Reduced plasma cholesterol and increased fecal sterol loss in multidrug resistance gene 2 P-glycoprotein-deficient mice.

Voshol PJ, Havinga R, Wolters H, Ottenhoff R, Princen HM, Oude Elferink RP, Groen AK, Kuipers F.

Groningen Institute for Drug Studies, Laboratory of Nutrition and Metabolism, University Hospital Groningen, Groningen, The Netherlands. p.j.voshol med.rug.nl

BACKGROUND & AIMS: mdr2 P-glycoprotein (Pgp) deficiency in mice leads to the absence of biliary phospholipids and cholesterol in the presence of normal bile salt secretion. The aim of this study was to evaluate the importance of the biliary pathway in cholesterol homeostasis by determining the effects of mdr2 Pgp deficiency on hepatic and plasma lipid levels and cholesterol kinetics in chow-fed mice. METHODS: Hepatic lipid content, enzyme activities, plasma lipoprotein levels, and fecal sterol excretion were measured in wild-type (+/+) and mdr2 Pgp-deficient (-/-) mice. Cholesterol kinetics were determined using radiotracer techniques. RESULTS: No differences in hepatic lipid content were observed between (-/-) and (+/+) mice. Plasma high-density lipoprotein cholesterol and apolipoprotein A-I levels were strongly reduced in (-/-) mice compared with controls, whereas the apolipoprotein B contents of very-low-density lipoprotein and low-density lipoprotein were increased. Hepatic activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase was threefold greater in (-/-) mice than in controls; however, compartmental analysis of plasma cholesterol decay showed no differences in cholesterol synthesis between (-/-) and (+/+) mice. A dual isotope approach for estimating cholesterol absorption yielded approximately 50% lower values in (-/-) mice than in controls. Surprisingly, (-/-) mice showed a fourfold increase in fecal neutral sterol secretion. CONCLUSIONS: This study unequivocally establishes the important direct role of biliary lipids in the regulation of plasma lipid levels in mice.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9558293&dopt=Abstract cholesterol




Lysine: arginine ratio of a protein influences cholesterol metabolism. Part 1--Studies on sesame protein having low lysine: arginine ratio.

Rajamohan T, Kurup PA.

Department of Biochemistry, University of Kerala Kariavattom, Thiruvananthapuram, India.

The effect of globulin fraction with a lysine: arginine (lys:arg) ratio 0.67, isolated from sesame (Sesamum Indicum) seeds on cholesterol metabolism was studied in rats fed cholesterol free and cholesterol containing diet and compared with casein (lys:arg ratio-2.0). Rats fed sesame seed globulin showed significantly lower concentrations of cholesterol in the serum and aorta. The decrease in serum was manifested in both HDL and LDL + VLDL fractions. There was increased cholesterogenesis in the liver as was evident from increased incorporation of labeled acetate into cholesterol and increased activity of 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Increased hepatic diversion of cholesterol to bile acid synthesis and increased fecal excretion of bile acids and sterols were also observed in rats fed sesame seed globulins. Rats fed sesame globulins also showed significantly higher activity of lipoprotein lipase in the heart and adipose tissue and that of plasma Lecithin: cholesterol acyltransferase (LCAT). These studies suggest that low lysine: arginine ratios of a protein exert hypocholesterolemic effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9567754&dopt=Abstract cholesterol




Low serum cholesterol levels predict high perioperative mortality in patients supported by a left-ventricular assist system.

Richartz BM, Radovancevic B, Frazier OH, Vaughn WK, Taegtmeyer H.

St. Luke's Episcopal Hospital, Texas Heart Institute, and Department of Internal Medicine, University of Texas-Houston Medical School, 77030, USA.

BACKGROUND: Although the use of a left-ventricular assist system (LVAS) provides circulatory support for end-stage heart failure patients awaiting heart transplantation, this procedure is accompanied by a relatively high perioperative mortality. The aim of this retrospective study was to identify those patients preoperatively which have the highest perioperative mortality. METHODS AND RESULTS: Forty-five consecutive patients undergoing LVAS implantation were evaluated for preoperative risk factors, including body mass index, hemodynamic data, and blood chemistry studies by multivariate analysis. They were divided into (1) patients who were successfully transplanted (n = 25) and (2) patients who died before transplantation (n = 20). The nonsurvivors were subclassified into patients who died within 14 days after surgery (n = 11) and patients who died after 2 weeks of device implantation (n = 9). Hemodynamic parameters were the same in both groups, but total cholesterol was significantly lower in the nonsurvivors than in the survivors (90 +/- 7 vs. 144 +/- 8 mg/dl, respectively, p < 0.0001). The sensitivity of predicting perioperative death with a serum cholesterol below 100 mg/dl was 100%, the specificity of predicting survival with a serum cholesterol above 120 mg/dl was 87%. CONCLUSION: In this small retrospective study, there was a correlation between total cholesterol levels and survival of patients with advanced heart failure on mechanical support. A cholesterol level below 100 mg/dl was accompanied by a high perioperative mortality. In contrast, a cholesterol level above 120 mg/dl was accompanied by a 87% chance of survival. The results suggest a predictive value of cholesterol which is independent of the hemodynamic status.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9570432&dopt=Abstract cholesterol




Lipid-protein complexes as cholesterol pronucleating agents in human bile.

Mala I, Zikova J, Spundova M, Marecek Z, Entlicher G.

Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.

Among the various substances which accelerate the formation of cholesterol crystals in cholesterol supersaturated bile are proteins obtained from the bile by affinity chromatography on con A-Sepharose. Several such con A binding proteins have been identified and shown to mediate acceleration of cholesterol crystal formation in vitro. However, the major protein fraction, which does not bind con A, has been studied rarely. Investigation of the effect of this latter bile protein fraction on cholesterol crystallization is the aim of this study. Contrary to results published to date, the con A nonbinding protein fraction exerted a higher cholesterol crystallization promoting activity than the con A binding fraction. Delipidation as well as proteolytic degradation sharply decreased the activity of both fractions. Albumin was identified as the main component of the con A nonbinding fraction. A lipid-protein complex formed from the lipid and albumin possessed a very high cholesterol crystallization promoting activity whereas albumin or the lipid alone showed much lower activity. Bivalent ions, especially Mn2+ and Ca2+, increased the promoting activity of the lipid-protein complex. Thus, albumin and other bile protein can bind noncovalently biliary lipid material and such lipid-protein complexes may act as the main cholesterol crystallization promoter in the human bile.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9608679&dopt=Abstract cholesterol




Dietary isoflavones reduce plasma cholesterol and atherosclerosis in C57BL/6 mice but not LDL receptor-deficient mice.

Kirk EA, Sutherland P, Wang SA, Chait A, LeBoeuf RC.

Department of Medicine and the Nutritional Sciences Program, University of Washington, Seattle, WA 98195, USA.

Susceptibility to atherosclerosis is determined by a combination of genetic and environmental factors, including diet. Consumption of diets rich in soy protein has been claimed to protect against the development of atherosclerosis. Potential mechanisms include cholesterol lowering, inhibition of lipoprotein oxidation and inhibition of cell proliferation by soy proteins or isoflavones, such as genistein, that are present in soy. This study was designed to determine whether soy isoflavones confer protection against atherosclerosis in mice and whether they reduce serum cholesterol levels and lipoprotein oxidation. C57BL/6 and LDL receptor-deficient (LDLr-null) mice were fed soy protein-based, high fat diets with isoflavones present (IF+, 20.85 g/100 g protein, 0.027 g/100 g genistein, 0.009 g/100 g daidzein) or diets from which isoflavones, and possibly other components, had been extracted (IF-, 20.0 g/100 g protein, 0.002 g/100 g genistein, 0.001 g/100 g daidzein). Because LDLr-null mice develop extensive atherosclerosis and hypercholesterolemia after minimal time on a high fat diet, they were fed the diets for 6 wk, whereas C57BL/6 mice were fed the diets for 10 wk. Plasma cholesterol levels did not differ between LDLr-null mice fed IF- and those fed IF+, but were 30% lower in C57BL/6 mice fed the IF+ diet than in those fed the IF- diet. Susceptibility of LDL to oxidative modification, measured as the lag phase of conjugated diene formation in LDLr-null mice, was not altered by isoflavone consumption. All LDLr-null mice developed atherosclerosis, and the presence or deficiency of dietary isoflavones did not influence atherosclerotic lesion area. In contrast, atherosclerotic lesion area was significantly reduced in C57BL/6 mice fed IF+ compared with those fed IF-. Thus, this study demonstrates that although the isoflavone-containing diet resulted in a reduction in cholesterol levels in C57BL/6 mice, it had no effect on cholesterol levels or on susceptibility of LDL to oxidative modification in LDLr-null mice. Further, dietary isoflavones did not protect against the development of atherosclerosis in LDLr-null mice but did decrease atherosclerosis in C57BL/6 mice. These findings suggest that soy isoflavones might lower cholesterol levels by increasing LDL receptor activity, and the reduction in cholesterol may offer some protection against atherosclerosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9614153&dopt=Abstract cholesterol




Dietary polyenylphosphatidylcholine decreases cholesterolemia in hypercholesterolemic rabbits: role of the hepato-biliary axis.

Polichetti E, Janisson A, de la Porte PL, Portugal H, Leonardi J, Luna A, La Droitte P, Chanussot F.

INSERM U. 476, Marseille, France.

The aim of this work was to study the cholesterol-lowering mechanisms induced by dietary soybean lecithin in hypercholesterolemic rabbits. Male New Zealand white rabbits (n = 6 in each group) were fed for 10 weeks either a low-fat control C diet, containing 27 g fat/kg, or high-fat diets enriched with 2 g cholesterol/kg and 77 g fat/kg. The high-fat diets contained 50 g lard (L), 50 g soybean triacylglycerol (SO), or 50 g pure soybean phosphatidylcholine (PLE). PLE diet decreased by 30% beta-VLDL-cholesterol, compared with SO diet. HDL2-, HDL3- and LDL-lipid contents were unchanged in the L, SO and PLE groups. In gallbladder bile, amounts of phospholipids, bile salts and cholesterol were significantly increased in PLE group by respectively 45%, 11% and 44%, in comparison with SO group. Intestinal and hepatic Hydroxy Methyl Glutaryl Coenzyme A reductase activities were not increased by PLE diet. Triacylglycerol hepatic content was lower in PLE group than in L or SO groups. Compared with triacylglycerol enriched diet, phosphatidylcholine enriched diet developed significant higher cholesterol- and triacylglycerol-lowering effects by a two-step mechanism: i) by reducing the beta-VLDLs, ii) by enhancing the secretion of bile cholesterol. Such results constitute promising effects of soybean phosphatidylcholine at the hepato-biliary level, in the treatment or prevention of hyperlipidemia and related atherosclerosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11104358&dopt=Abstract cholesterol




Cholesterol crystallization in human gallbladder bile: relation to gallstone number, bile composition, and apolipoprotein E4 isoform.

Van Erpecum KJ, Van Berge-henegouwen GP, Eckhardt ER, Portincasa P, Van De Heijning BJ, Dallinga-Thie GM, Groen AK.

Department of Gastroenterology, University Hospital Utrecht, The Netherlands.

Patients with multiple cholesterol gallstones are at increased risk of recurrence after nonsurgical therapy, possibly because of fast biliary cholesterol crystallization. Serum apolipoprotein E4 (apo E4) is a risk factor for primary cholesterol gallstone formation as well as recurrence. We examined potential effects of stone number and apolipoprotein E genotype on crystallization and on various crystallization-influencing factors in gallbladder biles of 36 cholesterol stone patients (25 multiple stones: 10 carrying the epsilon4 allele). Biliary cholesterol saturation, bile salt composition or concentrations of total protein, immunoglobulin (Ig)A, IgG, alpha1-acid glycoprotein, haptoglobin, or mucin--all crystallization promoters--did not differ between multiple and solitary stone patients, apparently not explaining different speed of crystallization (crystal observation time 3.5 +/- 0.6 days vs. 12.7 +/- 2.4 days, respectively; P = .0003). In contrast, biliary aminopeptidase-N activities (2,607 +/- 592 mU/mL vs. 947 +/- 185 mU/mL; P = .04) were higher and IgM levels (179 +/- 39 vs. 65 +/- 8 mg/L; P = .09) tended to be higher in the case of multiple stones. Although patients carrying the epsilon4 allele had similar stone numbers and crystallization as patients without the epsilon4 allele, their cholesterol saturation index (CSI) was lower (1.08 +/- 0.09 vs. 1.54 +/- 0.13; P = .01), whereas total protein and bile salt concentrations tended to be higher with preferential taurine-conjugation. In conclusion, fast cholesterol crystallization is associated with multiple stones but not with apolipoprotein E4. Whereas fast crystallization may contribute to high recurrence rates after nonsurgical therapy in case of multiple gallstones, the mechanism for increased risk of gallstone formation in patients carrying the epsilon4 allele remains unknown.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9620320&dopt=Abstract cholesterol




Inflammatory cytokines and the possible immunological role for lipoproteins in chronic heart failure.

Rauchhaus M, Koloczek V, Volk H, Kemp M, Niebauer J, Francis DP, Coats AJ, Anker SD.

Department of Clinical Cardiology, Imperial College School of Medicine at the National Heart and Lung Institute, London, UK. mathias.rachhaus medizin.uni-halle.de

AIMS: We studied the clinical and immunological importance of fasting cholesterol, HDL, LDL and triglycerides in patients with chronic heart failure in relation to plasma concentrations of tumor necrosis factor-alpha (TNFalpha), soluble TNF receptor-1 and -2 (sTNF-R1 and -R2), and a ratio potentially indicating recent endotoxin bioactivity (soluble [s] CD14/total cholesterol). METHODS AND RESULTS: Fifty-eight stable, non-oedematous patients with established heart failure and 19 controls were studied prospectively. Concentrations of sTNF-R1 and sCD14 were higher in patients than in controls (1238+/-96 vs. 632+/-72 pg/ml, P=0.005 and 3401+/-120 vs. 2775+/-139 pg/ml, P=0.007, respectively), whereas those of TNFalpha (9.3+/-1.1 vs. 6.7+/-0.6 pg/ml) and sTNF-R2 (2464+/-145 vs. 1920+/-303 pg/ml) were not. Cholesterol (5.6+/-0.1 vs. 5.5+/-0.2 mmol/l) and LDL (3.5+/-0.1 vs. 3.6+/-0.2 mmol/l) were not different (both P>0.75). Patients had lower HDL (1.10+/-0.04 vs. 1.4+/-0.06 mmol/l, P=0.0004) and higher triglycerides (2.1+/-0.1 vs. 1.1+/-0.1 mmol/l, P=0.0006). Aetiology and the presence of cardiac cachexia did not influence the lipid profile. Correlations in patients: cholesterol vs. TNFalpha (r=-0.40, P=0.003), vs. sTNF-R1 (r=-0.24, P=0.08), vs. sTNF-R2 (r=-0.29, P<0.04); sCD14 vs. TNFalpha (r=0.44, P=0.005), vs. sTNF-R1: (r=0.65, P<0.0001), vs. sTNF-R2 (r=0.59, P<0. 0001). The sCD14/cholesterol ratio related powerfully to TNFalpha (r=0.60), sTNF-R1 (r=0.74), and sTNF-R2 (r=0.65, all P<0.0001). This sCD14/cholesterol ratio emerged as the strongest predictor of TNFalpha, sTNF-R1 and -R2 (all P<0.01), independently of renal and hepatic function, and conventional measures of disease severity. A cholesterol level <5.2 mmol/l (n=18) significantly predicted a poor clinical outcome (P<0.04, RR 3.5, 95% CI 1.1-11.0) independently of peak VO(2) (P=0.07), NYHA class (P=0.08), aetiology (P=0.14), and age, body wasting, sodium, LVEF, heart rate, and blood pressure (all P>0.20, follow-up 12 months, event rate 26%). CONCLUSION: Our data supports previous findings that lower, rather than higher cholesterol levels are associated with poor clinical outcome in patients with chronic heart failure. This relationship is unrelated to heart failure aetiology, and suggests that the classic risk profile is not longer relevant in established heart failure. The little-recognised ability of all lipoprotein fractions to bind endotoxin and to serve as natural buffer substances may explain this relationship between lower lipoprotein levels, higher cytokine concentrations and impaired prognosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11104867&dopt=Abstract cholesterol




Individuals with high total cholesterol/HDL cholesterol ratios are insulin resistant.

Jeppesen J, Facchini FS, Reaven GM.

The Department of Medicine, Stanford University School of Medicine, CA, USA.

OBJECTIVES: To define the pathophysiologic characteristics of patients at high risk for coronary heart disease due to an increased ratio of total cholesterol (TC) to high density lipoprotein-cholesterol (HDL-C). DESIGN: Cross-sectional. SETTING: Clinical Research Center. SUBJECTS: One hundred-20 healthy, non-diabetic, normotensive, volunteers were screened for this study. From this pool, 40 individuals (20 females and 20 males) with the highest and the lowest TC/HDL-C ratios were selected for comparison. MAIN OUTCOME MEASURES: Values for body mass index (BMI), ratio of waist to hip girth (WHR), and blood pressure were obtained on all patients. In addition, measurements were made of fasting lipid and lipoprotein concentrations, plasma glucose and insulin responses to an oral glucose challenge, and insulin resistance as assessed by the insulin suppression test. RESULTS: Age, BMI, and WHR were the same in the two groups. However, the group with a high TC/HDL-C ratio had higher (P < 0.05) systolic and diastolic blood pressures. In addition, patients with a high TC/HDL-C ratio had significantly higher (P < 0.001) very low density (VLDL) and low density lipoprotein (LDL)-cholesterol concentrations and lower HDL-cholesterol concentrations, with significant (P < 0.001) correlations between the TC/HDL-C ratio and VLDL (r = 0.60), LDL (r = 0.54), and HDL (r = -0.73) cholesterol concentrations. Patients with a high TC/HDL-C ratio were also significantly (P < 0.05-0.001) more insulin resistant, glucose intolerant with a greater plasma insulin response to oral glucose, and hypertriglyceridemic. CONCLUSIONS: The results indicate that an increase in LDL-cholesterol concentration is not necessarily the major contributor to a high ratio of TC/HDL-C. Furthermore, individuals with this epidemiologic designation are insulin resistant, and liable to all the other abnormalities associated with this metabolic defect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9627143&dopt=Abstract cholesterol