by Alexandra M. Leung. / Thesis (M. Phil.)--Chinese University of Hong Kong, 1981. / Bibliography: leaves 208-224.

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Pantethine, a precursor of coenzyme A, has been shown to reduce serum cholesterol levels in hypercholesterolemic rabbits. The enzyme pantetheinase rapidly hydrolyzes pantethine to the vitamin pantothenic acid and the amino thiol cysteamine. This study was designed to compare the effect of cysteamine and pantothenate supplementation with that of pantethine on hypercholesterolemic rabbits. New Zealand white rabbits were fed a 0.5% cholesterol diet for 5 weeks; treatment groups received only the high cholesterol diet (control), or a high cholesterol diet supplemented with 1% pantethine, or an equimolar amount of pantothenic acid or cystamine (the disulfide of cysteamine). Blood samples were drawn weekly and total serum cholesterol levels analyzed enzymatically. Pantethine and cystamine both significantly reduced serum cholesterol levels (p < 0.05); pantothenic acid had no effect. Separation of serum lipoproteins using a preparative ultracentrifuge showed an increase in very low density, intermediate density and low density lipoproteins. A second experiment was conducted to compare the effect of cystamine with other small thiols; the protocol was similar to the first experiment with treatment groups consisting of a high cholesterol control, cystamine, cystine or 2,hydroxyethyl disulfide. There was no significant reduction in serum cholesterol levels between treatment groups, although the cystamine supplemented group tended to be lower than the other groups.

Charles University Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Student: Marie Šimková Supervisor: Mgr. Alena Prašnická Title of diploma thesis: Alternation of bile production due to iron depletion Introduction: Liver has an irreplaceable role in the production and secretion of bile. This body fluid serves as the main excretion way of some endogenous and exogenous substances. Another liver property is the ability to store substances essential for correct functions of the body, e.g. iron. It has been shown that iron could have an impact on the bile production and secretion. Aim: The aim of this diploma thesis was to discover an impact of iron depletion on the bile synthesis and metabolism, especially on bile acids, and the way it affects transporters expression. Methods: Male Wistar rats (n=6 in each group, 250 ± 20 g) were divided into two groups: control group (Chow diet) fed with standard diet and iron depletion group (ID), fed with iron depletion diet for 21 days. To investigate the changes in bile flow, the bile had been collected for 120 min during in vivo clearance study. The analysis of the changes in expression of bile transporters and enzymes responsible for de novo bile acid synthesis was performed at the mRNA (qRT-PCR) and protein (Western blot)...

Cyclodextrins (CDs) are naturally occurring cyclic oligosaccharides. Since it is believed that OxC blocks the removal of normal cholesterol from cells in the artery wall, it is possible that selective removal of OxC in the vessel wall in-vivo may prevent or reverse atherosclerosis.As a prelude to major studies, this research project was designed to answer two critical questions; 1/. What is the best route for delivery of CD. 2/. How do animals (apoE-/- mice) tolerate it. Pilot studies were established and results noted. These studies have provided valuable information in the apoE-/- mouse for subsequent studies to prevent or reverse atherosclerosis in this animal model. / Master of Science (Hons)

Liver X receptor (LXR), farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) are adopted orphan nuclear receptors that function as lipid sensors. These receptors respond to cellular lipid levels and regulate the expression of target gene. Previously, it was demonstrated that low doses of chlordecone (CD) pretreatment disturbed exogenous cholesterol distribution and cellular lipid transport, storage and metabolism pathway. The aim of this study was to determine whether low doses of CD affect nuclear receptor (LXR��/FXR or PPAR��)-mediated lipid homeostasis. Thus, hepatic microsomal protein contents of cytochrome P450 7a (cyp7a, regulated by LXR��/FXR), and P450 4a1 (cyp4a1, regulated by PPAR��) were determined in male C57BL/6N mice, fed AIN76 or AIN93M diet, received CD (2.5, 5.0 or 15 mg CD/kg body weight). Western blot analysis was used for protein measurements using appropriate antibodies. Cyp7a and cyp4a1 protein levels were confirmed by enzyme activities, cholesterol 7��-hydroxylase and lauric acid hydroxylase activities, respectively. Plasma total cholesterol and triglycerides, body and liver weights were also measured in these dose-response experiments. Plasma total cholesterol and triglycerides levels from animals fed AIN 93M diet were significantly lower than those from animals fed AN 76 diet. However, neither total plasma cholesterol nor triglycerides levels were changed in CD-treated mice fed AN 76 or AN 93M diet. Cyp7a protein level or its enzyme activity was not altered by CD treatment. Likewise, cyp4a1 protein level or its activity was not affected by CD treatment. In summary, the results of the present study do not support the hypothesis that CD treatment alters nuclear receptor (LXR��/FXR or PPAR��)-mediated lipid homeostasis. / Graduation date: 2002

Thesis (M.Sc. (Nutrition)--North-West University, Potchefstroom Campus, 2008.

The ATP-binding cassette transporter, sub-family A, member 1 (ABCA1) mediates the major pathway for cholesterol exit from non-hepatic cells and thereby controls the rate-limiting step in the biogenesis of high density lipoprotein (HDL) particles. In humans,ABCA1 deficiency results in Tangier disease, characterized by low levels of HDL cholesterol, cellular cholesterol accumulation and increased risk for atherosclerosis. More than 100 coding variants have been described in the ABCA1 gene. We attempted to understand how both naturally occurring and engineered mutations in ABCA1 impact its role in cholesterol transport in a variety of in vitro and in vivo systems. We attempted to correlate specific genetic variants in ABCA 1 with phenotypes in patients carrying the sevariants, and used an evolutionary approach to predict which specific variants in ABCA1would impact its function. We then turned to the study of tissue-specific genetic deletion of ABCA1 in mice to study its role in HDL biogenesis, atherosclerosis and glucose metabolism. We found that intestinal ABCA1 is an important site of HDL biogenesis and that activation of intestinal ABCA1 raises HDL levels in vivo. Hepatic ABCA1, which is a major site of HDL biogenesis, was shown to significantly contribute to susceptibility to atherosclerosis. Finally, we show that ABCA1 plays an unsuspected role in B-cell function and insulin secretion. These studies have contributed to our understanding of the impact of genetic variation in ABCA1 on diverse biological and pathological processes, and have identified novel aspects of ABCA 1 function in specific cell types.

M2 muscarinic receptor extracted from Sf9 cells in cholate-NaCl differs from that extracted from porcine sarcolemmal membranes. Whereas the latter has been shown to exhibit non-competitive effects in the binding of N-methylscopolamine (NMS) and quinuclidinylbenzilate (QNB), which can be explained in terms of cooperativity within a receptor that is at least tetravalent, binding to the former is essentially competitive. Levels of cholesterol in Sf9 membranes were only 5% of those in sarcolemmal membranes and were increased to about 100% by means of cholesterol-methyl-β-cyclodextrin. M2 receptors extracted from CHL-treated Sf9 membranes resembled those from heart; that is, cholesterol induced a pronounced heterogeneity detected in the binding of both radioligands, including a shortfall in the apparent capacity for [3H]NMS, and there were marked discrepancies in the apparent affinity of NMS as estimated directly and via the inhibition of [3H]QNB. The data can be described quantitatively in terms of cooperative effects among six or more interacting sites, apparently within an oligomer. Cholesterol also was found to increase the affinity of the receptor for NMS and QNB, and the effect was examined for its possible relationship to the known interconversion of cardiac muscarinic receptors between an agonist-specific (R*) and an antagonist-specific (R) state. Cholesterol and N-ethylmaleimide (NEM) were compared for their effect on the affinity of NMS, QNB and four muscarinic agonists, and the data were assessed in terms of an explicit mechanistic model for a receptor that interconverts spontaneously between two states. The data can be described equally well by an effect of cholesterol on either the distribution of receptors between R and R* or the affinity of all ligands for both states, with an accompanying effect of NEM on either the affinity or the distribution between states, respectively. Since NEM is known from other data to favor R* over R, cholesterol appears to increase affinity per se. Cholesterol therefore is a determinant of affinity and cooperativity in the binding of orthosteric ligands to the M2 receptor. Both effects are observed in solution and therefore appear to arise from a direct interaction between the lipid and the receptor.

Phagocytosis is an innate immune response that is paramount in the clearance of pathogenic particles. Recognition of target particles by phagocytic receptors expressed on phagocytes induces modifications in the underlying actin cytoskeleton to form pseudopods that encircle and internalize the target particle into a membrane bound organelle called the phagosome. The nascent phagosome undergoes a maturation sequence that is characterized by substantial remodeling of the membrane and its luminal contents through interactions with components of the endocytic pathway, culminating in an acidic and hydrolytic organelle capable of digesting and elminating pathogens. Phagosome maturation is a complicated pathway that involves many protein and lipid signaling molecules. Several factors that influence phagosome maturation particularly the participation of pH, lysosome-associated membrane proteins-1 and –2, cholesterol, in addition to the survival and escape mechanisms used by, Burkholderica cenocepacia were explored. All three tenets are essential for phagosome maturation, although each factor has different mechanistic consequences. Acidification alters Rab5 activation, while ablation of LAMPs and accumulation of cholesterol interferes with various aspects of Rab 7 turnover in phagosomes and/or endosome membranes. Moreover, Burkholderia cenocepacia, an intracellular pathogen, inactivates Rab7 on phagosome membranes from within the vacuole lumen. Herein, mechanisms that govern phagosome maturation are explored and several molecules are added to the long list of essential players in this complicated pathway.