| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
| First Page | Previous Page | Next Page | Last Page |
| Induction of aggregation and fusion of cholesterol-containing membrane vesicles by an anti-cholesterol monoclonal antibody Agirre, A., S. Nir, et al. (2000), J Lipid Res 41(4): 621-8. Abstract: A monoclonal IgM antibody that reacts with cholesterol was able to aggregate small and large unilamellar lipid vesicles. Vesicles aggregated by the antibody could be dispersed by trypsin digestion. Inclusion of unsaturated phosphatidylethanolamine in the vesicle formulation lowered the relative amount of cholesterol necessary for aggregation, and prevented disaggregation by trypsin treatment. Fluorimetric assays indicated that membrane mixing occurred in aggregates resistant to trypsinization, but the vesicles did not mix or leak their aqueous contents. Analysis of the kinetics of lipid-mixing showed an increase in the aggregation and fusion rate constants with increasing antibody concentrations, indicating that the antibody reaction promotes both processes. An apparent inactivation process whose rate increased with antibody dose has been considered.We conclude that the simultaneous binding of antibodies to more than one vesicle at densities that allow the contact of membrane surfaces, induces first aggregation followed by hemifusion, and with excess of antibody also results in inactivation of the latter process. |
| Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol Sparks, D. L., S. W. Scheff, et al. (1994), Exp Neurol 126(1): 88-94. Abstract: beta-amyloid and ALZ-50 immunocytochemical reactivity were determined in the brains of rabbits fed either a control or 2% cholesterol diet. Control rabbits demonstrated no accumulation of intracellular immunolabeled beta-amyloid within 3 min after death. In animals fed the experimental diet for 4, 6, and 8 weeks (postmortem interval < 3 min), there was an increasingly mild-to-moderate-to-severe accumulation of intracellular immunolabeled beta-amyloid. Whether or not beta-amyloid is causally linked to processes leading to dementia, it is related in some way to the prime cause of human death; heart disease. Hypercholesterolemic rabbits may provide an animal model to study altered beta-APP metabolism leading to Alzheimer-like beta-amyloid accumulation xe03and extracellular deposition in brain. |
| Induction of angiotensin converting enzyme and angiotensin II receptors in the atherosclerotic aorta of high-cholesterol fed Cynomolgus monkeys Song, K., N. Shiota, et al. (1998), Atherosclerosis 138(1): 171-82. Abstract: Antiatherogenic effects of imidapril and involvement of renin angiotensin system were examined in experimental atherosclerosis induced by feeding a high-cholesterol diet to Cynomolgus monkeys. Eighteen male monkeys were divided into three groups and placed under (1) normal diet (normal group), (2) high-cholesterol diet (control group), (3) high-cholesterol diet with imidapril (20 mg/kg body wt/day, orally) treatment (imidapril group). At the end of the experiment, the normal group showed no apparent atherosclerosis in their aorta evaluated by oil red-O staining, while the control group exhibited marked atherosclerotic involvement of the intimal surface of the aorta (58.4 +/- 9.3%, P < 0.01). Imidapril reduced systolic blood pressure and atherosclerotic involvement (24.1 +/- 5.5%, P < 0.05). Total cholesterol content of the descending thoracic aorta was also significantly reduced in the imidapril group. In the atherosclerotic vessels, angiotensin converting enzyme (ACE) activity evaluated by quantitative in vitro autoradiography was significantly increased in the intimal lesion. Further evaluation revealed angiotensin II (Ang II) type I (AT1) receptor density was significantly increased in the medial lesion and type II (AT2) receptor density in the adventitia. When the progression of atherosclerosis was impeded by imidapril treatment, the ACE activity level as well as the AT1 and AT2 receptor density remained at normal. Expression of mRNA for fibronectin, TGF-beta1, types I and III collagen was studied by Northern blot analysis. No significant differences in types I and III collagen mRNA levels were found between the control and imidapril group. On the other hand, mRNA expression for fibronectin and TGF-beta1 were much lower in the imidapril group than in the control group. These results suggest that increased production of Ang II and activated receptors may be involved in atherosclerotic process in this model and also antiatherogenic effect of imidapril may be derived from reduction of local Ang II production as well as its hypotensive action. |
| Induction of apoptosis and necrosis in human neuroblastoma cells by cholesterol oxides Rao, M. L., D. Lutjohann, et al. (1999), Ann N Y Acad Sci 893: 379-81. |
| Induction of apoptosis in endothelial cells treated with cholesterol oxides Lizard, G., V. Deckert, et al. (1996), Am J Pathol 148(5): 1625-38. Abstract: Cholesterol oxides have a wide range of cytotoxic effects on vascular cells. Therefore, 7-ketocholesterol, 7 beta-hydroxycholesterol, 19-hydroxycholesterol, cholesterol 5 alpha, 6 alpha-epoxide, and 25-hydroxycholesterol, identified in various foodstuffs and human tissues, were chosen to compare and characterize the mode of cell death they induce, apoptosis or necrosis, on bovine aortic endothelial cells. The toxic potency differed from one compound to another, and 7 beta-hydroxycholesterol and 7-ketocholesterol exhibited the most potent effects. Cytotoxicity was accompanied by a decreased number of adherent cells, an increased number of non-adherent cells, and an enhanced permeability to propidium iodide. By electron and fluorescence microscopy performed after staining with Hoechst 33342, apoptotic cells with fragmented and condensed nuclei were identified mainly among non-adherent cells. By flow cytometry, cells with a lower DNA content than cells in the G0/G1 phase were apparent, giving a characteristic sub-G1 peak. Quantification of apoptosis evaluated either by the proportion of apoptotic cells identified by fluorescence microscopy after staining with Hoechst 33342 or by the percentage of cells present in the sub-G1 peak indicated that the ability of cholesterol oxides in inducing apoptosis was in the following order: 7 beta-hydroxycholesterol > 7-ketocholesterol > 19-hydroxycholesterol > cholesterol 5 alpha, 6 alpha-epoxide > 25-hydroxycholesterol. By using electrophoresis on agarose gel, typical internucleosomal DNA fragmentations were detected; they were no longer observed when bovine aortic endothelial cells were simultaneously incubated with 0.5 mmol/L zinc chloride, known to inhibit Ca2+/Mg2+-dependent endonucleases. None of the cholesterol-oxide-induced apoptotic features described above were noted with cholesterol. It is concluded that cholesterol oxides constitute a new class of cholesterol derivatives that can induce cell death by apoptosis in cultured endothelial cells. |
| Induction of bile acid synthesis by cholesterol and cholestyramine feeding is unimpaired in mice deficient in apolipoprotein AI Jolley, C. D., J. M. Dietschy, et al. (2000), Hepatology 32(6): 1309-16. Abstract: High density lipoprotein (HDL) cholesterol is believed to be preferentially utilized for bile acid synthesis and biliary secretion. In mice, the deletion of apolipoprotein AI (apo AI), the major apolipoprotein in HDL, results in very low plasma HDL-cholesterol levels. This article describes bile acid metabolism in apo AI-deficient (Apo AI(-/-)) mice and their C57BL/6 (Apo AI(+/+)) controls fed either a basal rodent diet alone or containing cholesterol or cholestyramine. Basal plasma HDL-cholesterol levels in the (-/-) mice (<10 mg/dL) were less than 20% of those in their (+/+) controls, but there were no phenotypic differences in either the relative cholesterol content of gallbladder bile, bile acid pool size and composition, fecal bile acid excretion or the activity of, or mRNA level for, cholesterol 7alpha-hydroxylase. However, compared with their (+/+) controls, the (-/-) mice absorbed more cholesterol (33 vs. 24%) and manifested lower rates of hepatic sterol synthesis (534 vs. 1,019 nmol/h per g). Cholesterol feeding increased hepatic cholesterol levels in the (+/+) animals from 2.7 to 4.4 mg/g and in the (-/-) mice from 2.6 to 8.1 mg/g. Bile acid synthesis increased 70% in both genotypes. Cholestyramine feeding stimulated bile acid synthesis 3.7 fold in both (-/-) and (+/+) mice. We conclude that the virtual loss of HDL-cholesterol from the circulation in apo AI deficiency has no impact on the ability of the hepatocyte to adapt its rate of bile acid synthesis in concert with the amount of cholesterol and bile acid returning to the liver from the small intestine. |
| Induction of calcification in rabbit aortas by high cholesterol diets: roles of calcifiable vesicles in dystrophic calcification Hsu, H. H., N. C. Camacho, et al. (2002), Atherosclerosis 161(1): 85-94. Abstract: Atherosclerotic calcification may weaken the aorta wall and thereby lead to rupture of the vessel. The mechanism whereby aortas undergo calcification remains unclear. Previous reports in this laboratory showed that, after 2 months of cholesterol-supplemental feeding, an increase in calcifiability of membrane vesicles isolated from rabbit aortas precedes substantial arterial calcification. Further, the mineral was deposited by isolated calcifiable vesicles as an amorphous phase similar to minerals in human aortas at an early stage of atherosclerosis. In the current study, atherosclerotic calcification was induced by exposing rabbits to a 1% cholesterol-rich diet for 3 or 6 months. After 3 months of dietary interventions, atherosclerotic lesions were fully developed. Fatty streaks were evident in areas proximal to the heart and became less frequent in the distal areas. However, calcification was not yet identifiable histologically or by using Fourier transform spectroscopy (FT-IR). After 6 months of high cholesterol treatment, aortas were partially calcified. Histochemical staining for mineral revealed that calcification appeared to occur predominantly in the intimal areas immediately adjacent to the media. Fourier Transform Imaging analysis demonstrated that the mineral deposited in atherosclerotic rabbit aortas was a hydroxyapatite-like phase. To determine whether aorta vesicles play a role in mineral formation in aortas, vesicles were isolated from calcified aortas and then their calcifiability was compared to that in normal vesicles. Interestingly, during the course of vesicle isolation, we found that calcifiable vesicles with much higher calcifiability than normal vesicles could be readily isolated from atherosclerotic aortas simply by suspending minced tissues in PBS. The characteristics of the calcification process and the enzymatic contents of isolated vesicles were similar to those obtained using collagenase digestion. Correlatively, mineral deposited by calcifiable vesicles isolated from the calcified aortas was also of hydroxyapatite-like phases. Altogether, these observations indicate that (1) aortic calcification is a later event during atherogenesis, (2) calcifiable vesicles are loosely bound to the matrices of the lesions as the result of the disease process and (3) similarities in the mineral phases between those in aortas and by vesicles during atherogenesis further support the role of calcifiable vesicles in dystrophic calcification. |
| Induction of cellular cholesterol efflux to lipid-free apolipoprotein A-I by cAMP Sakr, S. W., D. L. Williams, et al. (1999), Biochim Biophys Acta 1438(1): 85-98. Abstract: In the present study apolipoprotein-mediated free cholesterol (FC) efflux was studied in J774 macrophages having normal cholesterol levels using an experimental design in which efflux occurs in the absence of contributions from cholesteryl ester hydrolysis. The results show that cAMP induces both saturable apolipoprotein (apo) A-I-mediated FC efflux and saturable apo A-I cell-surface binding, suggesting a link between these processes. However, the EC50 for efflux was 5-7-fold lower than the Kd for binding in both control and cAMP-stimulated cells. This dissociation between apo A-I binding and FC efflux was also seen in cells treated for 1 h with probucol which completely blocked FC efflux without affecting apo A-I specific binding. Thus, cAMP-stimulated FC efflux involves probucol-sensitive processes distinct from apo A-I binding to its putative cell surface receptor. FC efflux was also dramatically stimulated in elicited mouse peritoneal macrophages, suggesting that cAMP-regulated apolipoprotein-mediated FC efflux may be important in cholesterol homeostasis in normal macrophages. The presence of a cAMP-inducible cell protein that interacts with lipid-free apo A-I was investigated by chemical cross-linking of 125I-apo A-I with J774 cell surface proteins which revealed a Mr 200 kDa component when the cells were treated with cAMP. |
| Induction of early atherosclerosis in CBA/J mice by combination of Trypanosoma cruzi infection and a high cholesterol diet Sunnemark, D., R. A. Harris, et al. (2000), Atherosclerosis 153(2): 273-82. Abstract: In addition to established factors such as hyperlipidemia, smoking and hypertension, inflammation and infection have recently been implicated as major risk factors for atherosclerotic disease. Proatherogenic effects induced by infection may be related to both systemic inflammation and to direct effects on the vascular wall. We report here that a high fat diet combined with a protozoal infection with known tropism to the heart induced early atherosclerosis and intimal inflammatory infiltrates (CD4+, CD8+ cells and macrophages) in aortas of all (n = 7) CBA/J mice investigated. These mice are normally quite resistant to atherosclerotic development and in the control group (n = 7) receiving only a fatty diet, only one mouse presented a lesion. This lesion was completely devoid of infiltrating CD8+ cells. Parasite-infected mice receiving a normal diet exhibited vasculitis, but no signs of atherosclerosis and control mice receiving normal diet, as expected, exhibited neither signs of vasculitis nor atherosclerosis. Secretion of IL-6, TNF-alpha, and IFN-gamma were demonstrated in all atherosclerotic lesions and IL-6 appeared to be the dominant cytokine, both in the lesions themselves as well as in the intimal-medial junction. There were no traces of parasites present in the artery wall, indicating that atherosclerosis was induced via an indirect route. We conclude that a high fat diet in conjunction with infection and systemic (or localized) inflammation may have a strong proatherogenic effect. Finally, we suggest that CBA/J mice infected with T. cruzi parasites and given a fatty diet could serve as a useful experimental model in the continued analysis of factors contributing to the induction of atherosclerosis. |
| Induction of fatal inflammation in LDL receptor and ApoA-I double-knockout mice fed dietary fat and cholesterol Zabalawi, M., S. Bhat, et al. (2003), Am J Pathol 163(3): 1201-13. Abstract: Atherogenic response to dietary fat and cholesterol challenge was evaluated in mice lacking both the LDL receptor (LDLr(-/-)) and apoA-I (apoA-I(-/-)) gene, LDLr(-/-)/apoA-I(-/-) or double-knockout mice. Gender- and age-matched LDLr(-/-)/apoA-I(-/-) mice were fed a diet consisting of 0.1% cholesterol and 10% palm oil for 16 weeks and compared to LDLr(-/-) mice or single-knockout mice. The LDLr(-/-) mice showed a 6- to 7-fold increase in total plasma cholesterol (TPC) compared to their chow-fed mice counterparts, while LDLr(-/-)/apoA-I(-/-) mice showed only a 2- to 3-fold increase in TPC compared to their chow-fed controls. This differential response to the atherogenic diet was unanticipated, since chow-fed LDLr(-/-) and LDLr(-/-)/apoA-I(-/-) mice began the study with similar LDL levels and differed primarily in their HDL concentration. The 6-fold diet-induced increase in TPC observed in the LDLr(-/-) mice occurred mainly in VLDL/LDL and not in HDL. Mid-study plasma samples taken after 8 weeks of diet feeding showed that LDLr(-/-) mice had TPC concentrations approximately 60% of their 16-week level, while the LDLr(-/-)/apoA-I(-/-) mice had reached 100% of their 16-week TPC concentration after only 8 weeks of diet. Male LDLr(-/-) mice showed similar aortic cholesterol levels to male LDLr(-/-)/apoA-I(-/-) mice despite a 4-fold higher VLDL/LDL concentration in the LDLr(-/-) mice. A direct comparison of the severity of aortic atherosclerosis between female LDLr(-/-) and LDLr(-/-)/apoA-I(-/-) mice was compromised due to the loss of female LDLr(-/-)/apoA-I(-/-) mice between 10 and 14 weeks into the study. Diet-fed female and, with time, male LDLr(-/-)/apoA-I(-/-) mice suffered from severe ulcerated cutaneous xanthomatosis. This condition, combined with a complete depletion of adrenal cholesterol, manifested in fatal wasting of the affected mice. In conclusion, LDLr(-/-) and LDLr(-/-)/apoA-I(-/-) mice showed dramatic TPC differences in response to dietary fat and cholesterol challenge, while despite these differences both genotypes accumulated similar levels of aortic cholesterol. |
| Induction of geranyl pyrophosphate pyrophosphatase activity by cholesterol-suppressive isoprenoids Case, G. L., L. He, et al. (1995), Lipids 30(4): 357-9. Abstract: Diets supplemented (1 mmol/kg) with thymol, carvacrol, and beta-ionone significantly decreased the serum cholesterol levels of cockerels. These mevalonate-derived end products of plant secondary metabolism (isoprenoids) had no impact on two cytosolic prenyl alcohol (and ethanol) dehydrogenase activities; each treatment increased microsomal geranyl pyrophosphate pyrophosphatase activity by greater than twofold. The structural diversity of the isoprenoids which suppress cholesterol synthesis may be reconciled by their ability to increase pyrophosphatase activity, thus leading to the production of the endogenous, post-transcriptional regulator of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. |
| Induction of hepatic apolipoprotein B mRNA editing for reducing serum cholesterol levels: a breakthrough or a disaster? Greeve, J., J. R. Chowdhury, et al. (1996), Hepatology 24(4): 964-6. |
| Induction of hepatic inducible nitric oxide synthase by cholesterol in vivo and in vitro Kim, J. W., K. W. Kang, et al. (2002), Exp Mol Med 34(2): 137-44. Abstract: Cholesterol-rich diet impairs endothelial NO synthase (eNOS) and enhances inducible NOS (iNOS) expression. In this study, we investigated effects of cholesterol on iNOS expression in high-fat-fed rat models, HepG2 and RAW264.7 cells. The high-fat diet increased the plasma total cholesterol level 6-7 fold and low-density lipoprotein cholesterol level (LDL-C) approximately 70 fold and slightly increased the level of lipid peroxidation as determined by thiobarbituric acid-reactive substance assay. The high-fat diet also increased plasma nitric oxide (NO) concentrations up to 5 fold, and induced iNOS mRNA expression in liver. The contractile responses of the endothelium-denuded thoracic aortic rings to phenylephrine were significantly damaged in high-fat-fed rats when assessed by organ chamber study. Treatment with estrogen for 4 days failed to reduce iNOS expressions as well as aortic contractility, although it improved lipid profiles. In cultured HepG2 or murine macrophage RAW264.7 cells, 3 days treatment with either 25-hydroxycholesterol or 7-ketocholesterol induced iNOS mRNA expression, as determined by RT-PCR. Our data suggested that the chronic exposure of hepatocytes and macrophage cells to high concentration of cholesterol or oxysterols may induce iNOS expression and subsequent synthesis of NO, which may be important in the pathogenesis of atherosclerosis. |
| Induction of hepatic uptake of lipoprotein(a) by cholesterol-derivatized cluster galactosides Biessen, E. A., H. Vietsch, et al. (1996), Arterioscler Thromb Vasc Biol 16(12): 1552-8. Abstract: We have previously developed triantennary galactosides TG(4A)C and TG(20A)C that lower cholesterol levels by inducing liver uptake of lipoproteins via galactose-recognizing hepatic receptors. In this study, we have investigated whether this strategy could also be applied to reduce elevated serum levels of the atherogenic lipoprotein(a) Lp(a). Both TG(4A)C and TG(20A)C could be incorporated into Lp(a). Incorporation of these glycolipids induced a rapid clearance of Lp(a). Concomitantly, the hepatic uptake of 125I-Lp(a) was enhanced from 4 +/- 1% to 80 +/- 4% of the injected dose for TG(4A)C (P <.0001) and to 17 +/- 4% of the injected dose for TG(20A)C (P <.006). TG(4A)C was apparently more effective in accelerating the serum decay of 125I-Lp(a), which may be caused by the higher hydrophobicity of this glycolipid relative to TG(20A)C. The TG(4A)C- and TG(20A)C-induced stimulation of the serum decay and liver uptake of 125I-Lp(a) could be significantly inhibited (> 85%) by preinjection of N-acetyl-galactosamine (150 mg), indicating that galactose-recognizing receptors are involved in the liver uptake of the glycolipid/Lp(a) complexes. The TG(4A)C-induced liver uptake of 125I-Lp(a) could be ascribed mainly to Kupffer cells (76 +/- 7%), whereas the parenchymal liver cell was the major site for liver uptake of TG(20A)C-laden 125I-Lp(a) (55 +/- 12%). In conclusion, both TG(4A)C and TG(20A)C stimulate the catabolism of 125I-Lp(a) by enhancing hepatic uptake. Because endocytosis of the substrate via galactose-recognizing receptors on Kupffer and parenchymal liver cells is followed by lysosomal degradation, we anticipate that both approaches for Lp(a) targeting may prove valuable as therapeutic modalities for lowering atherogenic levels of Lp(a). |
| Induction of IG9 monocyte adhesion molecule expression in smooth muscle and endothelial cells after balloon arterial injury in cholesterol-fed rabbits Calderon, T. M., S. D. Gertz, et al. (2000), Arterioscler Thromb Vasc Biol 20(5): 1293-300. Abstract: The expression of monocyte-specific adhesion molecules and chemokines by cell types within the vessel wall plays an important role in foam cell accumulation during atherosclerotic plaque development. We previously identified IG9, a novel monocyte adhesion protein that is expressed on endothelial cells (ECs) overlying human and rabbit advanced atherosclerotic plaques. The present study was designed to determine the temporal and spatial expression of IG9 and the chemokine, monocyte chemoattractant protein-1 (MCP-1), after balloon injury with (double injury) or without (single injury) prior air desiccation EC injury in the femoral arteries of rabbits fed a high-cholesterol diet. By immunohistochemical analyses, intense reactivity with monoclonal antibodies to IG9 and MCP-1 was detected 24 hours after single injury in medial smooth muscle cells (SMCs) and in SMCs of adventitial microvessels. However, monocyte infiltration of the tunica media was minimal or not detected in these sections. IG9 and MCP-1 antibody reactivity in vessel sections 28 days after single injury and 24 hours, 7 days, and 28 days after double injury was localized to medial and neointimal SMCs, foam cells, and luminal ECs overlying the plaques. Uninjured rabbit (cholesterol or normal diet) vessel sections exhibited minimal IG9 and MCP-1 immunostaining. In vitro studies using human aortic SMCs demonstrated IG9 protein induction after 24 hours of treatment with platelet-derived growth factor-BB and interferon-gamma or epidermal growth factor. IG9 expression was further increased by pretreatment of SMCs with the proatherogenic lipid, minimally oxidized low density lipoprotein. After balloon injury (24 hours), IG9 is induced in vascular SMCs before the detectable accumulation of monocytes within the vessel wall. Thus, the expression of IG9 by SMCs as well as by ECs may be an important factor in the accumulation of foam cells in atherosclerotic plaque development after arterial injury. |
| Induction of MHC class I presentation of exogenous antigen by dendritic cells is controlled by CD4+ T cells engaging class II molecules in cholesterol-rich domains Machy, P., K. Serre, et al. (2002), J Immunol 168(3): 1172-80. Abstract: We investigated interactions between CD4+ T cells and dendritic cells (DC) necessary for presentation of exogenous Ag by DC to CD8+ T cells. CD4+ T cells responding to their cognate Ag presented by MHC class II molecules of DC were necessary for induction of CD8+ T cell responses to MHC class I-associated Ag, but their ability to do so depended on the manner in which class II-peptide complexes were formed. DC derived from short-term mouse bone marrow culture efficiently took up Ag encapsulated in IgG FcR-targeted liposomes and stimulated CD4+ T cell responses to Ag-derived peptides associated with class II molecules. This CD4+ T cell-DC interaction resulted in expression by the DC of complexes of class I molecules and peptides from the Ag delivered in liposomes and permitted expression of the activation marker CD69 and cytotoxic responses by naive CD8+ T cells. However, while free peptides in solution loaded onto DC class II molecules could stimulate IL-2 production by CD4+ T cells as efficiently as peptides derived from endocytosed Ag, they could not stimulate induction of cytotoxic responses by CD8+ T cells to Ag delivered in liposomes into the same DC. Signals requiring class II molecules loaded with endocytosed Ag, but not free peptide, were inhibited by methyl-beta-cyclodextrin, which depletes cell membrane cholesterol. CD4+ T cell signals thus require class II molecules in cholesterol-rich domains of DC for induction of CD8+ T cell responses to exogenous Ag by inducing DC to process this Ag for class I presentation. |
| Induction of postprandial inflammatory response in adult onset growth hormone deficiency is related to plasma remnant-like particle-cholesterol concentration Twickler, T. B., G. M. Dallinga-Thie, et al. (2003), J Clin Endocrinol Metab 88(3): 1228-33. Abstract: Increased cardiovascular mortality due to premature atherosclerosis is a clinical feature in the adult-onset GH deficiency (AGHD) syndrome. Inflammation is a key feature in atherogenesis and may be triggered by postprandial lipoprotein remnants. We hypothesized that increased postprandial lipoprotein remnant levels in AGHD may be associated with an inflammatory response. In this case-control study, 10 AGHD patients 6 males and 4 females; age, 48 +/- 9 yr; body mass index (BMI), 26.9 +/- 2.6 kg/m(2) and 10 healthy control subjects (matched for age, BMI, gender, baseline lipid levels, and apolipoprotein E genotype) were included. They all ingested an oral fat load. Fasting and postprandial levels of plasma remnant-like particle-cholesterol (RLP-C; 0.31 +/- 0.13 mmol/liter and 4.14 +/- 1.37 mmol/liter.h in GHD; 0.18 +/- 0.06 mmol/liter and 2.56 +/- 1.02 mmol/liter.h in controls, respectively) were significantly increased in AGHD patients compared with control subjects. The median inflammatory cytokines, IL-6 and TNF-alpha, were higher in the fasting 3.9 (range, 3.1-11.9) pg/ml and 6.8 (range, 2.5-27.6) pg/ml, respectively and postprandial 151.7 (range, 87.0-294.3) pg/ml.24 h and 289.9 (range, 87.5-617.6) pg/ml.24 h, respectively states in AGHD than in controls fasting, 0.9 (range, 0.2-5.2) pg/ml and 2.8 (range, 2.5-5.7) pg/ml; and postprandial, 54.5 (range, 11.50-126.5) pg/ml.24 h and 118.3 (range, 81.2-243.1) pg/ml.24 h, respectively. In addition, postprandial profile of RLP-C and IL-6 in AGHD and in the total group were significantly associated (r(2) = 0.44, P < 0.05; and r(2) = 0.38, P < 0.01, respectively). In conclusion, the increased postprandial RLP-C level in GHD is associated with an inflammatory response that may result in increased susceptibility for premature atherosclerosis. |
| Induction of the cholesterol metabolic pathway regulates the farnesylation of RAS in embryonic chick heart cells: a new role for ras in regulating the expression of muscarinic receptors and G proteins Gadbut, A. P., L. Wu, et al. (1997), Embo J 16(24): 7250-60. Abstract: We propose a novel mechanism for the regulation of the processing of Ras and demonstrate a new function for Ras in regulating the expression of cardiac autonomic receptors and their associated G proteins. We have demonstrated previously that induction of endogenous cholesterol synthesis in cultured cardiac myocytes resulted in a coordinated increase in expression of muscarinic receptors, the G protein alpha-subunit, G-alphai2, and the inward rectifying K+ channel, GIRK1. These changes in gene expression were associated with a marked increase in the response of heart cells to parasympathetic stimulation. In this study, we demonstrate that the induction of the cholesterol metabolic pathway regulates Ras processing and that Ras regulates expression of G-alphai2. We show that in primary cultured myocytes most of the RAS is localized to the cytoplasm in an unfarnesylated form. Induction of the cholesterol metabolic pathway results in increased farnesylation and membrane association of RAS. Studies of Ras mutants expressed in cultured heart cells demonstrate that activation of Ras by induction of the cholesterol metabolic pathway results in increased expression of G-alphai2 mRNA. Hence farnesylation of Ras is a regulatable process that plays a novel role in the control of second messenger pathways. |
| Induction of the cholesterol transporter ABCA1 in central nervous system cells by liver X receptor agonists increases secreted Abeta levels Fukumoto, H., A. Deng, et al. (2002), J Biol Chem 277(50): 48508-13. Abstract: The expression, function, and regulation of the cholesterol efflux molecule, ABCA1, has been extensively examined in peripheral tissues but only poorly studied in the brain. Brain cholesterol metabolism is of interest because several lines of evidence suggest that elevated cholesterol increases the risk of Alzheimer's disease. We found a largely neuronal expression of ABCA1 in normal rat brain by in situ hybridization. ABCA1 message was dramatically up-regulated in neurons and glia in areas of damage by hippocampal AMPA lesion after 3-7 days. Immunoblot analysis demonstrated ABCA1 protein in cultured neuronal and glial cells, and expression was induced by ligands of the nuclear hormone receptors of the retinoid X receptor and liver X receptor family. ABCA1 was induced by treatment with retinoic acid and several oxysterols, including 22(R)-hydroxycholesterol and 24-hydroxycholesterol. Expression of an ABCA1-green fluorescent protein construct in neuroblastoma cells demonstrated fluorescence in perinuclear compartments and on the plasma membrane. Because the Abeta peptide is important in Alzheimer's disease pathogenesis, we examined whether ABCA1 induction altered Abeta levels. Treatment of neuroblastoma cells with retinoic acid and 22(R)-hydroxycholesterol caused significant increases in secreted Abeta40 (29%) and Abeta42 (65%). Treatment with a nonsteroidal liver X receptor ligand, TO-901317, similarly increased levels of secreted Abeta40 (25%) and Abeta42 (126%). The increase in secreted Abeta levels was reduced by RNAi blocking of ABCA1 expression. These data suggest that the cholesterol efflux molecule ABCA1 may also be involved in the secretion of the membrane-associated molecule, Abeta. |
| Ineffective decrease of serum cholesterol by simvastatin in a subgroup of hypercholesterolemic coronary patients Miettinen, T. A. and H. Gylling (2002), Atherosclerosis 164(1): 147-52. Abstract: We measured serum cholesterol concentrations and synthesis markers (e.g. serum lathosterol to cholesterol ratio), and absorption markers (e.g. serum campesterol to cholesterol ratio) of cholesterol in 319 good responders (GR; dose 20 mg up to 1 year) and in 115 poor responders (PR; dose increased at 6 weeks to 40 mg) among Finnish participants in the Scandinavian Simvastatin Survival Study at baseline, 6 weeks and 1 year of the simvastatin treatment. The baseline cholesterol level and the ratios of the absorption markers were higher and those of the synthesis markers lower in PR than GR. The ratios of the precursor sterols were negatively related to the baseline cholesterol in GR only (P=0.003). The cholesterol levels, and the ratios of the precursor sterols were decreased and those of the absorption marker sterols increased less consistently in PR than GR by 20 mg, the group differences being only slightly lessened by the dose addition to 40 mg. One-year differences were still frequently significant. The baseline cholesterol concentrations were negatively related to the reduction of the precursor sterol ratios in GR, the change of cholesterol being positively related to those of the synthesis markers and negatively to those of the absorption markers only in PR. Thus, patients needing large statin dose for cholesterol normalization have high absorption and low synthesis of cholesterol, yet baseline synthesis is inversely related to cholesterol level only in GR. The synthesis rate is less markedly reduced by the large than by the small statin dose in the PR, and the reduction is related, in contrast to that in the GR, to lowering of cholesterol. |