Effect of deoxycholate on immunoglobulin G concentration in bile: studies in humans and pigs

Because an increase in biliary deoxycholate levels seems to be a risk factor for cholesterol gallstone formation, we determined the relationship between deoxycholate levels and levels of the pronucleating protein, immunoglobulin G (Ig) in human gallbladder bile. Patients with cholesterol gallstones had a higher concentration of biliary IgG compared with a pigmented stone group and control patients. This was associated with the simultaneous presence of two conditions in the cholesterol stone group, supersaturated bile and a high deoxycholate/cholate ratio. The other patient groups met only one of the two conditions. Next, animal studies were performed to determine if model biles mimicking the two conditions could affect IgG secretion by the gallbladder. Gallbladders were exposed in vivo and then in an Ussing chamber to model biles. The voltage clamp technique was used to monitor functional integrity of the preparation. Three different model biles were tested: (1) taurodeoxycholate (TDC), 80%; taurocholate (TC), 20%; and cholesterol saturation index (CSI), 1.2; (2) TDC, 20%; TC, 80%; and CSI, 1.2; and (3) TDC, 80%; TC, 20%; and CSI, 0.6. IgG concentrations became significantly higher in group 1 than in the other two groups. The concentration of mucous glycoprotein was also significantly greater in group 1 when compared with group 2. Plasma cells were increased in number in mucosal and submucosal layers in group 1. We conclude that cholesterol supersaturated model bile with high content of TDC induces gallbladder epithelial alterations, which increase the luminal concentration of IgG and mucous glycoprotein.     

Vitamin E modifies neither fructosamine nor HbA1c levels in poorly controlled diabetes

OBJECTIVE: To examine the effects of vitamin E on total serum protein glycation (fructosamine), hemoglobin glycation (HbA1c), and serum levels of glucose, total cholesterol, triglycerides, LDL-C, HDL-C, apolipoprotein A1 and apolipoprotein B. MATERIAL AND METHODS: Sixty poorly controlled diabetic patients were randomly assigned to receive either 1200 mg/day of vitamin E or identical placebo capsules during a two month period following a double blind cross-over design with a four week wash-out period between regimens. RESULTS: Seven patients were excluded from the study because of reasons not related to the medication. In the remaining 53 patients, the levels of serum glucose, fructosamine, HbA1c, total cholesterol, HDL-C, LDL-C, Apo A1 and Apo B did not vary significantly with vitamin E as compared with placebo. CONCLUSIONS: No significant effects of vitamin E on any of the parameters evaluated were observed in poorly controlled diabetic patients.     

Biological variability in serum vitamin E concentrations: relation to serum lipids

The components of biological variation in serum vitamin E in relation to serum cholesterol, triglycerides, high- and low-density lipoprotein cholesterol (HDL-C, LDL-C), apolipoprotein A-I (apo A-I), and apo B were examined in 26 healthy volunteers who had monthly blood samplings during one calendar year. The estimated CVs for vitamin E were: interindividual, 19.9%, and intraindividual, 11.9%; the index of individuality (I-index) was 0.59. The I-indices for all lipid variables were < 0.51. Serum concentrations of vitamin E, cholesterol, triglycerides, HDL-C, LDL-C, and apo B were lower in spring than in the other seasons. The peak-trough differences in the yearly variations, expressed as a percentage of the mean, were for vitamin E 14.5%, cholesterol 16.2%, triglycerides 14.5%, and LDL-C 24.3%. A significant common annual rhythm was expressed in vitamin E or lipid variables and in the changes in ambient temperature the weeks before blood sampling (inverse relations). There were highly significant positive time relations between serum vitamin E and cholesterol, triglycerides, and apo B. Subjects with higher homeostatic setpoints of cholesterol showed higher homeostatic setpoints of vitamin E, triglycerides, LDL-C, and apo B.     

Antenatal steroids, condition at birth and respiratory morbidity and mortality in very preterm infants

The study purpose was to compare the effect of exercise training on serum lipid and apolipoprotein concentrations and the activities of intravascular enzymes related to lipid transport in previously untrained eumenorrheic, premenopausal (PRM) women (n = 21; mean age, 36 +/- 3 years) and estrogen-free postmenopausal (POM) women (n = 16; mean age, 68 +/- 8 years). Subjects trained at a progressive intensity and duration (50% to 75% maximal O2 consumption [VO2max], 200 to 300 kcal/session) 4 d/wk for 12 weeks. Before and after training, VO2max, body weight, relative body fat, and fasting blood samples were obtained following 2 weeks on a standardized diet designed to maintain body weight and during the early follicular stage for the PRM group. Blood samples were analyzed for serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), the cholesterol content of the HDL3 subfraction, apolipoprotein (apo)A-I and apoB, lipoprotein(a), and the activity of lecithin:cholesterol acyltransferase (LCAT). Total and hepatic triglyceride lipase activity (HTGLA) were determined from plasma samples obtained after heparin administration. The cholesterol content of the low-density lipoprotein (LDL) and HDL2 subfractions and endothelial-bound lipoprotein lipase activity (LPLA) were calculated. A two (group) x two (time) multivariate ANOVA (MANOVA), with repeated measures for time indicated that the exercise-induced changes in physiological measurements, serum lipid or apolipoprotein concentrations, or enzyme activities did not differ between groups. Serum concentrations of TC, LDL-C, and HDL3 cholesterol, TG, and apo A-I and apoB were higher in POM women compared with the PRM group (P < .05 for all). For the combined groups, body weight and relative body fat did not change with training, but VO2max increased an average of 18.5% (P < .05). LPLA, HTGLA, and LCAT activity were unaltered with exercise training. Except for a small but significant decrease in HDL-C (-5.5%) and an elevation in apoB (4.3%; P < .05 for both), the concentrations of serum lipids and apolipoproteins did not change over the training period. We conclude that in previously untrained women, menopausal status does not influence the exercise training response of serum lipids or apolipoproteins or activities of intravascular enzymes related to lipid transport.     

Lecithin supplementation in healthy volunteers: effect on cholesterol esterification and plasma, and bile lipids

Plasma and bile lipids and in vitro cholesterol esterifying activity of plasma (mg CE/dl/6 h) were determined in healthy volunteers who supplemented their regular diets with 7.5 g doses of soya lecithin three times daily for a 4-week period. Lecithin ingestion by the 4 male and 6 female subjects did not produce any significant changes either in total plasma cholesterol (TC) level or cholesterol esterification. A small but significant reduction was observed in the plasma triglyceride (TG) and total phospholipid (TPL) levels after supplementation. The molar percent of bile acids (BA), TC and TPL as well as the lithogenic index (LI = TC/BA + TPL) in both hepatic and gallbladder bile were also unaltered by 4 weeks of lecithin supplementation. In vitro cholesterol esterification was found linearly related to plasma-free cholesterol (r = 0.60, p less than 0.01) cholesterol ester (r = 0.50, p less than 0.05), total phospholipid (r = 0.50, p less than 0.05), lecithin (r = 0.45, p less than 0.05), and triglyceride (r = 0.57, p less than 0.025) levels.     

Therapy of post-renal transplantation hyperlipidaemia: comparative study with simvastatin and fish oil

BACKGROUND: Recipients of renal transplantation (RT) exhibit disturbances of serum lipids and apoproteins that may contribute to their cardiovascular morbidity and mortality. In our renal transplant department the hypercholesterolaemia prevalence at the first and fifth year of RT is 70.0% and 81.2%, respectively. Lipid-lowering therapy has been utilized in many Transplant Units. The aim of our study was to evaluate post-RT hyperlipidaemia control with simvastatin or fish oil. METHODS: Forty-three RT patients (26 men and 17 women) with persistent hypercholesterolaemia and stable graft function which were resistant to a lipid-lowering diet (American Heart Association Step Two) were randomized into two groups and treated for 3 months with simvastatin (S) (10mg/day; n = 25) and fish oil (F) (6 g/day; n = 18). Total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), lipoprotein a (Lp(a)), apolipoprotein A1 (Apo A1), and apolipoprotein B (Apo B) were monitored and at the study baseline they were similar between the two groups. RESULTS: No side effects were detected after 3 months of therapy. In group S, the concentrations of TC (271 +/- 46 mg% vs 228 +/- 49 mg%; P < 0.001), TG (180 +/- 78 vs 134 +/- 45; P < 0.01), LDL-C (177 +/- 40 vs 144 +/- 43; P < 0.01) and Apo B (96 +/- 18 vs 82 +/- 16; P < 0.001) were significantly reduced, and Apo A1 concentration had increased (135 +/- 24 vs 149 +/- 30; P < 0.01). In group F, the concentrations of TC (266 +/- 25 vs 240 +/- 31; P < 0.001), TG (203 +/- 105 vs 156 +/- 72; P = 0.02) and HDL-C (63 +/- 15 vs 53 +/- 12; P < 0.01) were significantly reduced. CONCLUSIONS: We concluded that low-dose simvastatin and fish oil are both effective and safe in correcting post-RT hyperlipidaemia. Further prospective studies with larger follow-up are needed to clarify whether this therapy has an impact on cardiovascular morbidity and mortality in RT patients.     

Recognizing infective endocarditis: case study of a 28-year-old

We studied serum lipid and lipoprotein changes before and after induction treatment in 25 acute nonlymphocytic leukemia (ANLL) and in 18 acute lymphocytic leukemia (ALL) patients in order to investigate their relationship with disease activity and their prognostic relevance. ANLL at diagnosis is associated with significantly low levels of all lipid parameters, the same applies to ALL patients apart from plasma triglycerides and very-low-density-lipoprotein cholesterol (VLDL-C) which are significantly higher than in the normal population. In ANLL responders, after effective chemotherapy, a significant increase of total cholesterol, low-density-lipoprotein cholesterol (LDL-C) and apolipoprotein B levels, without changes of high-density-lipoprotein cholesterol (HDL-C) values, is observed. A further decrease of total cholesterol and LDL-C was found in nonresponders and in ANLL responders treated with granulocyte-macrophage colony-stimulating factor (GM-CSF), known for its cholesterol-lowering action; in fact after the completion of GM-CSF therapy, these parameters returned progressively toward normal values. In ALL responders an increase of total cholesterol, HDL-C and apolipoprotein A1 with a simultaneous decrease of triglycerides and VLDL-C is evident; no variation was found in the nonresponder group. These results suggest a close correlation between serum lipids and acute leukemia: total cholesterol and LDL-C in ANLL, and HDL-C and VLDL-C in ALL may be considered reliable markers of complete remission and may be useful in the follow-up of leukemic patients.     

Apolipoprotein A-I complexed with phospholipid promotes hepatic lipoprotein and apolipoprotein secretion in the perfused hamster liver

BACKGROUND: Apolipoprotein A-I within high density lipoprotein (HDL) plays a significant role in the process of reverse cholesterol transport from peripheral tissues to the liver. However, additional roles are not well defined for it in hepatic cholesterol metabolism. We have previously shown in the hamster that dietary cholesterol supplementation resulted in enhancement of apolipoprotein A-I (Apo A-I) in secreted nascent hepatic very low density lipoprotein (VLDL), suggesting that apolipoprotein A-I itself may play a role in hepatic lipoprotein secretion. METHODS: Using the isolated hamster liver with Apolipoprotein A-I perfusion, we then examined the hypothesis that Apo A-I alone or in association with phosphotidylcholine (PC) i.e., Apo A-I/PC as a HDL-like particle, has effects upon hepatic lipoprotein and bile secretion. Ultracentrifugation was performed on perfusate samples at 3 hours on control vs treated livers (Apo A-I/PC, Apo A-I, or PC) to access lipid and protein concentration in VLDL, low density lipoprotein (LDL) and HDL. Four to thirty percent gradient SDS polyacrylamide electrophoresis (PAGE) and Western blot analysis were used on delipidated lipoprotein fractions and microsomes to assess apolipoproteins Apo B, A-I, II, and E. RESULTS: We found that perfusion of reconstituted HDL vesicles containing human apolipoprotein A-I and PC (Apo A-I/PC) 10 mg and 10 mg, respectively, in 22 mL for 3 hours into isolated hamster liver increased cholesterol (CH) and triglyceride (TG) components in secreted HDL; 45- and 6-fold, and in LDL; 15- and 2-fold, respectively. No significant changes occurred in VLDL or in biliary lipids. Concomitantly, Apo A-I/PC perfusion increased Apo E and Apo A-II and HDL and Apo B in LDL, while Apo E decreased in VLDL. Apo A-I/PC perfusion did not change the apolipoprotein content of hepatic microsomes of the perfused liver. Perfusion of apolipoprotein A-I (without PC) or PC (without apolipoprotein A-I) had none of these effects. CONCLUSION: These results indicate that the perfused discoidal apolipoprotein A-I/PC particle affects hepatic lipoprotein assembly and secretion, whereby both lipid and apolipoprotein components are enhanced in secreted HDL and LDL of hepatic origin.     

Does lipid infusion affect bile composition in humans?

A prospective study was performed to investigate the effect of short-term lipid infusion on bile composition and its lithogenicity in humans. The study group comprised 44 patients scheduled for laparotomy. The patients were hospitalized 48 h prior to elective surgery and randomized to be infused with a lipid emulsion of either long chain triglycerides (LCT) or a mixture of medium and long chain triglycerides (MCT/LCT) for 6 h of each 24 h, or with glucose-saline. Bile samples were obtained by puncture of the gallbladder during operation. In non-gallstone patients, both lipids caused an elevation of biliary cholesterol and phospholipids, but this effect was more pronounced and significant (P <0.001) only with the mixture of MCT/LCT emulsion. The fatty acid composition of biliary phospholipids was not affected by either lipid infusion. The Cholesterol Saturation Index increased significantly (P <0.005) with the MCT/LCT emulsion and there was insignificant shortening in the nucleation time. In contrast to patients with cholelithiasis, no effects could be demonstrated on gallbladder bile composition, cholesterol saturation index, nucleation time, or fatty acid composition of phospholipids. The effects of both lipid emulsions on plasma lipids and lipoproteins were similar in all groups. Our results indicate that lipid emulsions containing MCT/LCT induce lithogenic changes in the composition of human bile. We propose that the lack of effect of lipid infusion on bile composition in patients with cholelithiasis may be due to precipitation of excess cholesterol in the gallbladder of cholesterol gallstone patients whose bile is already saturated. These findings imply that patients with cholesterol gallstones cannot be grouped with non-gallstone patients in studies of alterations of bile composition.     

Gallstone formation and gallbladder bile composition after colectomy in dogs

A high prevalence of gallstones has been described in patients following colectomy. The aim of this study was to examine whether lithogenicity is attributed to colectomy. In the present study, changes in gallbladder bile composition and the mechanism of gallstone formation after colectomy were examined in dogs. Ten mongrel dogs underwent restorative proctocolectomy. Seven dogs which received sham operations served as controls. Over a 12-week postoperative period, samples of gallbladder bile, formed gallstones and serum were collected and analyzed. In 7 of the 10 (70%) colectomized dogs, gallstones were found in the gallbladder, while the control dogs had no stones. Macroscopically the gallstones were similar to black pigment stones observed in humans. Chemical analysis and Fourier transform-infrared spectroscopy examination revealed that the stones were composed mainly of sodium bilirubinate and proteins, with minor amounts of calcium salts and cholesterol. Significant increases in biliary pH and concentrations of ionized calcium and unconjugated bilirubin were observed in the gallbladder bile of the colectomy group compared with that of the control group. The total bile acid and total bilirubin concentrations were significantly decreased in the colectomy group. Cholesterol crystal nucleation did not occur. The inhibitory effect of gallbladder bile on calcium carbonate precipitation in an in vitro assay system was preserved even after colectomy. In conclusion, proctocolectomy increases the concentration of unconjugated bilirubin in gallbladder bile and induces pigment gallstones which are composed mainly of sodium bilirubinate and proteins since calcium ions and cholesterol are stabilized in dogs.     

Differential effects of 1-naphthaleneacetic acid, indole-3-acetic acid and 2,4-dichlorophenoxyacetic acid on the gravitropic response of roots in an auxin-resistant mutant of arabidopsis, aux1

BACKGROUND/AIMS: Gallbladder mucus itself has been recognized to play an important role in gallstone development. Despite the diverse mechanisms of stone induction and the differences in stone composition, there is a quantitative increase in the epithelial mucus production period before stone formation. As brown pigment stones are found frequently in gallstone disease, we conducted a study on gallbladders with brown pigment stones or combination stones with a brown periphery to evaluate the mucin content in the gallbladder epithelium in comparison to gallbladders with cholesterol stones and those without stones. METHODS: Gallbladder specimens were fixed in 10% formalin immediately after cholecystectomy and then embedded in paraffin. The specimens were sectioned for periodic acid-Schiff-alcian blue (PAS-AB, pH 2.5) double stain to evaluate the intra-epithelial mucin content. The PAS-AB index was calculated as a proportion of the PAS-AB-positive mucin area to the total epithelial area, using a computerized image analyzer. RESULTS: Evaluation of the PAS-AB index on the lining epithelia of gallbladders showed that it was 32.43 +/- 9.96% in gallbladders with brown stones, which is significantly (p < 0.001) higher than in gallbladders with cholesterol stones (15.63 +/- 6. 75%) and gallbladders without stones (9.55 +/- 4.77%). CONCLUSION: The results show that gallbladders with brown stones contain more abundant mucin than gallbladders with cholesterol stones or those without stones. They also suggest that the gallbladder epithelium per se might play a more important role in stone formation in those with brown stones than in those with cholesterol stones.     

Marked increase in plasma high-density-lipoprotein cholesterol after prolonged fasting during Ramadan

We evaluated the effect of the Ramadan fasting on plasma lipids and lipoproteins in normal individuals. Twenty-four healthy subjects were studied before the end of the Ramadan month (Ram) and for 1 mo thereafter. Plasma total cholesterol (TC), triglycerides, low-density-lipoprotein cholesterol (LDL-C), and very-low-density-lipoprotein cholesterol (VLDL-C) did not change. High-density-lipoprotein cholesterol (HDL-C) was 30% higher (P < 0.005) at the end of Ram; apolipoprotein A-I also increased (P < 0.0001). Both the ratios of TC to HDL-C and LDL-C to HDL-C (P < 0.001) decreased at Ram. There was a striking nonpharmacologic improvement in plasma HDL-C and ratios of TC to HDL-C and LDL-C to HDL-C, which were most probably induced by eating one large evening meal a day. Further studies to determine the mechanism of this observation are underway.     

Applying radiobiological principles to combined modality treatment of head and neck cancer--the time factor

Although gallbladder stasis exists in most patients with cholesterol gallstones, it is unknown whether stasis is a causative factor of gallstone disease or merely a consequence of it. We studied the impact of sustained gallbladder stasis induced by a cholecystokinin (CCK)-A receptor antagonist (MK-329) on gallstone formation in ground squirrels fed either a trace or a high-cholesterol diet. MK-329 markedly inhibited gallbladder contraction in vitro in response to CCK (at EC100, control: 3.6 +/- 0.5 vs. MK-329: 1.1 +/- 0.3 g; P < .05) and increased gallbladder fasting volume in vivo (control: 462 +/- 66 vs. MK-329: 1,004 +/- 121 microL; P < .05). Whereas the high-cholesterol diet alone (1%-cholesterol diet + placebo) increased the cholesterol saturation index (CSI) in control animals (trace-cholesterol diet + placebo), MK-329 significantly (P < .05) decreased the CSI in both hepatic and gallbladder bile in animals on the trace-(trace-cholesterol diet + MK-329) as well as on the high-cholesterol diets (1%-cholesterol diet + MK-329). The mucin content of the mucus layer on the epithelial surface of the gallbladder wall more than doubled (P < .05) with the high-cholesterol diet; adding MK-329 to the latter group produced a further 82% increase (P < .05). The cholesterol diet + MK-329 group had the highest (100%) incidence of cholesterol crystals that were evident in fresh gallbladder bile, coincident with a shortened nucleation time (2.5 +/- 0.6 days; P < .05 vs. the cholesterol diet + placebo group, 5.8 +/- 1.0 days or the other 2 groups, >21 days). Bile from animals on the trace-cholesterol diet, whether or not receiving MK-329, lacked crystals in bile and exhibited a normal nucleation time (>21 days). Thus, stasis per se may lower the CSI, but its detrimental effect on the gallbladder predominates locally, and so accelerates cholesterol crystal formation in this model.     

Solitary versus multiple gallstones: the importance of total biliary protein concentration and other factors

BACKGROUND: Nucleating and antinucleating factors play an important role in the pathogenesis of cholesterol crystal nucleation. PATIENTS AND METHODS: In 88 gallstone patients (59 female, 29 male) bile was examined for total biliary protein and glycoprotein concentration, nucleation time and cholesterol saturation index. Gallstone density was measured by in vivo computed tomography. RESULTS: Total biliary protein concentration was positively correlated with the number of gallstones (r = 0.84, p < 0.01) and higher in radiologically detectable isodense gallstones as compared to non-isodense stones (p < 0.01). A negative correlation between total biliary protein concentration, glycoprotein concentration and nucleation time was observed (r = -0.45, p < 0.01 and r = -0.49, p < 0.05). Nucleation time was significantly shorter in the case of multiple versus solitary stones (2.6 +/- 1.3 versus 8.5 +/- 3.0 days, p < 0.01). Cholesterol saturation index and biliary cholesterol concentration were similar in both cases, however a negative correlation between cholesterol saturation index and stone density (r = -0.79, p < 0.01) was found. No correlation was found between cholesterol saturation index and nucleation time (r = -0.04, p > 0.1), independent of gallstone number. None of the examined parameters was related to sex, age, weight or gallbladder function. CONCLUSIONS: Multiple gallbladder stones seem to be associated with shorter nucleation time and higher biliary concentrations of total protein and glycoprotein than solitary stones.     

Knowledge of good clinical practice among Danish physicians. A questionnaire study among hospital-employed physicians in the Copenhagen area

Differences in cord serum low density lipoprotein (LDL) composition between male and female neonates with normal or high (> or = 100 mg/dl or > or = 2.59 mmol/l) serum cholesterol levels were studied in 548 full-term newborn infants of the Toledo Study (Spain), where the absence of known perinatal factors that would alter lipid levels in cord blood was confirmed. The percentage of females with a high serum total cholesterol (TC) level was higher (p < 0.02) than that of males. ANOVA two-way analysis shows significant interaction of gender and cholesterol level upon LDL-cholesterol, triglycerides and LDL-cholesterol/Apoprotein (Apo) B ratio. However, Apo B was higher in those neonates, both male and female, with high cholesterol levels. The LDL fraction carried about 55% of TC in females with high TC levels (HF), whereas it transported just 40% in males with high TC levels (HM). LDL appeared more enriched in cholesterol than in Apo B in HF than in HM (p < 0.01). An increased level of small LDL particles should be associated with the higher triglyceride level found amongst HM. Results in LDL composition suggest that metabolic gender-related differences in infants with normal or high TC are presented at birth.     

Clinical characteristics and coronary risk factors of patients with low concentrations of serum low-density lipoprotein cholesterol and total cholesterol

We investigated the clinical characteristics and coronary risk factors of Chinese patients with suspected coronary artery disease (CAD) having low serum concentrations of both low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). Of 1,450 patients with suspected CAD (age range, 30-92 years; 948 men and 502 women), 760 had established CAD. The patients were divided into three groups according to lipid profile patterns. Group 1 patients (n = 138) had low LDL-C concentrations (< 100 mg/dL) and low TC concentrations (< 160 mg/dL). They were characterized by lower triglyceride concentrations, lower frequencies of high TC/high-density lipoprotein cholesterol (HDL-C) ratios (> 5) and LDL-C/HDL-C ratios (> 5), and lower frequencies of a family history of CAD and obesity. Group 3 patients (n = 610) had LDL-C concentrations of 130 mg/dL or above and TC concentrations of 200 mg/dL or above, much higher than in group 1. The prevalence of CAD was 41.3% (57/138) in group 1. 46.7% (328/702) in group 2, and 61.5% (375/610) in group 3. Groups with higher TC and LDL-C concentrations had a higher CAD prevalence. Coronary risk factors of group 1 patients appeared to be low HDL-C concentration, high TC/HDL-C ratio, advanced age, cigarette smoking, hypertension, and diabetes mellitus. Among these risk factors, HDL-C and hypertension were independent predictors of CAD. Unlike in the other two groups, hypertension was the only independent nonlipid risk factor. We conclude that in therapy or prevention of CAD, the goals should be to reduce LDL-C concentration to below 100 mg/dL and the TC concentration to below 160 mg/dL. However, other risk factors should also be considered.     

Cholesterol absorption and synthesis related to low density lipoprotein metabolism during varying cholesterol intake in men with different apoE phenotypes

The aim of the present study was, first, to investigate whether cholesterol (C) absorption, enhanced by cholesterol feeding, was related to synthesis of cholesterol, serum level of low density lipoprotein (LDL)-C, and receptor activity for LDL apolipoprotein (apo) B in healthy men. Secondly, we were interested in whether apolipoprotein E (apoE) phenotypes contributed to cholesterol and LDL apoB metabolism under these conditions. We studied 29 home-living men aged 55 +/- 1 (mean +/- SE) years on a low-fat, low cholesterol (208 +/- 13 mg/day) diet followed by a low-fat high cholesterol (878 +/- 38 mg/day) diet during 5 weeks. Cholesterol feeding increased total cholesterol, LDL-C, high density lipoprotein (HDL)-C, and LDL apoB levels from 10% to 13% (P less than 0.05) and bile acid production and cholesterol turnover by 16% (P less than 0.05), decreased the fractional catabolic rate (FCR) for LDL apoB by 10% (P less than 0.05) and cholesterol absorption efficiency by 8% (P less than 0.05), while cholesterol synthesis only tended to decrease. During the cholesterol feeding, LDL-C was positively related to apoB production rate and cholesterol absorption efficiency (P less than 0.05), and negatively related to bile acid and cholesterol synthesis (P less than 0.05) and FCR for LDL apoB, which, in turn, was negatively related to cholesterol absorption efficiency and positively to bile acid synthesis. ApoE phenotype was positively related to TC, LDL-C, and LDL apoB levels and negatively to FCR for LDL apoB. The increase of the LDL-C level by the high cholesterol intake was positively correlated with LDL-C on high cholesterol diet and apoE phenotypes, so that the increase was 7% in apoE2 (ns), 11% in apoE3 (P less than 0.05), and 18% in apoE4 (P less than 0.05); the increase of bile acid synthesis was significant only in subjects with apoE2. Moreover, the increase of LDL-C was positively related to the absolute amount of dietary cholesterol absorbed and negatively to FCR for LDL apoB. The findings suggest that the higher the LDL-C level, the higher is the absorption efficiency of cholesterol and production of LDL apoB, and the lower is the removal of LDL apoB and synthesis of both bile acids and cholesterol, and the more frequently the subjects had epsilon 4 allele. The nonresponsiveness to dietary cholesterol was dependent on low LDL-C level, apoE2 phenotype, and effective bile acid synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of fluvastatin, a new inhibitor of HMG-CoA reductase, and niceritrol on serum lipids, lipoproteins and cholesterol ester transfer activity in primary hypercholesterolemic patients

Effects of a combination therapy of fluvastatin, a new inhibitor of HMG-CoA reductase, and niceritrol on lipid metabolism were investigated measuring a wide range of parameters in 42 patients with primary hypercholesterolemia. After a wash-out period patients were randomly allocated to 1 of the 2 groups, the fluvastatin-preceding group (G-1) and the niceritrol-preceding group (G-2). In G-1 fluvastatin monotherapy (30 mg/day) significantly decreased total cholesterol (TC) and LDL-cholesterol (LDL-C). There was no significant change in HDL-cholesterol (HDL-C), triglyceride (TG) and lipoprotein (a) (Lp(a)). Further effect in HDL-C and TG was observed after the addition of niceritrol (750 mg/day). On the other hand, in G-2, while niceritrol alone (750 mg/day) produced no significant change in TC, LDL-C, HDL-C, TG and Lp(a), the addition of fluvastatin (30 mg/day) reduced TC and LDL-C levels significantly. Cholesterol ester transfer (CET) activity was significantly reduced by niceritrol monotherapy. After the concomitant use of the 2 drugs CET activity was significantly reduced only in G-2. No significant change in lipoprotein lipase and hepatic triglyceride lipase activities were observed in the 2 groups at either point in time. No serious adverse effect was observed in this study. It is concluded that fluvastatin is an effective drug for lowering LDL-cholesterol and causes no adverse alteration in lipid metabolism. Combination with niceritrol at a dose of 750 mg/day dose not appear to augment or attenuate beneficial effects of fluvastatin.     

Cholelithiasis in Taiwan. Gallstone characteristics, surgical incidence, bile lipid composition, and role of beta-glucuronidase

The nature and occurrence of gallstones in Taiwan and their etiologic factors might not be the same as in Western countries and warranted a systematic investigation. Gallbladder biles and gallstones were obtained at surgery from 100 and 74 patients, respectively. Common duct bile and stones were either drained through an indwelling common duct T-tube or aspirated through a nasobiliary catheter in 108 patients. Gallstones were analyzed for bilirubin, cholesterol, bile acid, calcium, and residue, and biles for bile acid, cholesterol, phospholipid, bilirubin, and beta-glucuronidase. There were four major kinds of gallstones in Taiwan: cholesterol/mixed stones, high-residue black formed pigment stones, low-residue brown formed pigment stones, and muddy pigment stones. The surgical incidence of all types of stones increased steadily during the past four decades. During the past 15 years the relative frequencies for mixed, formed pigment, and muddy pigment stones had been roughly 40, 40, and 20%, respectively, with a further increase in the mixed stones and a decrease in the muddy pigment stones in recent years. Improvement of nutritional status and living standards might contribute to such changes. Cholesterol content in the common duct and gallbladder biles was higher in the mixed stone group than in other groups. Bacterial beta-glucuronidase activity was detected in 53% of patients with muddy pigment stones. Endogenous beta-glucuronidase activity and concentration were also highest in this group, intermediate in the formed pigment and mixed stone group, and lowest in the control. We concluded that hypercholesterobilia was responsible for increasing incidence of mixed stones during the past two decades, while both bacterial and human beta-glucuronidase might contribute to pigment cholelithiasis.     

The ability of bile to scavenge superoxide radicals and pigment gallstone formation in guinea pigs

After partial ligation of the common bile duct (CBD) of guinea pigs, 14 of 16 animals developed pigment gallstones within one week (S group). Intraperitoneal injection of Vit. E and C, each 10 mg/kg daily from 3 days before CBD ligation to one week after the operation (S+V group), decreased the gallstone incidence to 5/14 (exact probability < 0.01). The gallstone incidence in the control group, that only received laparotomy without ligation of the CBD, was 0/15. Biochemical analysis of the gallbladder bile showed that stricture of the CBD was associated with a significant increase in levels of unconjugated bilirubin (UCB) and Ca2+ (p < 0.05 and < 0.01). Simultaneously the scavenging rate (SR) of superoxide radical in bile significantly decreased (p < 0.05). Comparing S+V group with S group, the effect of Vit. E and C on the concentrations of UCB and Ca2+ in bile was not significant (both p > 0.05), but Vit. E and C normalized the SR, and the difference between S group and S+V group was significant (p < 0.05). These results suggested that Vit. E and C, known as antioxidants, enhanced the ability to scavenge oxygen radical in S+V group; and that in addition to the increases of UCB and Ca2+ concentrations, the participation of oxygen radicals might be of importance for pigment gallstone formation induced by bile duct obstruction.