoprotein cholesterol (sdLDL-C) and tumour necrosis factor α (TNF-α). Results Patients with NPD-B, compared with age and sex matched reference group, had higher triglycerides, PCSK9, apoB48, oxLDL and TNF-α and lower high density lipoprotein cholesterol (HDL-C) and apoA1. Treatment with ERT was associated with improved lipid parameters including total cholesterol, triglycerides, low density lipoprotein cholesterol (LDL-C), sdLDL-C, oxLDL and apoB100. Though there was an increase in apoA1, HDL-C was slightly reduced. TNF-α showed a reduction. ApoB100 decreased in parallel with a decrease in total serum PCSK9 mass after ERT. Conclusion This study demonstrated that patients with NPD-B had a proatherogenic lipid profile and higher circulating TNF-α compared to reference group. There was an improvement in dyslipidaemia after olipudase alfa. It was possible that reductions in LDL-C and apoB100 were driven by reductions in TNF-α and PCSK9 following ERT.

scholarly journals Type C Niemann-Pick disease. Abnormal metabolism of low density lipoprotein in homozygous and heterozygous fibroblasts.

1986 ◽  
Vol 261 (35) ◽  
pp. 16769-16774 ◽  
Author(s):  
H S Kruth ◽  
M E Comly ◽  
J D Butler ◽  
M T Vanier ◽  
J K Fink ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Niemann Pick Disease ◽  
Abnormal Metabolism ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

scholarly journals Changes in PCSK 9 and Apolipoprotein B100 in Niemann-Pick Disease After Enzyme Replacement Therapy with Olipudase Alfa

2021 ◽  
Author(s):  
Bethanie Garside ◽  
Jan Hoong Ho ◽  
See Kwok ◽  
Yifen Liu ◽  
Shaishav Dhage ◽  
...  
Keyword(s):  
Reference Group ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Enzyme Replacement ◽  
Niemann Pick Disease ◽  
Tnf Α ◽  
Niemann Pick ◽  
Lipid Parameters

Abstract Background: Enzyme replacement therapy (ERT) with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is being developed to treat patients with ASM deficiency (ASMD), commonly known as Niemann-Pick Disease (NPD) types A or B. This study assessed the effect of ERT on lipid parameters and inflammatory markers. Methods: Serum and plasma samples from five adults with NPD type B (NPD-B) who received olipudase alfa ERT for 26 weeks were analysed. We also collected fasting blood samples from fifteen age- and sex-matched participants as reference and comparison group. We measured fasting lipid profile, apolipoproteins B48 and B100 (apoB48 and apoB100), apolipoprotein A1 (apoA1), proprotein convertase subtilisin/klexin type 9 ( PCSK9) mass, oxidised low-density lipoprotein (oxLDL), small dense low-density lipoprotein cholesterol (sdLDL-C) and tumour necrosis factor α (TNF-α). Results: Patients with NPD-B, compared with age and sex matched reference group, had higher triglycerides, PCSK9, apoB48, oxLDL and TNF-α and lower high density lipoprotein cholesterol (HDL-C) and apoA1. Treatment with ERT was associated with improved lipid parameters including total cholesterol, triglycerides, low density lipoprotein cholesterol (LDL-C), sdLDL-C, oxLDL and apoB100. Though there was an increase in apoA1, HDL-C was slightly reduced. TNF-α showed a reduction. ApoB100 decreased in parallel with a decrease in total serum PCSK9 mass after ERT. Conclusion: This study demonstrated that patients with NPD-B had a proatherogenic lipid profile and higher circulating TNF-α compared to reference group. There was an improvement in dyslipidaemia after olipudase alfa. It was possible that reductions in LDL-C and apoB100 were driven by reductions in TNF-α and PCSK9 following ERT.

scholarly journals Targeting pro-protein convertase subtilisin kexin-9 as a novel therapy of hypercholesterolemia

2017 ◽  
Vol 26 (2) ◽  
pp. 152-7
Author(s):  
Bambang Dwiputra ◽  
Anwar Santoso ◽  
Kian K. Poh
Keyword(s):  
Ldl Cholesterol ◽  
Competitive Inhibition ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Plasma ◽  
Phase Iii ◽  
Loss Of Function ◽  
Novel Therapy ◽  
Phase Iii Clinical Trials

Reducing low density lipoprotein (LDL) cholesterol level is an established primary and secondary prevention strategy for coronary heart disease. However, not all patients are able to achieve their LDL targets as recommended by the guidelines. Over the last 10 years, high plasma LDL level is known to be associated with a higher level of pro-protein convertase subtilisin kexin-9 (PCSK-9). Loss-of-function mutations in the PCSK-9 gene is associated with lower plasma LDL level and cardiovascular risk. Since its discovery in 2003, PCSK-9 has triggered many researchers to design a PCSK-9 inhibitor to reduce LDL cholesterol through competitive inhibition of this molecule. Some phase III clinical trials have showed promising results of PCSK-9 inhibitor efficacy in lowering LDL level and improving clinical outcome. This article aims to discuss the role of PCSK-9 in LDL metabolism and the efficacy of PCSK-9 inhibitor in reducing plasma LDL level.

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