| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation Bjorkhem, I., D. Lutjohann, et al. (1998), J Lipid Res 39(8): 1594-600. Abstract: We have previously demonstrated that the brain contains about 80% of the 24S-hydroxycholesterol in the human body and that there is a net flux of this steroid from the brain into the circulation (Lutjohann, D. et al. 1996. Proc. Natl. Acad. Sci. USA. 93: 9799-9804). Combining previous data with new data on 12 healthy volunteers, the arteriovenous difference between levels of this oxysterol in the internal jugular vein and in a peripheral artery was found to be -10.2 +/- 2.8 ng/ml (mean +/- SEM) corresponding to a net flux of 24S-hydroxycholesterol from the brain of about 6.4 mg/24 h. The arteriovenous difference between levels of 24S-hydroxycholesterol in the hepatic vein and a peripheral artery of 12 other volunteers was found to be 7.4 +/- 2.2 ng/ml, corresponding to a hepatic uptake of about 7.6 mg/24 h. The concentrations of 24S-hydroxycholesterol in the renal vein were about the same as those in a peripheral artery, indicating that a renal elimination is not of importance. Intravenously injected deuterium-labeled racemic 24-hydroxycholesterol was eliminated from the circulation of two human volunteers with half-lives of 10 h and 14 h, respectively. A positive correlation was found between the levels of circulating cholesterol and 24S-hydroxycholesterol. The results are consistent with a cerebral origin of most of the circulating 24S-hydroxycholesterol and suggest that the liver is the major eliminating organ. It is concluded that conversion into 24S-hydroxycholesterol is a quantitatively important mechanism for elimination of cholesterol from human brain. The possibility is discussed that circulating levels of 24S-hydroxycholesterol can be used as a marker for pathological and/or developmental changes in the brain. |
| Cholesterol homeostasis in neurons and glial cells Vance, J. E., H. Hayashi, et al. (2005), Semin Cell Dev Biol 16(2): 193-212. Abstract: Cholesterol is highly enriched in the brain compared to other tissues. Essentially all cholesterol in the brain is synthesized endogenously since plasma lipoproteins are unable to cross the blood-brain barrier. Cholesterol is transported within the central nervous system in the form of apolipoprotein E-containing lipoprotein particles that are secreted mainly by glial cells. Cholesterol is excreted from the brain in the form of 24-hydroxycholesterol. Apolipoprotein E and cholesterol have been implicated in the formation of amyloid plaques in Alzheimer's disease. In addition, the progressive neurodegenerative disorder Niemann-Pick C disease is characterized by defects in intracellular trafficking of cholesterol. |
| Cholesterol homeostasis in rat astrocytoma cells GA-1 Zhang, L. Y., J. I. Ito, et al. (2000), J Biochem (Tokyo) 128(5): 837-45. Abstract: Astrocytes play a key role in cholesterol metabolism in central nervous system. We have shown that fetal rat astrocytes in primary culture secrete cholesterol-rich HDL with the endogenous apolipoprotein (apo) E and generate cholesterol-poor HDL with exogenous apoE and apoA-I Ito et al. (1999) J. Neurochem. 72, 2362. In order to study these reactions in relation to the stage of cell differentiation, we examined generation of HDL by rat astrocytoma cells. Lack of apoE secretion was found in three astrocytoma cell lines, human T98G, rat C6, and GA-1 Kano-Tanaka et al. (1986) Proc. Jpn. Acad. Ser. B 62, 109. GA-1 produced apoE at very low level and therefore generated much less HDL by itself than the astrocytes in primary culture. In contrast, GA-1 interacted with exogenous apoE and apoA-I to produce cholesterol-rich HDL while the astrocytes produced cholesterol-poor HDL with these apolipoproteins. Cholesterol biosynthesis rate measured from mevalonate was higher and down-regulated more by LDL in the astrocytes than GA-1. On the other hand, the cellular cholesterol level, uptake of LDL, and cyclodextrin-mediated non-specific diffusion of cholesterol from cell surface were same between these two cells. Treatment of GA-1 with acidic fibroblast growth factor influenced neither the production of apoE nor the baseline lipid secretion, but increased the cholesterol synthesis from mevalonate and the magnitude of its down-regulation by LDL, and decreased cholesterol content in the HDL produced by exogenous apoA-I. In conclusion, suppression of apoE biosynthesis in the undifferentiated astrocytes GA-1 resulted in poor secretion of cholesterol-rich HDL and in turn more production of HDL with exogenous apolipoprotein. Cellular cholesterol homeostasis was altered accordingly. |
| Cholesterol homeostasis is modulated by amphiphiles at transcriptional and post-transcriptional loci Lange, Y., H. Duan, et al. (1996), J Lipid Res 37(3): 534-9. Abstract: A variety of amphiphiles inhibit plasma membrane cholesterol esterification and induce 3-hydroxy-3-methylglutaryl-coenzyme A reductase accumulation in cultured cells; among these are steroids, hydrophobic amines, phenothiazines, ionophores, colchicine, and lysophosphatides. It has been proposed that these amphiphiles signal a sterol deficiency to regulatory sites by blocking the movement of plasma membrane cholesterol into the cell (Lange, Y., and Steck, T. L. 1994. J. Biol. Chem. 269: 29371-29374). If this were the case, these agents also should enhance transcription of sterol responsive genes and stabilize 3-hydroxy-3-methylglutaryl-coenzyme A reductase. As a test of this hypothesis, the effect of the amphiphiles on such transcriptional and post-transcriptional events was assessed. A mouse embryo cell line was transfected with a construct containing the promoter for the human low density lipoprotein receptor upstream of the DNA sequence coding for chloramphenicol acyltransferase (CAT). Incubation of these cells for 7-18 h with the aforementioned agents caused the level of expression of the promoter/CAT construct to increase 2- to 9-fold. We showed further that the amphiphiles stimulated 3-hydroxy-3 methylglutaryl-coenzyme A reductase activity by increasing gene transcription as well as by decreasing degradation of the enzyme. These are the predicted homeostatic responses to cell cholesterol deficiency. These findings support the hypothesis that certain amphiphiles falsely signal a cholesterol deficiency to the intracellular sites regulating cholesterol homeostasis. |
| Cholesterol homeostasis. Modulation by amphiphiles Lange, Y. and T. L. Steck (1994), J Biol Chem 269(47): 29371-4. Abstract: Diverse amphiphiles act on cellular cholesterol metabolism as if signaling regulatory sites. One class (oxysterols) mimics the homeostatic effects of excess cell cholesterol, inhibiting cholesterol biosynthesis and stimulating plasma membrane cholesterol esterification. A second class of amphiphiles has effects precisely opposite to the oxysterols, i.e. they immediately inhibit plasma membrane cholesterol esterification and progressively induce 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity and cholesterol biosynthesis. This second class of agents includes steroids, hydrophobic amines, phenothiazines, ionophores, colchicine, cytochalasins, and lysophosphatides, most of which interact with P-glycoproteins. These data support a general hypothesis describing cellular cholesterol homeostasis. (a) Proteins regulating sterol metabolism are embedded in intracellular membranes where their activities are governed by the local level of cholesterol. (b) Excess plasma membrane and lysosomal cholesterol circulates through those intracellular membranes and sets the homeostatic activities therein. (c) The two classes of agents mentioned above affect cholesterol homeostasis by increasing or decreasing, respectively, the ambient level of cholesterol at the sites of regulation. |
| Cholesterol homeostasis: a role for oxysterols Accad, M. and R. V. Farese, Jr. (1998), Curr Biol 8(17): R601-4. |
| Cholesterol homeostasis: clipping out a slippery regulator Osborne, T. F. (1997), Curr Biol 7(3): R172-4. Abstract: SREBPs are transcriptional activators central to cholesterol homeostasis. Recent work has shown that a two-step cleavage of membrane-bound SREBPs frees them to enter the nucleus. An activator of the first, sterol-regulated proteolysis step has also been identified. |
| Cholesterol homeostasis: ESCAPe from the ER Hampton, R. Y. (2000), Curr Biol 10(8): R298-301. Abstract: Transcriptional regulation and membrane traffic have traditionally been quite separate fields of biology, but they have been brought under the same roof by recent advances in understanding the cellular control of cholesterol metabolism. |
| Cholesterol homeostasis: not until the SCAP lady INSIGs Loewen, C. J. and T. P. Levine (2002), Curr Biol 12(22): R779-81. Abstract: Three new studies have wide implications for cholesterol homeostasis, identifying a novel mechanism by which a sterol-sensing domain functions in the regulated activation of sterol regulatory element binding proteins. |
| Cholesterol homeostasis: role of the LDL receptor Javitt, N. B. (1995), Faseb J 9(13): 1378-81. |
| Cholesterol homeostatic mechanisms in transgenic mice with altered expression of apoproteins A-I, A-II and A-IV Kalopissis, A. D. and J. Chambaz (2000), Int J Tissue React 22(2-3): 67-78. Abstract: Our understanding of the in vivo metabolic functions of apoA-I and A-II has greatly advanced with the use of transgenic mice, but the physiological role of apoA-IV remains elusive. Both apoA-I and A-II are necessary for the structural stability of high-density lipoprotein (HDL). Structural differences exist between human and mouse A apoproteins because: i) human cholesterol ester transfer protein, lecithin cholesterol acyl transferase and phospholipid transfer protein interact better with human apoA-I; ii) human apoA-I and A-II, alone or in combination, form polydisperse instead of monodisperse HDL particles. Human apoA-II overexpression has highlighted its inhibitory effect on lipoprotein lipase and hepatic lipase, resulting in hypertriglyceridemia and concomitantly decreased HDL and apoA-I. After long-term challenge with an atherogenic diet, mice are less protected against lesion formation by human apoA-II, mouse apoA-II being overtly proatherogenic. On the other hand, human apoA-I confers great protection against lesion formation and causes reduction of preexisting lesions. Human apoA-IV is also protective, although the mechanisms by which this protection is achieved remain to be determined. |
| Cholesterol hydroperoxides in erythrocyte membranes of alcoholic patients Adachi, J., M. Asano, et al. (1999), Alcohol Clin Exp Res 23(4 Suppl): 96S-100S. Abstract: Evidence for the presence of 5alpha-hydroperoxycholest-6-en-3beta-ol (cholesterol 5alpha-hydroperoxide, Ch 5alpha-OOH) and 7alpha- and 7beta-hydroperoxycholest-5-en-3beta-ols (cholesterol 7-hydroperoxides: Ch 7alpha-OOH and Ch 7beta-OOH, respectively) in human erythrocyte membrane was found. Blood samples were collected from alcoholic patients and healthy volunteers (controls), and their cholesterol hydroperoxides were analyzed by high-performance liquid chromatography postcolumn chemiluminescence and roughly identified by liquid chromatography-mass spectrometry. Ch 7alpha-OOH and Ch 7beta-OOH were present in each sample, being significantly higher in alcoholic samples than in control samples. Ch 5alpha-OOH was present in some alcoholic samples, but not in the control ones. The accumulation of cholesterol hydroperoxides suggests enhanced lipid peroxidation by active oxygen species and/or a reduced elimination system for lipid peroxide in alcoholic patients. |
| Cholesterol immobilization via ether-linked sepharose gels Satsangi, R. K. and G. E. Mott (1992), Analyst 117(6): 953-7. Abstract: Cholesterol has been immobilized on Sepharose-6B via oxyether linkages to the 3- or 25-position. The 3- or 25-hydroxysterol methanesulfonates were coupled with epoxy-Sepharose-6B at 80 degrees C for 24 h. Approximately 2% of the ligand was incorporated into the gel. These types of affinity columns may be useful in purifying proteins that specifically bind or metabolize cholesterol. |
| Cholesterol impairs the adenine nucleotide translocator-mediated mitochondrial permeability transition through altered membrane fluidity Colell, A., C. Garcia-Ruiz, et al. (2003), J Biol Chem 278(36): 33928-35. Abstract: Mitochondrial permeability transition (MPT) has been proposed to play a key role in cell death. Downstream MPT events include the release of apoptogenic factors that sets in motion the mitochondrial apoptosome leading to caspase activation. The current work examined the regulation of MPT by membrane fluidity modulated upon cholesterol enrichment. Mitochondria enriched in cholesterol displayed increased microviscosity resulting in impaired MPT induced by atractyloside, a c-conformation stabilizing ligand of the adenine nucleotide translocator (ANT). This effect was dependent on the dose of cholesterol loaded and reversed upon the fluidization of mitochondria by the fatty acid derivative A2C. Mitoplasts derived from cholesterol-enriched mitochondria responded to atractyloside in a similar fashion as intact mitochondria, indicating that a significant amount of cholesterol is still found in the inner membrane. The effects of cholesterol on MPT induced by atractyloside were mirrored by the release of intermembrane proteins, cytochrome c, Smac/Diablo, and apoptosis inducing factor. However, cholesterol loading did not affect the uptake rate of adenine nucleotide hence dissociating the function of ANT as a MPT-mediated protein from its adenine nucleotide exchange function. Thus, these findings indicate that the ability of atractyloside to induce MPT via ANT requires an appropriate membrane fluidity range. |
| Cholesterol import by Aspergillus fumigatus and its influence on antifungal potency of sterol biosynthesis inhibitors Xiong, Q., S. A. Hassan, et al. (2005), Antimicrob Agents Chemother 49(2): 518-24. Abstract: High mortality rates from invasive aspergillosis in immunocompromised patients are prompting research toward improved antifungal therapy and better understanding of fungal physiology. Herein we show that Aspergillus fumigatus, the major pathogen in aspergillosis, imports exogenous cholesterol under aerobic conditions and thus compromises the antifungal potency of sterol biosynthesis inhibitors. Adding serum to RPMI medium led to enhanced growth of A. fumigatus and extensive import of cholesterol, most of which was stored as ester. Growth enhancement and sterol import also occurred when the medium was supplemented with purified cholesterol instead of serum. Cells cultured in RPMI medium with the sterol biosynthesis inhibitors itraconazole or voriconazole showed retarded growth, a dose-dependent decrease in ergosterol levels, and accumulation of aberrant sterol intermediates. Adding serum or cholesterol to the medium partially rescued the cells from the drug-induced growth inhibition. We conclude that cholesterol import attenuates the potency of sterol biosynthesis inhibitors, perhaps in part by providing a substitute for membrane ergosterol. Our findings establish significant differences in sterol homeostasis between filamentous fungi and yeast. These differences indicate the potential value of screening aspergillosis antifungal agents in serum or other cholesterol-containing medium. Our results also suggest an explanation for the antagonism between itraconazole and amphotericin B, the potential use of Aspergillus as a model for sterol trafficking, and new insights for antifungal drug development. |
| Cholesterol improves the utilization of parenteral lipid emulsions Druml, W. and M. Fischer (2003), Wien Klin Wochenschr 115(21-22): 767-74. Abstract: Lipid emulsions have become an indispensable component of parenteral nutrition. Commercially available emulsions mostly have an identical composition of triglycerides (from plant oils) and egg-yolk phospholipids as emulsifier. Previous attempts to improve the composition of lipid emulsions have focused mainly on the triglyceride moiety. In the first fundamental modification of a lipid emulsion since their broader introduction into clinical medicine, we included free cholesterol in a lipid emulsion. We evaluated elimination and hydrolysis of triglycerides and lipid oxidation (by indirect calorimetry) in 10 healthy male normolipemic volunteers, comparing a conventional lipid emulsion (20% triglycerides) with an otherwise identical emulsion with the addition of 4 g/l free cholesterol. The rise in plasma triglycerides was mitigated during infusion of the cholesterol-enriched solution (323.8 +/- 27.5 vs. 202.0 +/- 18.9 mg.dL-1, p < 0.001), plasma half-life was reduced (41.6 +/- 5.4 vs. 29.3 +/- 5.1 min, p < 0.05), and total-body clearance was enhanced (0.96 +/- 0.1 vs. 1.52 +/- 0.2 ml.b.w.min-1, p < 0.02). The rise in plasma free fatty acids (400.7 +/- 39.0 vs. 532.2 +/- 64.0 mumol.L-1; p < 0.02) and ketone bodies (beta-hydroxybutyrate) (151.6 +/- 37.0 vs. 226.3 +/- 33.01 mumol.L-1; p < 0.02) was augmented. Increases in plasma insulin and glucagon were less pronounced (p < 0.05). The fall in respiratory quotient was greater and the fraction of lipid oxidation as a percentage of total energy expenditure was increased (66.2% +/- 6.0 vs. 70.9% +/- 6.3, p < 0.05) during infusion of the modified solution. No impairment of gas exchange or other side effects were observed. Taken together these results indicate that the elimination of a cholesterol-supplemented lipid emulsion is accelerated, triglyceride hydrolysis is enhanced, and lipid oxidation is augmented. Thus, addition of cholesterol to a lipid emulsion might not only present a means of providing cholesterol in parenteral nutrition but also help to reshape artificial lipid particles to a more chylomicron-resembling composition and improve lipid utilization. |
| Cholesterol in a historic perspective. Report of the professor C.D. de Langen symposium. The Netherlands, December 4, 1998 Kesteloot, H. and D. Kromhout (1999), Acta Cardiol 54(3): 121. |
| Cholesterol in adolescents: whom to screen & how to treat Kohn, M. R. and M. S. Jacobson (1996), Compr Ther 22(12): 817-25. |
| Cholesterol in Alzheimer's disease and tauopathy Burns, M. and K. Duff (2002), Ann N Y Acad Sci 977: 367-75. Abstract: Cholesterol has been implicated in the pathogenesis of amyloid plaques in Alzheimer's disease (AD) and in the formation of neurofibrillary pathology in Niemann-Pick disease. Several epidemiology studies have implicated high cholesterol as a risk factor for AD and have shown that the use of cholesterol-reducing agents (statins) can be protective against the disease. We and others have shown that cholesterol levels modulate the processing of the amyloid precursor protein (APP) both in vivo and in vitro, affecting the accumulation of A-beta (Abeta) peptides that may directly impact the risk of AD. Mutations in the Niemann-Pick C gene (NPC) result in deficient cholesterol transport/storage. Clinically, Niemann-Pick disease causes a severe childhood lipidosis, with neurodegeneration characterized by the presence of AD-type neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Studies of mouse models of NPC show that defects in cellular cholesterol trafficking are associated with enhanced generation of Abeta and the hyperphosphorylation of tau, further implicating the cholesterol homeostasis pathway as a risk factor for amyloidosis. |
| Cholesterol in beef, pork, chicken and their products commercialized in Maringa, Parana, Brazil Rowe, A., S. A. Bertoni, et al. (1997), Arch Latinoam Nutr 47(3): 282-4. Abstract: A rapid method developed by Al-Hasani et al. with modifications for cholesterol determination was applied in samples of beef, pork, chicken and meat products. Analyses of cholesterol were performed by capillary gas chromatography. The obtained results showed that chicken presented higher concentration (126.96 to 188.29 mg/100 g) of cholesterol in comparison to beef and pork and similar to meat products, except bovine liver that presented 265.03 mg/100 g. Cholesterol values of beef and pork samples were considered low due to the absence of superficial fat in meat samples. |