| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Fermentation products of sugar-beet fiber by cecal bacteria lower plasma cholesterol concentration in rats Hara, H., S. Haga, et al. (1998), J Nutr 128(4): 688-93. Abstract: Plasma cholesterol concentration is reduced by feeding some dietary fibers but the mechanism is not fully understood. We examined whether cecal fermentation products are involved in lowering plasma cholesterol by feeding rats a highly fermentable sugar-beet fiber (SBF) in four separate experiments. These were designed to investigate the effects on plasma cholesterol of oral ingestion of fermentation products on plasma cholesterol, the effects of the products in comparison with that of a short-chain fatty acid (SCFA) mixture, effects of individual SCFA and effects of alteration of energy and nitrogen ratio in the diet by the addition of the SCFA mixture. Cecal contents of rats were cultured with SBF by using a jar fermenter under anaerobic conditions, and the supernatant from the culture medium, containing fermentation products of SBF, was collected and freeze-dried before feeding to rats. Yield of fermentation products as dry weight from the fiber was 80-90%. In rats fed a diet containing fermentation products (80 g/kg diet), plasma cholesterol concentrations were lower than in rats of the fiber-free group 3, 7 and 14 d after feeding the test diet. Major SCFA in the fermentation products were sodium salts of acetic, propionic and butyric acids. Plasma cholesterol concentration in rats fed the diet containing a mixture of equal amounts of the three SCFA salts (66 g/kg diet) as the fermentation products diet was also lower than that in the fiber-free group and was not different from those in rats fed SBF (100 g/kg diet) and the fermentation products. In rats fed an acetate-containing diet but not in rats fed diets without acetate, plasma cholesterol was significantly lower than in the fiber-free group. In conclusion, absorption of SCFA from cecal fermentation products lowers plasma cholesterol. Acetate, and not propionate, may be responsible for lowering plasma cholesterol concentration. |
| Fertilization potential in vitro is correlated with head-specific mannose-ligand receptor expression, acrosome status and membrane cholesterol content Benoff, S., I. Hurley, et al. (1993), Hum Reprod 8(12): 2155-66. Abstract: Normozoospermic men who do not fertilize human eggs in vitro constitute a clearly identifiable class of occult male factor infertility. We have studied the relationships between in-vitro fertilization (IVF) outcomes and the appearance of sperm surface mannose lectin/zona pellucida ligand activity measured by the binding of fluorescein isothiocyanate (FITC)-labelled mannosylated albumin. Of 338 semen specimens with normal profiles, 10 (2.96%) failed to fertilize in vitro (IVF-). Motile spermatozoa from six of these were analysed retrospectively for zona ligand binding activity on the sperm head in relation to acrosome status and the free cholesterol content of their plasma membrane. IVF+ males and fertile donors served as controls. The six IVF- occult male factor cases were distinguished from controls by their failure to show time-dependent increases in the percentage of spermatozoa exhibiting head-directed mannose ligand activity, by the slow loss or apparent increase in membrane cholesterol and by the absence of spontaneous and/or mannose-induced acrosome exocytosis. |
| Fiber intake, serum cholesterol levels, and cardiovascular disease in European individuals with type 1 diabetes. EURODIAB IDDM Complications Study Group Toeller, M., A. E. Buyken, et al. (1999), Diabetes Care 22 Suppl 2: B21-8. Abstract: OBJECTIVE: A cross-sectional analysis of dietary fiber intake was performed in European type 1 diabetic patients enrolled in the EURODIAB IDDM Complications Study to explore its potential relationship to serum cholesterol levels and the prevalence of cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: Dietary intake was assessed by a standardized 3-day dietary record. For analysis of fiber intake (total, soluble, and insoluble) and its associations with CVD (past history or electrocardiogram abnormalities), complete data were available from 1,050 male and 1,012 female individuals. Relationships of fiber intakes to serum cholesterol levels (total, HDL, and LDL cholesterol) were examined in 926 men and 881 women with type 1 diabetes. RESULTS: Higher intakes of total fiber (g/day) were independently associated with significantly higher levels of HDL cholesterol in male (P = 0.01) and female individuals (P = 0.03). Fiber intakes of men with type 1 diabetes were also inversely related to ratios of total cholesterol to HDL cholesterol (P = 0.0001) and levels of LDL cholesterol (P = 0.0002). A protective effect of total fiber intake against CVD was observed for female subjects, where a significant trend was maintained after adjustment for potential confounders, including energy and saturated fat (P = 0.03 vs. P = 0.2 in men). Results were similar in separate analyses of soluble and insoluble fiber. CONCLUSIONS: The present study demonstrates that higher fiber intakes are independently related to beneficial alterations of the serum cholesterol pattern in men and to a lower risk for CVD in European insulin-dependent women. Beneficial effects can already be observed for fiber amounts within the range commonly consumed by outpatients with type 1 diabetes. |
| Fibrates and HDL cholesterol Murphy, M. J., C. J. Packard, et al. (1997), Ann Clin Biochem 34 (Pt 1): 114. |
| Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase expression Post, S. M., H. Duez, et al. (2001), Arterioscler Thromb Vasc Biol 21(11): 1840-5. Abstract: Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases bile acid excretion, leading to an increased incidence of cholesterol gallstones. In this study, we investigated the effect of fibrates on bile acid synthesis. Ciprofibrate and the PPARalpha agonist Wy14,643 decreased bile acid synthesis in cultured rat hepatocytes and suppressed cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase activities, paralleled by a similar reduction of the respective mRNAs. Treatment of rats with 0.05% (wt/wt) ciprofibrate decreased cholesterol 7alpha-hydroxylase enzyme activity and mRNA. The functional involvement of PPARalpha in the suppression of both enzymes was proven with the use of PPARalpha-null mice. In wild-type mice, ciprofibrate reduced cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase enzyme activities and mRNA. The decrease in mRNA of both enzymes is regulated transcriptionally and posttranscriptionally, respectively, resulting in a decline in the output of fecal bile acids (-45%) and a 3-fold increase in fecal cholesterol secretion. These effects were completely abolished in PPARalpha-null mice. A decreased bile acid production by PPARalpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase may contribute to the increased risk of gallstone formation after fibrate treatment. |
| Fibrinogen, cholesterol and smoking as risk factors for non-arteritic anterior ischaemic optic neuropathy Talks, S. J., N. H. Chong, et al. (1995), Eye 9 (Pt 1): 85-8. Abstract: Non-arteritic anterior ischaemic optic neuropathy (AION) is thought to be due to occlusion of the posterior ciliary circulation. Raised lipid and fibrinogen concentrations are recognised risk factors for vessel occlusion in cardiovascular disease and stroke but, although suspected as risk factors in non-arteritic AION, they have not been studied in this condition. We therefore performed a case-control study on 41 patients with non-arteritic AION, looking at these and other atherosclerotic risk factors. The odds ratio of cholesterol being > 6.5 mmol/l in non-arteritic AION was 2.7 (95% confidence interval 1.09 to 6.65; p < 0.05) and of fibrinogen being > 3.6 g/l was 5 (2.66 to 9.39; p < 0.05). Smoking was also found to be significantly associated with non-arteritic AION, the odds ratio being 16 (3.23 to 79.23; p < 0.001). These were the only risk factors found to be significantly associated with non-arteritic AION. This raises the possibility that appropriate medical management of these factors could be given to prevent recurrence in the fellow eye. |
| Fibrinogen, factor VII, antithrombin III, cholesterol and triglycerides in young men with myocardial infarction and in their sons Jastrzebska, M., B. Torbus-Lisiecka, et al. (1997), Mater Med Pol 29(1-4): 3-7. Abstract: The concentrations of fibrinogen (Fb) and the activities of factor VII (F VIIC) and antithrombin III (AT III) both in men less than 55 years old with a history of myocardial infarction (MI) and with normolipemia (MI-NLP) or hyperlipoproteinemia (MI-HLP) and in their sons have been measured. A significantly higher levels of Fb were found in both MI groups. Significantly higher levels of F VIIC and AT III were found only in the MI-NLP group. No lipid or haemostatic disorders were noted in sons. Furthermore, a positive correlation between the level of F VIIC and triglycerides (TG) or total cholesterol (TCh) in the patients and sons was revealed. A positive correlation was found between: (a) Fb levels in MI-HLP patients and in their sons; (b) TG levels in MI-HLP patients and in their sons; and (c) AT III activity in MI patients and in their sons. Fibrinogen appears to be associated with ischemic heart disease more closely than factor VII, the latter being strongly linked with hypertriglyceridemia. Elevated activities of AT III may reflect the haemostatic response to the prothrombotic state in IHD on the one hand whereas they may contribute to the development of IHD on the other. |
| Fibrinolytic response in subjects with hypertriglyceridemia and low HDL cholesterol Cimminiello, C., P. Vigorelli, et al. (1997), Biomed Pharmacother 51(4): 164-9. Abstract: The combination of hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) appears to be an excessively high risk factor for coronary artery disease (CAD). In the Helsinki study, both coronary events and mortality were decreased by gemfibrozil, especially in subjects with low HDL-C and high triglycerides (TG). On the other hand, it is known that high levels of TG can be associated with high levels of circulating plasminogen activator inhibitor (PAI), which is also a possible risk factor for CAD. The aim of the present study was to see: 1) whether the combination of low HDL-C and high TG is associated with a more impaired fibrinolytic response than in either isolated condition, and 2) whether gemfibrozil administration can improve fibrinolysis in patients with both high TG and low HDL-C. Twelve non-obese, non-diabetic subjects (eight men, four women; mean age 55 +/- 13 yrs) with low HDL-C (< 35 mg/dL men; < 45 mg/dL women) and high TG (mean 253.6 +/- 42.6 mg/dL) entered the study (Group A). Additionally fourteen comparable subjects with normal HDL-C were also investigated (Group B), plus 12 comparable subjects with isolated low HDL-C (Group C). Ten healthy people served as the control group. The following plasma fibrinolytic parameters were measured: tissue plasminogen activator antigen, PAI antigen and activity, euglobulin fibrinolytic activity (EFA) on fibrin plates, plasminogen and alpha-2-antiplasmin activities. All except the latter two values were also measured after venous occlusion (vo). In baseline conditions, patients in Groups A and B had higher EFA values before vo and higher PAI-1 antigen and alpha-2-antiplasmin levels after vo than those of controls or the subjects in Group C. The relationship between PAI antigen and PAI activity and TG was not confirmed in our population (n = 48). We also saw no interference due to HDL-C, while there was a significant relationship between EFA before vo and both TG and cholesterol. After gemfibrozil treatment (600 mg bid for 12 weeks), the lipid profiles of subjects with high TG and low HDL-C were significantly improved. There was also a slight reduction of PAI activity after vo, while the PAI-1 antigen had decreased significantly from baseline after vo (56.3 +/- 13 ng/mL before vo; 48.4 +/- 21 ng/mL after vo; P = 0.04). The higher risk of CAD in patients with low HDL-C and high TG might be in part related to impairment of fibrinolysis, which occurs in patients with isolated high TG. The close relationship existing between both TG and cholesterol levels and fibrinolytic activity confirm the key role of this latter process in the development of CAD. |
| Fibroblasts and antigen-presenting cells in the renal interstitium of streptozotocin-induced diabetic rats on a high cholesterol diet Hosoyamada, Y., H. Kudo, et al. (2002), Arch Histol Cytol 65(4): 307-15. Abstract: The cortical peritubular interstitium of the normal kidney contains both fibroblasts and antigen-presenting dendritic cells. Characteristics of these interstitial cells were analyzed in an overnutrition model by electron microscopy after the cold-dehydration technique and immunohistochemistry for antigen-presenting cells. In control rats, fibroblasts and dendritic cells were clearly identified by electron microscopy on the basis of their distinct ultrastructures. Fibroblasts possessed slender cell processes, and contained an abundance of actin filament bundles occasionally anchoring to surrounding structures, whereas dendritic cells possessed irregularly-shaped cell processes with a clear cytoplasm and a paucity of actin filament bundles. In the experimental kidney from diabetic rats given a high cholesterol diet, the peritubular interstitium contained fibroblasts and vacuolated cells, and the extracellular matrices such as collagen bundles were distinctly increased compared with the control rat kidney. Immunohistochemical staining with OX6 and ED1 revealed that the peritubular interstitium in the control rat kidney contained dendritic cells, while that in the experimental rats was occupied by macrophages. The present study provides the first evidence indicating that overnutrition may dramatically affect the immune cells in nonlymphoid tissue. |
| Fibronectin in human gallbladder bile: cholesterol pronucleating and/or mucin "link" protein? Miquel, J. F., C. Von Ritter, et al. (1994), Am J Physiol 267(3 Pt 1): G393-400. Abstract: Some biliary proteins (pronucleators) seem to be essential factors for cholesterol crystal formation and crystal growth in bile. A recent study suggests that fibronectin is such a pronucleator in bile. Fibronectin also seems to closely interact with intestinal mucin. Since biliary mucin plays an important role in gallstone formation, such an interaction in bile may be of relevance in cholesterol gallstone formation. To more clearly elucidate the role of fibronectin in cholesterol gallstone disease, we measured the concentration of fibronectin in native bile of cholesterol gallstone patients and checked its influence on the cholesterol nucleation time of model bile. We further looked for a molecular interaction between biliary fibronectin and gallbladder mucin. We found that fibronectin is present in gallbladder bile of gallstone patients in low concentrations (2.6 +/- 1.2 micrograms/ml). Bile fibronectin did not interact with gallbladder mucin. Moreover, in a wide range of concentrations fibronectin had no influence on the nucleation time of model bile. We conclude that fibronectin does not seem to play a major role in cholesterol gallstone disease. |
| Fibronectin, cholesterol and triglycerides ascitic fluid concentration in the prediction of malignancy Colloredo Mels, G., G. Bellati, et al. (1991), Ital J Gastroenterol 23(4): 179-86. Abstract: There have been few trials comparing the efficacy of determinations of cholesterol, fibronectin and triglycerides for diagnosis of malignant ascites. In this study we measured these in 200 ascitic fluids from 93 cirrhotic patients (Group A), 47 hepatocellular-carcinoma patients (Group B), 60 extra-hepatic tumour patients (Group C), 44 of them with malignant cells (Group Cpos) and 16 without (Group Cneg). Anova one-way and the Bonferroni test for multiple comparisons showed that fibronectin and cholesterol were significantly higher in the ascitic fluids of patients of group C than of groups A and B (mean +/- ESM) (Cholesterol in A: 27.2 +/- 2.8; in B 23.5 +/- 1.5; in C: 68.6 +/- 5.3 mg/dl. Fibronectin in A: 32.7 +/- 2.8; in B 31.3 +/- 2.6; in C 127.7 +/- 11.1 mg/l). Both were significantly higher in Group Cpos than in Group Cneg (Cholesterol in Cneg: 41.2 +/- 6.7; in Cpos: 78.6 +/- 6.2 mg/dl. Fibronectin in Cneg: 55.0 +/- 11.2; in Cpos 154 +/- 12.3 mg/dl). We found no differences between cirrhotic ascites and malignant ascites due to primary liver hepatocellular-carcinoma. No difference at all in triglycerides were detected. With the Receiver-Operating Characteristic (ROC) curve, cholesterol had the best Youden Index (57%) at a cut-off of 32 mg/dl (sensitivity 78.3%, specificity 79.3% at this level); the best Youden Index (64%) for fibronectin had a cut-off of 60 mg/dl (sensitivity 65%, specificity 89.3%). Triglycerides appeared to be a great deal less effective as a diagnostic marker, with their best Youden Index (23%) at a cut-off 32 mg/dl (sensitivity 66.7%, specificity 56.4%).(ABSTRACT TRUNCATED AT 250 WORDS) |
| Fibronectin: a possible factor promoting cholesterol monohydrate crystallization in bile Chijiiwa, K., A. Koga, et al. (1991), Biochim Biophys Acta 1086(1): 44-8. Abstract: To examine the hypothesis that fibronectin physiologically present in bile might be a possible nucleating factor, the concentrations of fibronectin in gallbladder bile were determined and its induced effect on nucleation time and on the form of vesicle were examined in bile-model and human gallbladder bile. The gallbladder bile samples taken from patients with cholesterol gallstone had a significantly higher concentration of fibronectin and the faster nucleation time than the control. However, no significant correlation was found between nucleation time and endogenous fibronectin concentration. The addition of 0.5, 1.2, 10 micrograms/ml of fibronectin into two kinds of bile-model significantly shortened the nucleation time in a dose-related manner. Nucleation time was significantly shortened by the addition of 1 microgram/ml exogenous fibronectin into abnormal bile while such an effect was absent in the control. The addition of fibronectin increased the size of vesicles observed by the electron microscope. The results suggest that fibronectin physiologically present in bile may be one of the possible nucleating factors. |
| Filamentous, helical, and tubular microstructures during cholesterol crystallization from bile. Evidence that cholesterol does not nucleate classic monohydrate plates Konikoff, F. M., D. S. Chung, et al. (1992), J Clin Invest 90(3): 1155-60. Abstract: Precipitation of cholesterol in gallbladder bile is believed to produce platelike cholesterol monohydrate crystals directly. We report complementary time-lapse microscopic studies of cholesterol crystallization from model bile that reveal initial assembly of filamentous cholesterol crystals covered by a monomolecular layer of lecithin. Over a few days, the filaments evolved through needle, helical, and tubular microstructures to form classical platelike cholesterol monohydrate crystals. Similar crystallization phenomena were observed in human gallbladder biles from cholesterol but not pigment stone patients. Synchrotron x-ray diffraction of the earliest filaments suggested a cholesterol monohydrate polymorph or admixture with an anhydrous cholesterol precursor. However, density gradient centrifugation of filamentous crystals revealed that their density was 1.032 g/ml, consistent with anhydrous cholesterol. Conventional x-ray diffraction of transitional crystalline forms was consistent with pure cholesterol monohydrate crystals, as were the equilibrium platelike crystals. These novel findings suggest that crystalline cholesterol in bile may not be completely mature or hydrated initially, but undergoes a series of transformations to become thermodynamically stable monohydrate plates. These observations have important implications for understanding the control of cholesterol crystallization in bile, as well as explaining putative crystal cytotoxicity during gallstone formation. |
| Filipin and its interaction with cholesterol in aqueous media studied using static and dynamic light scattering Castanho, M. A., W. Brown, et al. (1994), Biopolymers 34(4): 447-56. Abstract: Aggregation of filipin in aqueous medium and filipin-induced changes in cholesterol micelles have been studied using intensity and dynamic light scattering. The dependencies of filipin aggregate dimensions on concentration, solvent, and temperature were studied, and revealed that the aggregates do not have a well-defined geometry, i.e., a critical micelle concentration cannot be detected and stable structures are not formed. The aggregates are of size Rg approximately 110 nm and Rh approximately 63 nm, referring to the radius of gyration and hydrodynamic radius, respectively. In the concentration range studied (1 microM < C < 30 microM), a low molecular weight species (monomer/dimer) is always present together with the aggregates. In ethanol/water mixtures, large (Rg approximately 500 nm), narrow distribution aggregates are formed in the water volume fraction range 0.45 < phi H2O < 0.65. Aggregation also occurs on changing the temperature; In the range 7-37 degrees C, smaller aggregates (10-30 nm form and the process is only partially reversible. No pronounced effect of filipin on the structure of the cholesterol micelles was observed (a small increase in Rg and Rh is noted). These results rule out any "specificity" for the filipin interactions with cholesterol, which has been considered a key event in the filipin biochemical mode of action. A reevaluation of this question is suggested and some alternatives are advanced. |
| Filipin vs enzymatic localization of cholesterol in guinea pig, mink, and mallard duck testicular cells Pelletier, R. M. and M. L. Vitale (1994), J Histochem Cytochem 42(12): 1539-54. Abstract: To test the validity of filipin cytochemistry for localization of cholesterol in testicular cells, we compared the results obtained by this technique with those obtained by a two-step enzymatic method involving cholesterol esterase and cholesterol oxidase. In all the animals models tested (guinea pig, mink, and mallard duck) the disappearance of subsurface filaments along Sertoli cell junctional membranes was accompanied by a significant increase in the number of filipin-cholesterol complexes/microns 2 in these membranes. Enzyme histochemistry allowed localization of free cholesterol in the limiting membrane of multivesicular bodies, in membranes within lysosomes, in mitochondrial membranes, and in junctional membranes, with or without subsurface filaments. The method also permitted selective visualization of cholesterol esters in lipid droplets. We conclude that filipin mapping of cholesterol induces false-negative cytochemical results. The enzymatic method is superior to filipin because it allows localization of free cholesterol in junctional membranes and of cholesterol esters in lipid droplets. This compartmentalization of the compounds may represent the basis of a system that helps to maintain constant free cholesterol levels in the testis. |
| Filtered coffee raises serum cholesterol: results from a controlled study Strandhagen, E. and D. S. Thelle (2003), Eur J Clin Nutr 57(9): 1164-8. Abstract: OBJECTIVE: Earlier studies and trials have shown a serum cholesterol raising effect of unfiltered coffee, which is reduced by about 80% in filtered coffee. Recent cross-sectional studies and trials, however, have indicated that filtered coffee may have a more pronounced serum cholesterol raising effect than previously anticipated. The objective of this controlled study was to assess the effects of the intake and abstention of filtered brewed coffee on blood lipids. DESIGN: A prospective, controlled study with four consecutive trial periods. The first and third periods were 3 weeks of total coffee abstention. The second and fourth periods consisted of 4 weeks with the subjects consuming 600 ml filter brewed coffee/day. SETTING: Free-living population. Volunteers. SUBJECTS: A total of 121 healthy, nonsmoking men and women aged 29-65 y. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Serum total cholesterol, serum HDL cholesterol, serum triglycerides, serum lipoprotein (a) (Lp(a)), blood pressure and heart rate. RESULTS: The two coffee abstention periods were associated with a decline in serum cholesterol of 0.22 mmol/l (95% CI -0.31, -0.13) and 0.36 mmol/l (95% CI -0.46, -0.26), respectively. Filtered coffee/day 600 ml increased serum cholesterol by 0.25 mmol/l (95% CI 0.15, 0.36) and 0.15 mmol/l (95% CI 0.04, 0.26) during the two coffee drinking periods. CONCLUSIONS: Coffee abstention for 3 weeks decreased total serum cholesterol by 0.22-0.36 mmol/l. A volume of 600 ml (about four cups) of filtered coffee/day during 4 weeks raised total serum cholesterol by 0.15-0.25 mmol/l. |
| Finally, a noncontroversial role for Apo A-I in HDL-mediated cholesterol flux to cells Rothblat, G. H. (1996), J Clin Invest 97(11): 2405-6. |
| Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolaemia in multiple communities Lee, M. H., D. Gordon, et al. (2001), Eur J Hum Genet 9(5): 375-84. Abstract: Sitosterolaemia (also known as phytosterolaemia, MIM 210250) is a rare recessive autosomal inherited disorder, characterised by the presence of tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease. The defective gene is hypothesised to play an important role in regulating dietary sterol absorption and biliary secretion, thus defining a molecular mechanism whereby this physiological process is carried out. The disease locus was localised previously to chromosome 2p21, in a 15 cM interval between microsatellite markers D2S1788 and D2S1352 (based upon 10 families, maximum lodscore 4.49). In this study, we have extended these studies to include 30 families assembled from around the world. A maximum multipoint lodscore of 11.49 was obtained for marker D2S2998. Homozygosity and haplotype sharing was identified in probands from non-consanguineous marriages from a number of families, strongly supporting the existence of a founder effect among various populations. Additionally, based upon both genealogies, as well as genotyping, two Amish/Mennonite families, that were previously thought not to be related, appear to indicate a founder effect in this population as well. Using both homozygosity mapping, as well as informative recombination events, the sitosterolaemia gene is located at a region defined by markers D2S2294 and Afm210xe9, a distance of less than 2 cM. |
| Finnish cholesterol discussion Salminen, K. (1993), Duodecim 109(17): 1498. |
| Fish eye syndrome: a molecular defect in the lecithin-cholesterol acyltransferase (LCAT) gene associated with normal alpha-LCAT-specific activity. Implications for classification and prognosis Klein, H. G., S. Santamarina-Fojo, et al. (1993), J Clin Invest 92(1): 479-85. Abstract: We have identified the molecular defect in two siblings presenting with classical clinical and biochemical features of Fish Eye disease (FED), including corneal opacities, HDL cholesterol < 10 mg/dl, normal plasma cholesteryl esters, and elevated triglycerides. In contrast to previously reported patients with FED who are unable to esterify HDL-associated cholesterol, our patients' plasma lecithin-cholesterol acetyltransferase (alpha-LCAT)-specific activities assayed using an HDL-like proteoliposome substrate were 12.7-25.7 nmol/micrograms (19.5 +/- 1.8 in controls). In addition, significant residual cholesterol esterification was present in VLDL/LDL-depleted plasma, confirming the presence of HDL-associated alpha-LCAT activity. DNA sequence analysis of the proband's LCAT gene identified deletion of the triplet coding for leu300, which resulted in the loss of a restriction site for MlnI. Digestion of PCR-amplified DNA using MlnI established that both siblings are homozygous for this defect. Expression of LCAT300-del. in human embryonic kidney-293 cells revealed normal mRNA and intracellular LCAT concentrations. However, reduced amounts of LCAT300-del., which had a normal specific alpha-LCAT activity, were present in the media. In summary, we report the first case of FED associated with a mutant enzyme that has a normal alpha-LCAT-specific activity. The functional significance of this LCAT gene defect has been established in an in vitro expression system, which demonstrates that very small amounts of this functional LCAT mutant enzyme accumulate in the media. Characterization of LCAT300-del. established that selective alpha-LCAT deficiency is not a prerequisite for the development of FED. On the basis of our combined results, we propose that the residual amounts of total plasma LCAT activity and not its distribution on lipoproteins primarily determines the heterogeneity in phenotypic expression observed in familial LCAT deficiency syndromes. |