| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Altered composition of lipoproteins in liver cirrhosis compromises three homogeneous methods for HDL-cholesterol Camps, J., J. M. Simo, et al. (1999), Clin Chem 45(5): 685-8. |
| Altered epitope expression of human interstitial fluid apolipoprotein A-I reduces its ability to activate lecithin cholesterol acyl transferase Wong, L., L. K. Curtiss, et al. (1992), J Clin Invest 90(6): 2370-5. Abstract: In human peripheral interstitial fluid, esterification of cholesterol by lecithin cholesterol acyltransferase (LCAT) was found to occur at a rate of only 10% of that in plasma (5.6 +/- 1.8 compared with 55.6 +/- 7.8 nmol/ml per h). Measurement of cholesterol esterification in the presence of excess reconstituted apoA-I HDL (rA-I HDL) revealed an LCAT activity in interstitial fluid of 24% of that in plasma, indicating that the low rate of esterification could not be caused by limiting mass of LCAT enzyme. When plasma was diluted to the same concentration as in interstitial fluid, the percent cholesterol esterification rate was the same as undiluted plasma and significantly higher than that of interstitial fluid. These findings led us to postulate that poor activation of LCAT in interstitial fluid may result from a change in conformation in apoA-I. To test this hypothesis, a monoclonal antibody AI-11 that inhibits apoA-I activation of LCAT was used to measure apoA-I in interstitial fluid and plasma. Antibody AI-11 recognized interstitial fluid apoA-I poorly, whereas a polyclonal antibody recognized interstitial fluid apoA-I normally. Incubation of antibody AI-11 with high density lipoprotein or rA-I HDL inhibited apoA-I activation of LCAT. We conclude that the altered conformation of apoA-I in interstitial fluid may render it a poor activator of LCAT. |
| Altered expression of caveolin-1 and increased cholesterol in detergent insoluble membrane fractions from liver in mice with Niemann-Pick disease type C Garver, W. S., R. P. Erickson, et al. (1997), Biochim Biophys Acta 1361(3): 272-80. Abstract: Niemann-Pick type C (NPC) is an autosomal recessive disease characterized by impaired cholesterol homeostasis due to a defect in the intracellular transport of unesterified cholesterol. While accumulation of lysosomal cholesterol is the most apparent microscopic finding, cholesterol has also been shown to accumulate in the trans-cisternae of the Golgi apparatus. Caveolin-1, a cholesterol-binding protein that cycles between the Golgi apparatus and the plasma membrane, has been hypothesized to participate in cholesterol transport. Using the BALB/c murine model for NPC disease, we found that the expression of caveolin-1 in total liver homogenates from heterozygous and homozygous affected animals was altered. Immunoblot analysis of liver homogenates from heterozygous mice revealed that caveolin-1 is significantly (p < 0.005) elevated, 4.9 fold, compared to normal mice. Total liver homogenates from homozygous affected mice also had a significant (p < 0.05) increase in caveolin-1 expression, 1.6 fold, compared to normal mice. Immunohistochemical staining of liver cross-sections revealed that the increased caveolin-1 was localized to sinusoidal endothelial cells in heterozygous mice. The Triton insoluble floating fraction (TIFF) was isolated using liver from each genotype and analyzed for caveolin-1 expression. Caveolin-1 in the TIFF from heterozygous mice was significantly (p < 0.01) elevated, 1.8 fold, compared to normal and homozygous affected animals; normal and homozygous affected animals, however, were not significantly different from each other. The TIFF isolated from homozygous affected mice revealed a 15 fold increase in unesterified cholesterol compared to the TIFF isolated from heterozygous and normal mice. In summary, these findings demonstrate an altered expression of caveolin-1 in liver from heterozygous and homozygous NPC mice and increased concentration of cholesterol from TIFF in homozygous affected NPC mice. The identification of these alterations in the TIFF suggests involvement of detergent insoluble membrane structures, possibly caveolae and/or detergent insoluble glycosphingolipid-enriched complexes (DIGs), in the cholesterol trafficking defect in this disorder. |
| Altered fatty acid, cholesterol and Na+/K+ ATPase activity in erythrocyte membrane of rheumatoid arthritis patients Masoom-Yasinzai, M. (1996), Z Naturforsch C 51(5-6): 401-3. Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease whose cause remains obscure. Blood from 15 RA patients and controls was taken and their ghosts separated. The ghosts were analysed for cholesterol content, Na+/K+ ATPase activity and eicosapentaenoic acid. The cholesterol content in the ghosts of RA patients was significantly lower as compared with the set of controls. There was a major difference in the activity of Na+/K+ ATPase between the two groups with RA patients showing significantly elevated activity. The ghosts of the RA patients exhibited major abnormality in the polyunsaturated fatty acids of phospholipids with the level of eicosapentaenoic acid (omega-3, 20:5) being significantly reduced. |
| Altered hepatic cholesterol metabolism compensates for disruption of phosphatidylcholine transfer protein in mice Wu, M. K. and D. E. Cohen (2005), Am J Physiol Gastrointest Liver Physiol 289(3): G456-61. Abstract: Phosphatidylcholine transfer protein (PC-TP) is a member of the steroidogenic acute regulatory transfer protein-related domain superfamily and is enriched in liver. To explore a role for PC-TP in hepatic cholesterol metabolism, Pctp-/- and wild-type C57BL/6J mice were fed a standard chow diet or a high-fat, high-cholesterol lithogenic diet. In chow-fed Pctp-/- mice, acyl CoA:cholesterol acyltransferase (Acat) activity was markedly increased, 3-hydroxy-3-methylglutaryl-CoA reductase activity was unchanged, and cholesterol 7alpha-hydroxylase activity was reduced. Consistent with increased Acat activity, esterified cholesterol concentrations in livers of Pctp-/- mice were increased, whereas unesterified cholesterol concentrations were reduced. Hepatic phospholipid concentrations were also decreased in the absence of PC-TP and consequently, unesterified cholesterol-to-phospholipid ratios in liver remained unchanged. The lithogenic diet downregulated 3-hydroxy-3-methylglutaryl-CoA reductase in wild-type and Pctp-/- mice, whereas Acat was increased only in wild-type mice. In response to the lithogenic diet, a greater reduction in cholesterol 7alpha-hydroxylase activity in Pctp-/- mice could be attributed to increased size and hydrophobicity of the bile salt pool. Despite higher hepatic phospholipid concentrations, the unesterified cholesterol-to-phospholipid ratio increased. The lack of Acat upregulation suggests that, in the setting of the dietary challenge, the capacity for esterification to defend against hepatic accumulation of unesterified cholesterol was exceeded in the absence of PC-TP expression. We speculate that regulation of cholesterol homeostasis is a physiological function of PC-TP in liver, which can be overcome with a cholesterol-rich lithogenic diet. |
| Altered lipid metabolism in apolipoprotein E-deficient mice does not affect cholesterol balance across the liver Kuipers, F., J. M. van Ree, et al. (1996), Hepatology 24(1): 241-7. Abstract: Adaptation of cholesterol and bile acid synthesis and of biliary cholesterol secretion represent key metabolic responses to maintain cholesterol homeostasis and have been suggested to be influenced by apolipoprotein E (apoE) phenotype in humans. We have investigated hepatic metabolism and secretion of cholesterol into bile in homozygous apoE-deficient (apoE -/-) mice fed normal lab chow. Plasma cholesterol levels were 10 times higher in apoE (-/-) mice than in controls (+/+); triacylglycerol levels were only minimally affected. Hepatic cholesterol (+56%) and triacylglycerol (+232%) contents were significantly increased in apoE (-/-) mice, whereas those of cholesteryl ester and of phospholipids were similar in both groups. Lipid accumulated predominantly in periportal areas of apoE (-/-) livers. Hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) messenger RNA (mRNA) level and activity were reduced by 45% and 50%, respectively, in apoE (-/-) mice. In contrast, plasma lathosterol/cholesterol ratios, indicative for whole-body cholesterol synthesis, were fourfold increased in these mice. Acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity was similar in livers of both groups. Despite the marked changes in hepatic cholesterol metabolism, neither hepatic bile acid synthesis, bile acid pool size and composition, nor hepatic cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase mRNA levels differed between apoE (-/-) and (+/+) mice. In addition, biliary cholesterol secretion was unaffected in the knock-out mice. Our results show that lack of apoE leads to marked changes in hepatic cholesterol metabolism without altering cholesterol balance across the liver. The data are compatible with increased peripheral cholesterol biosynthesis in apoE-deficient mice. |
| Altered maternal thyroid function: fetal and neonatal heart cholesterol and phospholipids Kumar, R. and B. N. Chaudhuri (1993), Indian J Physiol Pharmacol 37(3): 176-82. Abstract: The influence of maternal thyroid function on the fetal and neonatal myocardial cholesterol and phospholipid content was studied in rats. Fetuses born to hyperthyroid mothers had decreased total cholesterol and increased esterified cholesterol while offsprings born to hypothyroid mothers had increased total, free and esterified cholesterol during late gestation and/or at term. Phospholipid fractions phosphatidyl choline and phosphatidyl ethanolamine in offsprings born to hyperthyroid mothers were not significantly changed. Offsprings born to hypothyroid mothers had decreased total phospholipids, phosphatidyl choline and phosphatidyl ethanolamine at fetal and neonatal stages. 3H-acetate incorporation in phosphatidyl choline and phosphatidyl ethanolamine was also decreased. Maternal thyroid seems to have important role in the regulation of cholesterol and phospholipid metabolism in fetal and neonatal hearts. |
| Altered migrating myoelectrical complex in an animal model of cholesterol gallstone disease: the effect of erythromycin Xu, Q. W., R. B. Scott, et al. (1998), Gut 43(6): 817-22. Abstract: BACKGROUND: The ground squirrel on a high cholesterol diet exhibits prolonged intestinal transit, a pathogenetic factor in cholesterol gallstone formation. AIMS: To examine the effect of a high cholesterol diet on the characteristics of the migrating myoelectrical complex (MMC) and the potential benefit of erythromycin. METHODS: Twenty four animals received either a trace (controls) or a 1% (high) cholesterol diet. After four weeks, five bipolar jejunal and terminal ileal electrodes were implanted. Seven days later, myoelectric activity was measured in conscious, fasted animals before and after treatment with erythromycin. Biliary lipid composition was assessed. RESULTS: Compared with controls, animals fed the high cholesterol diet exhibited a prolonged MMC cycle period (70 (6) versus 83 (3) minutes; p<0.05), whereas MMC migration velocity and the proportions of the MMC represented by phases I, II, and III were unchanged. Oral erythromycin significantly shortened the MMC cycle period in animals on the control and high cholesterol diet by 59% and 54% respectively, and increased the proportion of the cycle period occupied by phase III of the MMC in both dietary groups. Gall bladder bile became saturated with cholesterol and crystals developed in nine of 12 animals on the high cholesterol diet; controls had none. CONCLUSION: Animals fed a high cholesterol diet had a prolonged MMC cycle period. This, along with diminished gall bladder motility, impairs the enterohepatic cycling of bile salts and reduces their hepatic secretion, contributing to the formation of abnormal bile. Erythromycin initiated more frequent cycling of the MMC. Its therapeutic value in cholesterol gallstone formation warrants further evaluation. |
| Altered mitochondrial function and cholesterol synthesis influences protein synthesis in extended HepG2 spheroid cultures Damelin, L. H., S. Coward, et al. (2004), Arch Biochem Biophys 432(2): 167-77. Abstract: Cultures of hepatocytes and HepG2 cells provide useful in vitro models of liver specific function. In this study, we investigated metabolic and biosynthetic function in 3-D HepG2 spheroid cultures, in particular to characterise changes on prolonged culture. We show that HepG2 cells cultured in spheroids demonstrate a reduction in mitochondrial membrane potential and respiration following 10 days of culture. This coincides with a modest reduction in glycolysis but an increase in glucose uptake where increased glycogen synthesis occurs at the expense of the intracellular ATP pool. Lowered biosynthesis coincides with and is linked to mitochondrial functional decline since low glucose-adapted spheroids, which exhibit extended mitochondrial function, have stable biosynthetic activity during extended culture although biosynthetic function is lower. This indicates that glucose is required for biosynthetic output but sustained mitochondrial function is required for the maintenance of biosynthetic function. Furthermore, we show that cholesterol synthesis is markedly increased in spheroids cf. monolayer culture and that inhibition of cholesterol synthesis by lovastatin extends mitochondrial and biosynthetic function. Therefore, increased cholesterol synthesis and/or its derivatives contributes to mitochondrial functional decline in extended HepG2 spheroid cultures. |
| Altered positional specificity of human plasma lecithin-cholesterol acyltransferase in the presence of sn-2 arachidonoyl phosphatidyl cholines. Mechanism of formation of saturated cholesteryl esters Subbaiah, P. V., M. Liu, et al. (1992), Biochim Biophys Acta 1128(1): 83-92. Abstract: The positional specificity of purified human lecithin-cholesterol acyltransferase (LCAT) was studied by analyzing the labeled cholesteryl ester (CE) species formed in the presence of proteoliposome substrates containing mixed chain phosphatidylcholine (PC) species, labeled cholesterol and apoprotein A-I. Whereas over 90% of the acyl groups used for CE synthesis were derived from the sn-2 position of most of the naturally occurring PC substrates, about 75% of the CE species formed in the presence of sn-1-myristoyl 2-arachidonoyl PC, sn-1-palmitoyl-2-arachidonoyl (PAPC) and sn-1-palmitoyl 2-docosahexaenoyl PC were derived from the sn-1-position. On the other hand, rat LCAT utilized mostly sn-2-acyl group from either PAPC or from sn-1-palmitoyl 2-linoleoyl PC. The positional specificity of the human enzyme was not affected by the alteration in the matrix fluidity, type of the apoprotein activator used, or by the free cholesterol/PC ratio in the substrate. These results show that the positional specificity of human plasma LCAT is altered in the presence of sn-2-arachidonoyl PC, or sn-2-docosahexaenoyl PC, probably due to steric restrictions at the active site, and this may account for the formation of disproportionately high concentrations of saturated CE, and low concentrations of long-chain polyunsaturated CE in human plasma, relative to the composition of sn-2-acyl groups in plasma PC. |
| Altered regulation of cholesterol and cholesteryl ester synthesis in Chinese-hamster ovary cells overexpressing the oxysterol-binding protein is dependent on the pleckstrin homology domain Lagace, T. A., D. M. Byers, et al. (1997), Biochem J 326 (Pt 1): 205-13. Abstract: Oxysterol-binding protein (OSBP) is a high-affinity receptor for a variety of oxysterols, such as 25-hydroxycholesterol, that down-regulate cholesterol synthesis and stimulate cholesterol esterification. To examine a potential role for OSBP in regulating cholesterol metabolism, we stably overexpressed this protein in Chinese-hamster ovary (CHO)-K1 cells. Compared with mock-transfected controls, several cell lines overexpressing wild-type OSBP (CHO-OSBP) displayed a 50% decrease in cholesteryl ester synthesis when cultured in medium with delipidated serum, 25-hydroxycholesterol or low-density lipoprotein (LDL). CHO-OSBP cells showed a 40-60% decrease in acyl-CoA:cholesterol acyltransferase activity and mRNA, a 50% elevation in mRNA for three sterol-regulated genes LDL receptor, 3-hydroxy-3-methylgluraryl (HMG)-CoA reductase and HMG-CoA synthase, and an 80% increase in 14Cacetate incorporation into cholesterol. CHO-K1 cells overexpressing two OSBP mutants with a complete or N-terminal deletion of the pleckstrin homology (PH) domain had cholesterol esterification and synthesis rates that were similar to those shown by mock-transfected controls. Unlike wild-type OSBP, both PH domain mutants displayed diffuse cytoplasmic immunofluorescence staining and did not translocate to the Golgi apparatus in the presence of 25-hydroxycholesterol. CHO-K1 cells overexpressing OSBP have pronounced alterations in cholesterol esterification and synthesis, indicating a potential role for this receptor in cholesterol homoeostasis. The phenotype observed in cells overexpressing OSBP is dependent on the PH domain, which appears to be necessary for ligand-dependent localization of OSBP to the Golgi apparatus. |
| Altered regulation of cholesterol metabolism in type I diabetic women during the menstrual cycle Owens, D., M. Cox, et al. (1993), Diabet Med 10(7): 647-53. Abstract: This study examines the relationship of cellular cholesterol metabolism to oestrogen and progesterone during the menstrual cycle in diabetic and non-diabetic subjects. Nine premenopausal diabetic women were compared to nine non-diabetic women of the same age. Oestrogen, progesterone, lipoproteins, including lipoprotein (a) (Lp(a)) and cholesteryl ester transfer protein (CETP) were determined in serum. Cellular cholesterol content and cellular cholesterol synthesis were measured in mononuclear leucocytes. There was no significant change in serum lipoproteins including Lp(a) during the cycle in either group. CETP activity was significantly higher over the 4 weeks in the diabetic patients compared with non-diabetic subjects (mean 463 +/- 30 mumol l-1 h-1 vs 405 +/- 28 mumol l-1 h-1, p < 0.01). Serum high density lipoprotein (HDL) cholesterol was significantly lower during the 4 weeks in the diabetic patients (1.7 +/- 0.1 mmol l-1 vs 1.8 +/- 0.1 mmol-1, p < 0.05). Cellular cholesterol synthesis decreased steadily up to the third week in cells from the control subjects whereas there was no significant change in cells from diabetic patients whose cellular cholesterol synthesis was higher at week 3 compared with non-diabetic subjects (663 +/- 54 nmol mg-1 cell protein vs 432 +/- 43 nmol mg-1 cell protein, two-way interaction p < 0.05). There was a significant negative correlation between cellular cholesterol synthesis and serum oestrogen in the non-diabetic subjects (p < 0.05) but not in the diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Altered sensitivities to potential inhibitors of cholesterol biosynthesis in Niemann-Pick type C fibroblasts Ohno, K., E. Nanba, et al. (1993), Cell Struct Funct 18(4): 231-40. Abstract: Cultured fibroblasts from patients with Niemann-Pick disease type C (NP-C) are characterized by the lysosomal accumulation of unesterified cholesterol and the inability of low-density lipoprotein (LDL) to stimulate cholesterol esterification, in addition to impaired LDL-mediated down-regulation of LDL receptor activity and cellular cholesterol synthesis. Although a defect in the transport of cholesterol from lysosomes to other intracellular membrane sites has been suggested, it is unclear how cells regulate the levels of cellular sterols and whether their membrane cholesterol requirements are satisfied or not. We studied the esterification of exogenously added cholesterol, total levels of cellular cholesterol and cholesteryl ester, cholesterol synthesis from a two-carbon precursor, and sensitivities to potential inhibitors of cholesterol biosynthesis in proliferating NP-C cells. We observed the following: (a) esterification of 3Hcholesterol was decreased but the total amount of cellular cholesteryl ester was not decreased; (b) synthesis of cholesterol from 3Hacetate was increased; and (c) cells were hypersensitive to cholecalciferol, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, and were resistant to filipin, which binds to membrane sterols and presumably damages the membrane. The results indicate that NP-C cells depend on the cellular cholesterol synthetic pathway for their proliferation, but the plasma membrane sterols are presumably decreased. The altered sensitivities to potential inhibitors of cholesterol biosynthesis should be a useful marker for diagnosis and genetic studies. |
| Alternate pathways of bile acid synthesis in the cholesterol 7alpha-hydroxylase knockout mouse are not upregulated by either cholesterol or cholestyramine feeding Schwarz, M., D. W. Russell, et al. (2001), J Lipid Res 42(10): 1594-603. Abstract: Bile acids are synthesized via the classic pathway initiated by cholesterol 7alpha-hydroxylase (CYP7A1), and via alternate pathways, one of which is initiated by sterol 27-hydroxylase (CYP27). These studies used mice lacking cholesterol 7alpha-hydroxylase (Cyp7a1(-/-)) to establish whether the loss of the classic pathway affected cholesterol homeostasis differently in males and females, and to determine if the rate of bile acid synthesis via alternate pathways was responsive to changes in the enterohepatic flux of cholesterol and bile acids. In both the Cyp7a1(-/-) males and females, the basal rate of bile acid synthesis was only half of that in matching Cyp7a1(+/+) animals. Although bile acid pool size contracted markedly in all the Cyp7a1(-/-) mice, the female Cyp7a1(-/-) mice maintained a larger, more cholic acid-rich pool than their male counterparts. Intestinal cholesterol absorption in the Cyp7a1(-/-) males fell from 46% to 3%, and in the matching females from 58% to 17%. Bile acid synthesis in Cyp7a1(+/+) males and females was increased 2-fold by cholesterol feeding, and 4-fold by cholestyramine treatment, but was not changed in matching Cyp7a1(-/-) mice by either of these manipulations. In the Cyp7a1(-/-) mice fed cholesterol, hepatic cholesterol concentrations increased only marginally in the males, but rose almost 3-fold in the females. CYP7A1 activity and mRNA levels were greater in females than in males, and were increased by cholesterol feeding in both sexes. CYP27 activity and mRNA levels did not vary as a function of CYP7A1 genotype, gender, or dietary cholesterol intake. We conclude that in the mouse the rate of bile acid synthesis via alternative pathways is unresponsive to changes in the enterohepatic flux of cholesterol and bile acid, and that factors governing gender-related differences in bile acid synthesis, pool size, and pool composition play an important role in determining the impact of CYP7A1 deficiency on cholesterol homeostasis in this species. |
| Aluminum accumulation and membrane fluidity alteration in synaptosomes isolated from rat brain cortex following aluminum ingestion: effect of cholesterol Silva, V. S., J. M. Cordeiro, et al. (2002), Neurosci Res 44(2): 181-93. Abstract: In the present work, we studied the effect of cholesterol/phospholipid (CH/PL) molar ratio on aluminum accumulation and aluminum-induced alteration of membrane fluidity in rat brain cortex synaptosomes. We observed that sub-acute (daily supply of 1.00 g of AlCl(3) during 10 days) and chronic (daily supply of 0.03 g of AlCl(3) during 4 months) exposure to dietary aluminum leads to a synaptosomal aluminum enrichment of 45 and 59%, respectively. During chronic exposure to AlCl(3), the enhancement of aluminum content was prevented by administration of colestipol (0.31 g/day), which decreased the synaptosomal membrane CH/PL molar ratio (nmol/nmol) from 1.2 to 0.4. Fluorescence anisotropy analysis, using 1,6-diphenyl-1,3,5-hexatriene (DPH) and 1-(4-(trimethylamino)phenyl)-6-phenylhexa-1,3,5-triene (TMA-DPH), showed that after treatment with colestipol a decrease in membrane order occurs at the level of hydrophilic lipid-water surface and deeper hydrophobic region of the synaptosomal membrane. When the rats were exposed to aluminum, it was observed a significant enhancement of membrane fluidity, which was more pronounced at the level of the membrane hydrophilic regions. Meanwhile, when chronic exposure to dietary AlCl(3) was accompanied by treatment with colestipol, the aluminum-induced decrease in membrane order was negligible when compared to TMA-DPH and DPH anisotropy values measured upon colestipol treatment. In contrast, in vitro incubation of synaptosomes (isolated from control rats) with AlCl(3) induced a concentration-dependent rigidification of this more hydrophilic membrane region. The opposite action of aluminum on synaptosomal membrane fluidity, during in vivo and in vitro experiments, appears to be explained by alteration of synaptosomal CH/PL molar ratio, since a significant reduction (approximately 80%) of this parameter occurs during in vivo exposure to aluminum. In conclusion, during in vivo exposure to aluminum, fluidification of hydrophilic regions and reduction of CH/PL molar ratio of presynaptic membranes accompany the accumulation of this cation, which appear to restrict aluminum retention in brain cortex nerve terminals. |
| Alzheimer disease and cholesterol Yanagisawa, K. (1999), No To Shinkei 51(2): 116-24. |
| Alzheimer's disease and cholesterol Yanagisawa, K. (2002), Seikagaku 74(6): 455-60. |
| Alzheimer's disease: the cholesterol connection Puglielli, L., R. E. Tanzi, et al. (2003), Nat Neurosci 6(4): 345-51. Abstract: A hallmark of all forms of Alzheimer's disease (AD) is an abnormal accumulation of the beta-amyloid protein (Abeta) in specific brain regions. Both the generation and clearance of Abeta are regulated by cholesterol. Elevated cholesterol levels increase Abeta in cellular and most animals models of AD, and drugs that inhibit cholesterol synthesis lower Abeta in these models. Recent studies show that not only the total amount, but also the distribution of cholesterol within neurons, impacts Abeta biogenesis. The identification of a variant of the apolipoprotein E (APOE) gene as a major genetic risk factor for AD is also consistent with a role for cholesterol in the pathogenesis of AD. Clinical trials have recently been initiated to test whether lowering plasma and/or neuronal cholesterol levels is a viable strategy for treating and preventing AD. In this review, we describe recent findings concerning the molecular mechanisms underlying the cholesterol-AD connection. |
| Alzheimer's disease--a dysfunction in cholesterol and lipid metabolism Lukiw, W. J., M. Pappolla, et al. (2005), Cell Mol Neurobiol 25(3-4): 475-83. Abstract: 1. Strong etiological association exists between dysfunctional metabolism of brain lipids, age-related changes in the cerebral vasculature and neurodegenerative features characteristic of Alzheimer's disease (AD) brain. 2. In this short review, recent experimental evidence for these associations is further discussed below. |
| Alzheimer's peptides A beta 1-40 and A beta 1-28 inhibit the plasma cholesterol esterification rate Koudinov, A. R., N. V. Koudinova, et al. (1996), Biochem Mol Biol Int 38(4): 747-52. Abstract: The amyloid fibrils of Alzheimer's disease and Down's syndrome amyloid deposits are composed mainly of aggregated amyloid beta protein (A beta) which also exists in a soluble form. It has been shown that both Alzheimer's disease and Down's syndrome share another common feature: the decrease in plasma cholesterol esterification in affected individuals. In the present work the effect of synthetic peptides A beta 1-40 and A beta 1-28 on normal human plasma cholesterol esterification rate was studied. Both peptides at a concentration of 1 ng/ml inhibited plasma cholesterol esterification rate to 40-50 % of control value. Statistical analysis showed no differences in the effect of A beta 1-40 and A beta 1-28 on the inhibition, suggesting the importance of A beta sequence 1-28 for this effect. |