scholarly journals Defective activity of acyl-CoA:cholesterol O-acyltransferase in Niemann-Pick type C and type D fibroblasts

1989 ◽  
Vol 262 (3) ◽  
pp. 713-719 ◽  
Author(s):  
D M Byers ◽  
S R Rastogi ◽  
H W Cook ◽  
F B St C Palmer ◽  
M W Spence
Keyword(s):  
Normal Cell ◽  
Normal Values ◽  
Cell Types ◽  
Serum Lipoproteins ◽  
Acat Activity ◽  
Type D ◽  
Cell Extracts ◽  
Type C ◽  
Niemann Pick ◽  
Stimulation Of

The activity of acyl-CoA:cholesterol acyltransferase (ACAT; EC 2.3.1.26) was measured in fibroblast homogenates from Niemann-Pick Type C (NPC) and Type D (NPD) patients to determine whether these cells exhibit similar defects in the regulation of cholesterol esterification. ACAT activity in normal cells cultured in the absence of serum lipoproteins responded rapidly (within 6 h) to the addition of serum and reached peak levels at 12-24 h, whereas little stimulation of activity in NPC cells was observed. In contrast, ACAT activity in NPD fibroblasts (cell lines from four different patients) began to increase between 6 and 12 h after serum addition, reaching levels up to 50% of normal values at 24 h. ACAT activity in NPC and NPD cell extracts could not be stimulated by preincubation with normal cell homogenates, nor was complementation between NPC and NPD homogenates observed. Addition of 25-hydroxycholesterol to fibroblasts cultured in delipidated serum increased ACAT activity for all three cell types, although stimulation in NPD cells was less than that observed in NPC cells. ACAT activity of deoxycholate-solubilized homogenates reconstituted into phosphatidylcholine vesicles was independent of the presence of serum lipoproteins during culture and dependent on cholesterol present in the vesicles for all cell types. However, ACAT activities of mutant fibroblasts in vesicles plus cholesterol were significantly (about 40%) lower than control levels. These results suggest that the metabolic lesions in NPC and NPD cells are biochemically distinct and that both may involve factors in addition to the availability of cholesterol substrate for the ACAT enzyme.

scholarly journals NF-κB signaling and crosstalk during carcinogenesis

4open ◽  
2019 ◽  
Vol 2 ◽  
pp. 13 ◽  
Author(s):  
Björn L.D.M. Brücher ◽  
Florian Lang ◽  
Ijaz S. Jamall
Keyword(s):  
Cell Proliferation ◽  
Dna Sequences ◽  
Genetic Information ◽  
Normal Cell ◽  
Cell Types ◽  
Nuclear Factor ◽  
Kappa Light Chain ◽  
Sequence Of Events ◽  
Light Chain Enhancer ◽  
Stimulation Of

Transcription factors (TFs) are proteins that control the transcription of genetic information from DNA to mRNA by binding to specific DNA sequences either on their own or with other proteins as a complex. TFs thus support or suppress the recruitment of the corresponding RNA polymerase. In general, TFs are classified by structure or function. The TF, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), is expressed in all cell types and tissues. NF-κB signaling and crosstalk are involved in several steps of carcinogenesis including in sequences involving pathogenic stimulus, chronic inflammation, fibrosis, establishment of its remodeling to the precancerous niche (PCN) and transition of a normal cell to a cancer cell. Triggered by various inflammatory cytokines, NF-κB is activated along with other TFs with subsequent stimulation of cell proliferation and inhibition of apoptosis. The involvement of NF-κB in carcinogenesis provides an opportunity to develop anti-NF-κB therapies. The complexity of these interactions requires that we elucidate those aspects of NF-κB interactions that play a role in carcinogenesis, the sequence of events leading to cancer.

scholarly journals The Stimulation of Adenosine A2A Receptors Ameliorates the Pathological Phenotype of Fibroblasts from Niemann-Pick Type C Patients

2013 ◽  
Vol 33 (39) ◽  
pp. 15388-15393 ◽  
Author(s):  
Sergio Visentin ◽  
Chiara De Nuccio ◽  
Antonietta Bernardo ◽  
Rita Pepponi ◽  
Antonella Ferrante ◽  
...  
Keyword(s):  
Adenosine A2a Receptors ◽  
A2a Receptors ◽  
Type C ◽  
Niemann Pick ◽  
Adenosine A2a ◽  
Stimulation Of

scholarly journals Generation and function of astroglial lipoproteins from Niemann–Pick type C1-deficient mice

2005 ◽  
Vol 387 (3) ◽  
pp. 779-788 ◽  
Author(s):  
Barbara KARTEN ◽  
Hideki HAYASHI ◽  
Gordon A. FRANCIS ◽  
Robert B. CAMPENOT ◽  
Dennis E. VANCE ◽  
...  
Keyword(s):  
Conditioned Medium ◽  
Cell Types ◽  
Apolipoprotein A1 ◽  
Functional Assay ◽  
Atp Binding Cassette Transporter ◽  
Apo E ◽  
Type C ◽  
Niemann Pick ◽  
And Function ◽  
Endosomal System

NPC (Niemann–Pick type C) disease is a progressive neurological disorder characterized by defects in intracellular cholesterol trafficking, accumulation of cholesterol in the endosomal system and impaired cholesterol homoeostasis. Although these alterations appear to occur in all NPC1-deficient cell types, the consequences are most profound in the nervous system. Since glial cells are important mediators of brain cholesterol homoeostasis, we proposed that defective generation and/or function of lipoproteins released by glia might contribute to the neurological abnormalities associated with NPC disease. We found that, as in other cell types, Npc1−/− glia accumulate cholesterol intracellularly. We hypothesized that this sequestration of cholesterol in glia might restrict the availability of cholesterol for lipoprotein production. Cerebellar astroglia were cultured from a murine model of NPC disease to compare the lipoproteins generated by these cells and wild-type glia. The experiments demonstrate that the amount of cholesterol in glia-conditioned medium is not reduced by NPC1 deficiency. Similarly, cholesterol efflux to apo (apolipoprotein) A1 or glial expression of the transporter ATP-binding-cassette transporter A1 was not decreased by NPC1 deficiency. In addition, the ratio of apo E:cholesterol and the density distribution of lipoproteins in Npc1−/− and Npc1+/+ glia-conditioned medium are indistinguishable. Importantly, in a functional assay, apo E-containing lipoproteins generated by Npc1−/− and Npc1+/+ glia each stimulate axonal elongation of neurons by approx. 35%. On the basis of these observations, we speculate that the neuropathology characteristic of NPC disease can quite probably be ascribed to impaired processes within neurons in the brain rather than defective lipoprotein production by astroglia.

scholarly journals Linkage of Niemann-Pick Disease Type D to the Same Region of Human Chromosome 18 as Niemann-Pick Disease Type C

1997 ◽  
Vol 61 (1) ◽  
pp. 139-142 ◽  
Author(s):  
W.L. Greer ◽  
D.C. Riddell ◽  
D.M. Byers ◽  
J.P. Welch ◽  
G.S. Girouard ◽  
...  
Keyword(s):  
Human Chromosome ◽  
Disease Type ◽  
Chromosome 18 ◽  
Type D ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

Regulation of intracellular cholesterol metabolism is defective in lymphoblasts from Niemann-Pick type C and type D patients

1994 ◽  
Vol 1226 (2) ◽  
pp. 173-180 ◽  
Author(s):  
David M. Byers ◽  
Jo-Anne Douglas ◽  
Harold W. Cook ◽  
Frederick B.St.C. Palmer ◽  
Neale D. Ridgway
Keyword(s):  
Cholesterol Metabolism ◽  
Type D ◽  
Type C ◽  
Intracellular Cholesterol ◽  
Niemann Pick

Regulation of low density lipoprotein receptor and 3-hydroxy-3-methyl-glutaryl-CoA reductase activities are differentially affected in Niemann–Pick type C and type D fibroblasts

1993 ◽  
Vol 71 (9-10) ◽  
pp. 467-474 ◽  
Author(s):  
Harkirat S. Sidhu ◽  
Stella A. R. Rastogi ◽  
David M. Byers ◽  
Duane L. Guernsey ◽  
Harold W. Cook ◽  
...  
Keyword(s):  
Reductase Activity ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cell Types ◽  
Low Density ◽  
Hmg Coa Reductase ◽  
Type D ◽  
Density Lipoprotein Receptor ◽  
Niemann Pick ◽  
Coa Reductase

Defective regulation of intracellular cholesterol metabolism has been investigated in cultured fibroblasts from two subtypes of Niemann–Pick type II disease: the panethnic Niemann–Pick type C (NPC) and the Nova Scotia type D (NPD). Cell extracts from NPC and NPD fibroblasts cultured in lipoprotein-deficient medium exhibited activities of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase that were two-fold greater than in normal cells. Addition of serum resulted in only a 15% decrease in HMG-CoA reductase activity within 6 h in these cells, compared with a decrease of 80% in normal fibroblasts. The initial rate of return to maximal values for the first 6 h after removal of serum was similar in all three cell types; thereafter, the rate was faster in the mutant fibroblasts. Binding and internalization of 125I-labeled low density lipoprotein (LDL) was not decreased within 12 h of incubation of NPC fibroblasts with serum, while a decrease of 50% was observed for both NPD and normal fibroblasts over this time period. Northern blot analysis also indicated a slower decrease in steady-state LDL receptor mRNA in NPC relative to normal and NPD cells. In all three cell types, inhibition of HMG-CoA reductase with mevinolin had no effect on serum-stimulated cholesterol esterification, while inhibition of acyl-CoA:cholesterol acyltransferase with Sandoz 58-035 did not influence HMG-CoA reductase activity, indicating that defects in these regulatory mechanisms are independent. Together with previous observations that NPC and NPD fibroblasts exhibit different levels of cholesterol accumulation and esterification, our results suggest that NPD may result from a distinct mutation in a Niemann–Pick type II gene, in which different mutations can differentially alter the various mechanisms of cholesterol regulation.Key words: Niemann–Pick disease, cholesterol regulation, low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA:cholesterol acyltransferase.

scholarly journals Cyclodextrin triggers MCOLN1-dependent endo-lysosome secretion in Niemann-Pick type C cells

2018 ◽  
Author(s):  
Fabrizio Vacca ◽  
Stefania Vossio ◽  
Vincent Mercier ◽  
Dimitri Moreau ◽  
Shem Johnson ◽  
...  
Keyword(s):  
Storage Disease ◽  
Cell Types ◽  
Cytosolic Calcium ◽  
C Cells ◽  
Low Concentrations ◽  
Transient Rise ◽  
Type C ◽  
Niemann Pick ◽  
Lysosome Related Organelles ◽  
Cholesterol Storage

ABSTRACTIn specialized cell types, lysosome-related organelles support regulated secretory pathways, while in non-specialized cells, lysosomes can undergo fusion with the plasma membrane in response to a transient rise in cytosolic calcium. Recent evidence also indicates that lysosome secretion can be controlled transcriptionally and promote clearance in lysosome storage diseases. In addition, evidence is also accumulating that low concentrations of cyclodextrins reduce the cholesterol storage phenotype in cells and animals with the cholesterol storage disease Niemann-Pick type C, via an unknown mechanism. Here, we report that cyclodextrin triggers the secretion of the endo/lysosomal content in non-specialized cells, and that this mechanism is responsible for the decreased cholesterol overload in Niemann-Pick type C cells. We also find that that the secretion of the endo/lysosome content occurs via a mechanism dependent on the endosomal calcium channel MCOLN1, as well as FYCO1, the AP1 adaptor and its partner Gadkin. We conclude that endolysosomes in non-specialized cells can acquire secretory functions elicited by cyclodextrin, and that this pathway is responsible for the decrease in cholesterol storage in Niemann-Pick C cells.

Cultured fibroblasts from patients with Niemann-Pick disease type C and type D exhibit distinct defects in cholesterol esterification

1992 ◽  
Vol 1124 (1) ◽  
pp. 29-35 ◽  
Author(s):  
Harkirat S. Sidhu ◽  
Stella A.R. Rastogi ◽  
David M. Byers ◽  
Harold W. Cook ◽  
Frederick B.St.C. Palmer ◽  
...  
Keyword(s):  
Disease Type ◽  
Cholesterol Esterification ◽  
Cultured Fibroblasts ◽  
Type D ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

ANALYSIS OF CHOLESTEROL AND OXYSTEROL LEVELS IN NIEMANN PICK DISEASE TYPE C MICE AND PATIENTS

2006 ◽  
Vol 37 (S 1) ◽  
Author(s):  
S Tay ◽  
X He ◽  
AM Jenner ◽  
BS Wong ◽  
WY Ong
Keyword(s):  
Disease Type ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease
Sign in / Sign up

Export Citation Format

Share Document