Soluble dietary fiber protects against cholesterol gallstone formation.

Schwesinger WH, Kurtin WE, Page CP, Stewart RM, Johnson R.

Department of Surgery, University of Texas Health Science Center at San Antonio, 78284-7842, USA.

BACKGROUND: Epidemiological studies have suggested that soluble dietary fibers are hypocholesterolemic and may inhibit cholelithiasis. METHODS: Thirty prairie dogs were placed on a cholesterol-supplemented lithogenic diet. Ten animals received 5% psyllium (PSY) and 10 animals received 5% cellulose. After 6 weeks all gallbladders were inspected for stones; blood and bile were collected for analysis. RESULTS: Cholesterol stones were present in 8 of 10 of the control animals, in 6 of 10 of the cellulose group, and 3 of 10 of the PSY animals (P <0.05). Concentrations of cholesterol and chenodeoxycholic acid (CDCA) were significantly lower in the PSY group compared with controls (0.49 versus 0.88 mM and 4.2 versus 9.2 mM, respectively) leading to a significant reduction in the cholesterol saturation index (0.62 versus 1.2). CONCLUSIONS: A dietary soluble fiber (PSY) inhibits cholesterol stone formation by reducing the biliary cholesterol saturation index. This protective effect is associated with a selective decrease in biliary cholesterol and CDCA.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10326849&dopt=Abstract cholesterol




Oxidative stress during acute respiratory exacerbations in cystic fibrosis.

McGrath LT, Mallon P, Dowey L, Silke B, McClean E, McDonnell M, Devine A, Copeland S, Elborn S.

Department of Therapeutics and Pharmacology, The Queen's University of Belfast, Belfast BT9 7BL, UK.

BACKGROUND: Patients with cystic fibrosis experience chronic systemic oxidative stress. This is coupled with chronic inflammation of the lung involving bronchial polymorphonuclear neutrophil accumulation and activation. We hypothesised that, during periods of acute respiratory exacerbation, free radical activity and consequent damage would be most marked and that intensive treatment of the infection would result in improvement towards values found during stable periods. METHODS: Plasma and red blood cells were collected from 12 healthy normal volunteers and from 12 patients with cystic fibrosis with an acute respiratory exacerbation (increased respiratory symptoms, reduction in forced expiratory volume in one second (FEV1) of more than 10%, and a decision to treat with intravenous antibiotics). Further samples were collected from patients following two weeks of treatment. Samples were analysed for inflammatory markers, markers of free radical damage, and aqueous and lipid phase scavengers. RESULTS: During respiratory exacerbations FEV1 and forced vital capacity (FVC) were lower than in controls (mean differences -2.82 (95% CI -2.12 to -3.52) and -3. 79 (-3.03 to -4.55) l, respectively) but improved following treatment (mean change 0.29 (95% CI 0.18 to 0.40) and 0.33 (0.23 to 0.43) l, respectively). Inflammatory markers during exacerbations were significantly higher in patients than in controls with the following mean (95% CI) differences: C reactive protein (CRP), 46 (17 to 75) g/l; neutrophil elastase alpha1-antiprotease complexes (NEAPC), 4.4 (1.77 to 7.07) mg/l; white cell count (WCC), 5.3 (4.7 to 5.9) x 10(9)/l. These markers decreased significantly following treatment with the following mean (95% CI) changes: CRP -26 (-10 to -42) g/l; NEAPC -3.1 (-1.3 to -4.9) mg/l; WCC -1.5 (-1.3 to -1.7) x 10(9)/l. Malondialdehyde (MDA) as a marker of free radical activity was significantly higher in patients during exacerbations than in controls with a mean (95% CI) difference of 193 (107 to 279) which improved with treatment (mean change -56 (95% CI -28 to -84) nmol/mmol cholesterol). Red blood cell polyunsaturated fatty acids were significantly lower in patients than in controls with a mean difference of -4.4(95% CI -2.6 to -6.2) moles percent, but did not improve significantly after treatment. Protein carbonyls during exacerbations were not different from controls but did increase with treatment compared with levels during the exacerbation (mean change 0.39 (95% CI 0.11 to 0.67) micromol/g protein). Aqueous and lipid phase scavengers in patients during exacerbations were significantly lower than in controls with the following mean (95% CI) differences: ascorbate, -19.0 (-2.7 to -35.3) micromol/l; sulphydryls, -122 (-77 to -167) micromol/l; retinol, -237 (-47 to -427) nmol/mmol cholesterol; beta-carotene, -52.8 (-11.8 to -93.8) nmol/mmol cholesterol; luteine, -50.4 (-10.4 to -90.4) nmol/mmol cholesterol; lycopene, -90.1 (-30.1 to -150.1) nmol/mmol cholesterol. Treatment resulted in improvement with the following mean (95% CI) changes: sulphydryls, 50 (32 to 68) micromol/l; retinol, 152 (47 to 257) nmol/mmol cholesterol; alpha- and beta-carotene, 0.6 (0.0 to 1.2) and 7.6 (0.0 to 15.2) nmol/mmol cholesterol, respectively; alpha-tocopherol, 839 (283 to 1405) nmol/mmol cholesterol; and lycopene, 8.2 (0.0 to 16.2) nmol/mmol cholesterol. CONCLUSIONS: Abnormalities of markers of inflammation, free radical activity, and radical scavengers were significantly more extreme during acute respiratory exacerbations and showed improvement with treatment. The need to provide protection from inflammation and free radical damage should therefore be dynamic and related to the inflammatory and oxidative processes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10335006&dopt=Abstract cholesterol




[Serum lipids and blood pressure levels in the +Mapuche population living in the Chilean region of Araucania]

[Article in Spanish]

Stockins B, Larenas G, Charles M, Standen D, Espinoza O, Illesca M, Opazo JA, Carrasco B, Lanas F, Davis M.

Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Frontera, Temuco.

BACKGROUND: Chilean aboriginal populations (Mapuche) predominantly live in the region of Araucania, in the southern part of the country. Their cardiovascular risk factors have not been systematically assessed. AIM: To study the prevalence of cardiovascular risk factors in the Mapuche population. SUBJECTS AND METHODS: Blood pressure, weight, height, dietary habits, fasting serum total cholesterol, HDL cholesterol and triglycerides were measured in 1.948 adults living in 28 Mapuche communities. RESULTS: Thirteen percent of males and 16% of females had high blood pressure. Body mass index was 25.5 kg/m2 in males and 28.1 kg/m2 in females. Forty five percent of women and 24% of men were classified as obese. Mean serum total cholesterol was 186.7 +/- 9.6 mg/dl, HDL cholesterol was 58.7 +/- 30.7 mg/dl, total cholesterol/HDL cholesterol was 3.4 +/- 2 and triglycerides were 155.2 +/- 91.2 mg/dl. Twenty eight percent of males and 9.6% of females smoked. CONCLUSIONS: Mapuche individuals have higher levels of HDL cholesterol a better total cholesterol/HDL cholesterol ratio and lower frequency of smoking than non aboriginal Chileans subjects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10349171&dopt=Abstract cholesterol




A novel mutant, ApoA-I nichinan (Glu235-->0), is associated with low HDL cholesterol levels and decreased cholesterol efflux from cells.

Han H, Sasaki J, Matsunaga A, Hakamata H, Huang W, Ageta M, Taguchi T, Koga T, Kugi M, Horiuchi S, Arakawa K.

Department of Internal Medicine, School of Medicine, Fukuoka University, Japan.

A novel variant of apolipoprotein (apo) A-I associated with low high density lipoprotein (HDL) cholesterolemia has been identified in a Japanese family during screening for apoA-I variants by isoelectric focusing (IEF) gel analysis. ApoA-I (Glu235-->0) Nichinan was caused by a 3-bp deletion of nucleotides 1998 through 2000 in exon 4 of the apoA-I gene. Four subjects in the family were heterozygous carriers for this mutation; the mean plasma concentrations of apoA-I and HDL cholesterol of affected family members were 30% and 32% lower, respectively, than those of unaffected family members. There were no differences in the levels of very low density lipoprotein and low density lipoprotein cholesterol, triglycerides, and other apolipoproteins between the carriers and the noncarrier family members. In the proband, plasma lecithin:cholesterol acyltransferase activity was normal. Functional consequences of the mutation were examined by expressing the mutated and wild-type proapoA-I cDNAs in Escherichia coli. Cholesterol efflux to recombinant proapoA-I Nichinan from mouse peritoneal macrophages loaded with [3H]cholesterol-labeled acetylated low density lipoprotein was decreased by 54% when compared that of normal recombinant proapoA-I. In vivo turnover studies in normal rabbits demonstrated that the recombinant proapoA-I Nichinan was rapidly cleared (22% faster) compared with normal recombinant proapoA-I. We conclude that apoA-I (Glu235-->0) Nichinan induced a critical structural change in the carboxyl-terminal domain of apoA-I for cellular cholesterol efflux and increased the catabolism of apoA-I, resulting in low HDL cholesterol levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10364075&dopt=Abstract cholesterol




The pentaene macrolide antibiotic filipin prefers more rigid DPPC bilayers: a fluorescence pressure dependence study.

Castanho MA, Prieto M, Jameson DM.

Centro de Quimica Fisica Molecular, Complexo I, IST, P-1096, Lisboa Codex, Portugal. pcmcastanho popsrv.ist.utl.pt

Filipin is a pentaene macrolide antibiotic which was previously shown to incorporate more extensively into DPPC bilayers below the main phase transition temperature than above this temperature. This result was extremely unusual because drugs tend to be expelled from ordered gel phases. However, such results could not be safely attributed to the phase change of the bilayer itself because the temperature was changing concomitantly. In this work we changed the bilayer phase isothermally (53 degrees C) by hydrostatic pressure variation and discovered that filipin has a slightly more extensive incorporation in the pure DPPC gel phase (P>ca. 54.4 MPa): Kp,lc approximately 3x10(3) vs. Kp,gel approximately 6x10(3). The presence of sterols (45% molar ergosterol or cholesterol) caused an increase in the partition coefficients, regardless of pressure, ergosterol having a more pronounced effect (Kp approximately 2x10(4)-6x10(4)). Kp was pressure dependent in both cases, but mainly with cholesterol (Kp approximately 2x10(3)-2x10(4)). At variance with cholesterol, when ergosterol was used, no phase transition was detected. This difference cannot be due to a more extended uptake of filipin by cholesterol-containing membranes, and so must be due to specific interactions with cholesterol. In agreement with this finding, we discovered that filipin is more tightly packed (lower partial molar volume) in the cholesterol-rich phase than in the ergosterol-rich phase. Our results also point to a 2:1 DPPC:cholesterol stoichiometry in the cholesterol-rich phase (17% molar cholesterol). All partition coefficients were calculated from steady-state fluorescence anisotropy measurements.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10366665&dopt=Abstract cholesterol




Correlation between cholesterol esterification, MDR1 gene expression and rate of cell proliferation in CEM and MOLT4 cell lines.

Batetta B, Pani A, Putzolu M, Sanna F, Bonatesta R, Piras S, Spano O, Mulas MF, Dessi S.

Istituto di Patologia Sperimentale, Universita degli Studi di Cagliari, Italy.

A positive correlation between cholesterol esterification and growth rate potential was previously found in our laboratory during the growth of CEM and MOLT4 lymphoblastic cells. In the current study, we investigated whether the rates of cholesterol esters synthesis correlate with changes of acyl-CoAcholesterol acyltransferase (ACAT) mRNA levels and of other genes implied in cholesterol biosynthesis and uptake, such as 3-hydroxy-3-methylglutaryl-CoA (HMGCoA) reductase and low density lipoprotein (LDL) receptor. The results showed that the more rapid growing CEM cells had lower levels of expression of HMGCoA-reductase and LDL receptors compared to MOLT4. By contrast, ACAT mRNA levels were higher in CEM cells, further supporting the concept of a possible involvement of cholesterol esters in the regulation of cell growth and division. In this study, high levels of cholesterol esterification and of expression of ACAT gene were also associated with a markedly increased expression of multidrug resistance (MDR1) gene, suggesting that MDR1 activity might contribute to regulate the rate of cell growth and division by modulating intracellular cholesterol ester levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10371303&dopt=Abstract cholesterol




Relationship of human pancreatic cholesterol esterase gene structure with lipid phenotypes.

Aleman-Gomez JA, Colwell NS, Vyas K, Borecki I, Shonfeld G, Lange LG, Kumar VB.

Department of Medicine, Washington University Medical Center, St. Louis, Missouri, USA.

Pancreatic cholesterol esterase is one of the enzymes that plays a pivotal role in cholesterol absorption. Differences in the genotype of this enzyme could affect the susceptibility of individuals to dyslipidemia and/or cardiovascular disease. We undertook this study to investigate if any correlation exists between restriction fragment length polymorphism in the human pancreatic cholesterol esterase gene and serum lipid levels. DNA from 96 healthy adults was restricted with Stu I, Southern blotted, and probed with cDNA of human pancreatic cholesterol esterase. Results revealed six distinct patterns which were classified as A, B, C, D, E, and F which had a population frequency of 1%, 34.5%, 49%, 12.5%, 1% and 2% respectively. Correlation of the distribution of lipid and lipoprotein levels by pattern and sex revealed a significant interaction between pattern type and HDL (p=0.03) in the most common group (group C) for males. Male patients of pattern C tended to have a lower LDL cholesterol than non-pattern C males (p=0.07); in addition, 80% of all males in the study population with LDL cholesterol under 100 mg/dl were found in pattern C. Thus, the most common Stu I RFLP genotype is associated with a favorable lipid phenotype. This report shows an association between the human pancreatic cholesterol esterase genotype and serum lipid levels. Further analysis of a larger study group with Stu I and alternative polymorphic restriction enzymes is warranted, to confirm this biologically plausible result.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10374906&dopt=Abstract cholesterol




Plasma levels of 24S-hydroxycholesterol in patients with neurological diseases.

Bretillon L, Siden A, Wahlund LO, Lutjohann D, Minthon L, Crisby M, Hillert J, Groth CG, Diczfalusy U, Bjorkhem I.

Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, Huddinge, SE-141 86, Stockholm, Sweden.

The brain is the exclusive or almost exclusive site of formation of 24S-hydroxycholesterol and we have shown that the circulating level of 24S-hydroxycholesterol is dependent upon the relation between cerebral production and hepatic clearance. In the present work we determined plasma levels of 24S-hydroxycholesterol in patients with various neurological diseases. Eleven subjects with brain death occurring 6-10 h before collection of the plasma samples had markedly reduced circulating levels of 24S-hydroxycholesterol (-43%, P<0.001). Patients with advanced Alzheimer's disease and cerebral inflammatory diseases had slightly lower levels of 24S-hydroxycholesterol in plasma when compared to matched controls. Patients with acute ischemic stroke, multiple sclerosis and primary brain tumors had levels not significantly different from those of controls. The conditions leading to reduced plasma levels of 24S-hydroxycholesterol had no significant effect on plasma levels of another side-chain oxidized oxysterol, 27-hydroxycholesterol. Except for conditions characterized by very marked destruction of the central nervous system, different severe neurological diseases seem to have relatively small effects on the flux of 24S-hydroxycholesterol from the brain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11027840&dopt=Abstract cholesterol




Vitamin E status in patients with liver cirrhosis: normal or deficient?

Look MP, Reichel C, von Falkenhausen M, Hahn C, Stockinger K, von Bergmann K, Rao GS, Spengler U, Sauerbruch T.

Department of General Internal Medicine, University of Bonn, Germany.

The study aim was to compare the ratio of vitamin E to serum cholesterol with the serum vitamin E level alone as a measure of vitamin E status in patients with different degrees of liver dysfunction. Assessment of serum vitamin E and total serum cholesterol was performed in 85 patients with liver cirrhosis at Child's stage A (n = 26), B (n = 26), and C (n = 33) and 50 patients with noncirrhotic liver disease. As surrogate markers of liver function, 7alpha-hydroxycholesterol and prealbumin concentrations and the plasma prothrombin time were determined. Mean serum vitamin E concentrations in Child A, B, and C patients were 27.4%, 36.9%, and 37.3% lower, respectively, than in healthy controls (P<.01). Twelve of 26 Child A, 14 of 26 Child B, and 14 of 33 Child C patients had vitamin E deficiency with respect to the absolute values, i.e., serum levels less than 13.76 micromol/L (5% percentile of healthy controls). In contrast, only two of 26 Child A, five of 26 Child B, and five of 33 Child C patients (P<.01 for Child A/B and P<.05 for Child C) were vitamin E-deficient according to the serum vitamin E to cholesterol ratio, i.e., less than 2.86 micromol/mmol. Serum vitamin E was correlated significantly with prealbumin, 7alpha-hydroxycholesterol, and the plasma prothrombin time, but the vitamin E to cholesterol ratio was not. Correcting serum vitamin E for total serum cholesterol in patients with liver cirrhosis leads to the phenomenon of reduced serum vitamin E levels inadvertently shifted toward normal values. In patients with liver cirrhosis, the absolute vitamin E concentration correlates better with the typical clinical and biochemical findings of the disease than the vitamin E to cholesterol ratio. Therefore, a considerable number of patients with advanced liver cirrhosis might actually be vitamin E-deficient.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9920150&dopt=Abstract cholesterol