Bile acid metabolism in young-old parabiotic rats.

Uchida K, Takase H, Nomura Y, Satoh T, Igimi H, Takeuchi N.

Strategic Information Unit, Shionogi & Co., Ltd., Tokyo, Japan.

Serum cholesterol, triglyceride and phospholipid levels, liver cholesterol concentration, bile flow, biliary cholesterol, phospholipid and bile acid secretion rates, fecal sterol and bile acid levels and their bile acid compositions were examined in young-old parabiotic rats and compared with those in young and old control rats and young-young parabiotic rats. Bile acid composition was expressed in terms of the cholic acid group/chenodeoxycholic acid group (CA/CDCA) ratio. Body weight (BW) gain decreased after parabiosis especially in old rats, but the liver weight (g/100 g BW), diet-intake, feces dry weight, liver cholesterol concentration and fecal sterol level were almost the same in all the groups. The biliary bile acid secretion rate was higher and the fecal bile acid level was lower in old rats than those in young rats but both the levels became comparable with those in young rats after parabiosis of old rats with young rats. Young rats, however, showed no changes in these levels after parabiosis. The serum cholesterol level and the biliary and fecal CA/CDCA ratios in old rats were higher than those in young rats but decreased after parabiosis with young rats, although they were still higher than those in young rats. The serum cholesterol level in young rats increased after parabiosis with old rats, but not after parabiosis with young rats, and the fecal bile acid level and the CA/CDCA ratio were not changed in either case. It is concluded from these findings that the serum cholesterol level and the CA/CDCA ratio increased with age and that these increases were prevented after parabiosis with young rats while young rats, although their serum cholesterol level was increased, showed no increase in the CA/CDCA ratio after parabiosis with old rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9113626&dopt=Abstract cholesterol




Comparative hypocholesterolemic effects of capybara (Hydrochoerus hydrochaeris dabbenei) oil, horse oil, and sardine oil in cholesterol-fed rats.

Fukushima M, Takayama Y, Habaguchi T, Nakano M.

Department of Bioresource Chemistry, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido, Japan.

The hypocholesterolemic efficacy of various polyunsaturated fatty acids was compared in rats given cholesterol-enriched diets. Capybara oil (CO, linoleic + alpha-linolenic acids), horse oil (HO, alpha-linolenic acid), and sardine oil (SO, eicosapentaenoic + docosahexaenoic acids) were added to diets at 50 g/kg. The weight gain, food intake, and liver weight in the CO-fed group were significantly higher than those in other groups during the 6-wk experimental period. The serum total and very low density lipoprotein (VLDL) + intermediate density lipoprotein (IDL) + low density lipoprotein (LDL) cholesterol concentrations of the CO-fed and SO-fed groups were significantly lower than in the HO-fed group after 6 wk. The serum high density lipoprotein cholesterol concentration in the SO-fed group was significantly higher than that in the CO-fed and HO-fed groups. The fecal neutral sterol concentration in the CO-fed group was reduced significantly compared with the other groups, and the fecal bile acid concentration in the HO-fed group was significantly higher than that in the SO-fed group. The results of this study demonstrate that CO lowers the serum total cholesterol and VLDL + IDL + LDL-cholesterol concentrations in the presence of excess cholesterol in the diet as well as SO.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9113627&dopt=Abstract cholesterol




Serum lipid and lipoprotein patterns in patients with liver cirrhosis and chronic active hepatitis.

Cicognani C, Malavolti M, Morselli-Labate AM, Zamboni L, Sama C, Barbara L.

Istituto di Clinica Medica e Gastroenterologia, Universita degli Studi di Bologna, Italy.

BACKGROUND: An impaired lipid metabolism is often found in patients with chronic liver diseases. Unfortunately, few studies are available concerning serum lipid and lipoprotein levels in patients with liver cirrhosis and chronic active hepatitis (CAH). OBJECTIVES: To evaluate low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and total cholesterol serum levels in patients with cirrhosis and CAH and control patients and to relate the findings to the severity of the cirrhosis (Child classification). METHODS: We measured the serum lipid pattern in 34 consecutive patients with liver cirrhosis (15 men and 19 women; mean [+/-SD] age, 55 +/- 14 years; Child classes: 14 in A, 9 in B, 11 in C; patients with biliary cirrhosis were excluded), 34 patients with CAH, and 34 control patients. The 3 groups were matched for sex and age. Total serum, HDL cholesterol, and triglyceride levels were measured by enzymatic methods; serum LDL and VLDL levels were calculated. RESULTS: In patients with cirrhosis, there was a significant decrease in LDL, HDL, and total cholesterol serum levels compared with both the patients with CAH and the control patients, while the VLDL cholesterol level in patients with cirrhosis was significantly lower compared with the control patients alone. A significant decrease in total cholesterol levels was also observed in the CAH group when compared with the control patients. In patients with cirrhosis, levels of LDL, HDL, and total serum cholesterol were progressively lower when comparing patients in Child class A with patients in class C. CONCLUSIONS: In this study, the striking decrease in the level of serum LDL cholesterol in patients with liver disease was related to the increasing severity of the disease. Accordingly, the assessment of the serum LDL cholesterol level is important for an effective treatment and prognostic evaluation of patients with chronic liver disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9125012&dopt=Abstract cholesterol




Differential scanning calorimetric studies of the interaction of cholesterol with distearoyl and dielaidoyl molecular species of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine.

McMullen TP, McElhaney RN.

Department of Biochemistry, University of Alberta, Edmonton, Canada.

We have carried out a comparative study of the effect of cholesterol on the thermotropic phase behavior of the distearoyl and dielaidoyl molecular species of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine using high-sensitivity differential scanning calorimetry. For both molecular species of phosphatidylcholine, cholesterol incorporation produces bimodal endotherms at lower and unimodal endotherms at higher sterol concentrations. In both cases, heating and cooling endotherms are identical, and high concentrations of cholesterol (50 mol %) completely abolish the gel to liquid-crystalline phase transition. For the distearoyl molecular species of phosphatidylserine and phosphatidylethanolamine, heating and cooling endotherms are not identical, and cholesterol exhibits a considerably reduced miscibility in the gel as compared to the liquid-crystalline phase, particularly in the latter case. Thus, in neither case does the addition of 50 mol % cholesterol completely abolish the cooperative hydrocarbon chain-melting phase transition. However, the dielaidoyl molecular species of phosphatidylserine and phosphatidylethanolamine exhibit much closer correspondence in the heating and cooling modes than do the distearoyl species, and 50 mol % cholesterol is sufficient to almost or completely abolish the gel to liquid-crystalline phase transition of dielaidoylphosphatidylethanolamine and dielaidoylphosphatidylserine. In general, there is an inverse correlation between the strength of intermolecular phospholipid-phospholipid interactions, as manifested by the relative gel to liquid-crystalline phase transition temperatures of the pure phospholipids, and the miscibility of cholesterol in bilayers, particularly gel-state bilayers, formed from these phospholipids. These results indicate that the nature of cholesterol-phospholipid interactions, and thus the miscibility of cholesterol in the bilayer, depends on both the structure of the phospholipid polar headgroup and the hydrocarbon chains, as well as on the temperature and phase state of the phospholipid bilayer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9125520&dopt=Abstract cholesterol




Human low-density lipoproteins: oxidative modification and its relation to age, gender, menopausal status and cholesterol concentrations.

Mosinger BJ.

Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

Recently much evidence has accumulated indicating that oxidative modification of atherogenic lipoproteins plays an important role in atherogenesis. The goal of this study was to ascertain whether any association exists between this and the previously incriminated risk factors of atherosclerotic cardiovascular disease like age, gender and cholesterol concentration. Serum lipid profile, low-density lipoprotein (LDL) composition and indicators of LDL oxidation were examined in a cohort of healthy, predominantly middle aged men and women. LDL oxidation was assessed using the copper catalysis method, and monitored routinely by the increase in conjugated dienes over 4 to 24 hours. A more objective computer-aided technique was used to estimate the oxidative indices based on the sigmoidal fit to data. No marked differences between men and women were found with respect to mean age, total and LDL cholesterol, LDL protein and oxidation of LDL. The post-menopausal as compared to pre-menopausal status was associated with a greater extent of LDL oxidation, as well as with higher total serum cholesterol and its fractions, LDL cholesterol and LDL protein. No such differences were found in the data for men appropriately separated according to age. In a group with high risk LDL cholesterol, the total LDL oxidation was higher, as well as age and total cholesterol. Lag time and half-time of LDL oxidation were significantly shorter, while the oxidation rate of LDL was significantly faster when compared with data in the lower quartile. About six percent of participants had a considerably prolonged initial oxidation phase. These persons also showed low total and LDL cholesterol. High oxidation resistance was reversible and most probably caused by very low pre-existent oxidation products. Multiple regression analysis showed that the closest association among age, gender, lipid profiles and LDL oxidation indices existed between LDL cholesterol and conjugated diene production in both sexes (men: r = 0.93; women: r = 0.81). This association remained high even if adjusted for age. As in earlier epidemiological studies using logistic regression and showing age- and gender-related rising frequency of coronary heart disease, the present paper demonstrated age- and gender-related rising frequency of highly oxidized LDL. In both cases it was closely associated with an increasing LDL cholesterol concentration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9127742&dopt=Abstract cholesterol




Changes in population cholesterol levels and coronary heart disease deaths in seven countries.

Menotti A, Blackburn H, Kromhout D, Nissinen A, Fidanza F, Giampaoli S, Buzina R, Mohacek I, Nedeljkovic S, Aravanis C, Toshima H.

Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, USA.

BACKGROUND: Are trends in coronary heart disease deaths based on risk factor changes? OBJECTIVE: To study the relationship between trends in coronary deaths and changes in blood cholesterol in the Seven Countries Study. MATERIAL AND METHODS: Sixteen cohorts of men aged 40-59 years from seven countries (U.S.A., Finland, the Netherlands, Italy, Croatia (former Yugoslavia), Serbia (former Yugoslavia), Greece, Japan) were units for the analyses of serum cholesterol measured at entry and after 5 and 10 years, and for mortality over 25 years. RESULTS: In the populations, the ecological relationship of mean serum cholesterol at entry to late coronary heart disease death rates during the 10- to 25-year follow-up was weak, with an R-square of 0.31. Cholesterol measurements made at year 10, and an indicator of cholesterol change during the first 10 years, increased the association (R-square, 0.49). A negative and significant interaction was shown between baseline population cholesterol levels and their 10-year change. As an indicator of acceleration in mortality, cholesterol change over 10 years was also positively correlated (partial R-square 0.44) with the ratio of 25-year to 5-year deaths. CONCLUSIONS: In the Seven Countries Study, late coronary heart disease death rates are largely "explained' by changes in blood cholesterol levels during the early phases of the study, mainly due to increases in lower cholesterol levels among some cohorts.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9129884&dopt=Abstract cholesterol




RPR 107393, a potent squalene synthase inhibitor and orally effective cholesterol-lowering agent: comparison with inhibitors of HMG-CoA reductase.

Amin D, Rutledge RZ, Needle SN, Galczenski HF, Neuenschwander K, Scotese AC, Maguire MP, Bush RC, Hele DJ, Bilder GE, Perrone MH.

Department of Cardiovascular Biology, Rhone Poulenc Rorer, Collegeville, Pennsylvania, USA.

Squalene synthase catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene and is the first committed step in sterol synthesis. A specific inhibitor of squalene synthase would inhibit cholesterol biosynthesis but not prevent the formation of other products of the isoprenoid pathway, such as dolichol and ubiquinone. RPR 107393 [3-hydroxy-3-[4-(quinolin-6-yl)phenyl]-1-azabicyclo[2-2-2]octane dihydrochloride] and its R and S enantiomers are potent inhibitors of rat liver microsomal squalene synthase, with IC50 values of 0.6 to 0.9 nM. One hour after oral administration to rats, RPR 107393 inhibited de novo [14C]cholesterol biosynthesis from [14C]mevalonate in the liver with an ED50 value of 5 mg/kg. Diacid metabolites of [14C]farnesyl pyrophosphate were identified after acid treatment of the livers of these animals. These results support in vitro data demonstrating that these compounds are inhibitors of squalene synthase. In rats, RPR 107393 (30 mg/kg p.o. b.i.d. for 2 days) reduced total serum cholesterol by < or = 51%. In the same paradigm, the HMG-CoA reductase inhibitor lovastatin failed to lower serum cholesterol in rats. In marmosets, RPR 107393 (20 mg/kg b.i.d.) reduced plasma cholesterol concentration by 50% after 1 week of administration; this was greater than the reduction observed with lovastatin or pravastatin, neither of which produced > 31% reduction in plasma cholesterol when administered for 1 week at a dose of 50 mg/kg b.i.d. The R and S enantiomers of RPR 107393 (20 mg/kg p.o. q.d. for 7 days) reduced plasma low density lipoprotein cholesterol by 50% and 43%, respectively, whereas high density lipoprotein cholesterol was unchanged. In summary, RPR 107393 is a potent inhibitor of squalene synthase. It is an orally effective hypocholesterolemic agent in rats and marmosets that has greater efficacy than lovastatin or pravastatin in the marmoset.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9152381&dopt=Abstract cholesterol




Control of human sperm intracellular pH by cholesterol and its relationship to the response of the acrosome to progesterone.

Cross NL, Razy-Faulkner P.

Department of Anatomy, Pathology, and Pharmacology, Oklahoma State University, Stillwater 74078, USA. ncross vm1.ucc.okstate.edu

When incubated in vitro, human sperm gradually become capable of acrosome-reacting in response to the agonist progesterone. Loss of unesterified cholesterol is required for sperm to become responsive to progesterone, but how cholesterol regulates acrosomal responsiveness is unknown. These experiments tested the hypothesis that loss of sperm cholesterol leads to a rise in the intracellular pH (pH(i)) that makes the sperm responsive to progesterone. pH(i) was measured using BCECF (2',7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein) in freshly ejaculated sperm (T0 sperm) and in sperm incubated in vitro overnight (T24 sperm). During incubation, pH(i) increased from 6.94 +/- 0.03 to 7.08 +/- 0.01 (mean +/- SEM, n = 4, p < 0.01). Incubating sperm 24 h in medium supplemented with 1 microM cholesterol to prevent loss of sperm cholesterol suppressed the rise of pH(i) (T24C sperm, pH(i) = 6.96 +/- 0.03, n = 4, p = 0.64 compared to T0 sperm). To test whether their lower pH(i) prevents T24C sperm from reacting, we treated T24C sperm with the alkalinizing agents trimethylamine chloride (TMA) or NH4Cl. These agents did cause T24C sperm to respond to progesterone in a dose-dependent fashion, but they also caused a similar increase in the number of reacting T24 sperm. These agents probably do not reverse the inhibiting effects of high cholesterol but rather make responsive a subpopulation of sperm that is present regardless of the cholesterol content. NH4Cl and TMA did not make T0 sperm responsive to progesterone. The acidifying agent sodium propionate did not diminish the response of T24 sperm to progesterone. In summary, pH(i) increases during incubation in vitro in a cholesterol-dependent fashion. Elevated pH(i) alone is probably not sufficient to make sperm acrosomally responsive.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9160715&dopt=Abstract cholesterol




Effect of exogenous hyperinsulinaemia on atherogenesis in cholesterol-fed rabbits.

Nordestgaard BG, Agerholm-Larsen B, Stender S.

Department of Clinical Biochemistry, Herlev Hospital, University of Copenhagen, Denmark.

To examine the hypothesis that hyperinsulinaemia promotes atherosclerosis, cholesterol-fed rabbits were injected subcutaneously with 6 i.u. of human insulin (n = 16) or placebo (n = 20) daily for 24 weeks; injection of insulin resulted in hyperinsulinaemia for up to 16 h after injection. Compared to placebo rabbits, insulin-treated rabbits had higher levels of insulin antibodies in plasma, similar levels of intermediate density, low density and high density lipoprotein cholesterol and similar activities of hepatic and lipoprotein lipase in post-heparin plasma, but lower levels of plasma C-peptide, blood glucose, postprandial plasma triglycerides, plasma cholesterol and very low density lipoprotein cholesterol. On univariate analysis, with and without adjustment for differences in plasma cholesterol levels between the two groups, there were no significant differences in extent or severity of atherosclerosis between insulin and placebo rabbits. Furthermore, after combining the results from all the rabbits to examine plasma insulin levels and the other variables mentioned above as predictors of atherosclerosis severity, plasma insulin level was not a predictor, on univariate or multiple linear regression analysis; the first ranked independent predictors were postprandial intermediate density lipoprotein cholesterol in the arch, and postprandial plasma triglyceride in both the thoracic and abdominal aorta. These results suggest that exogenous hyperinsulinaemia does not promote atherogenesis in cholesterol-fed rabbits, but that postprandial levels of intermediate density lipoprotein cholesterol or plasma triglycerides may be involved in atherogenesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9165218&dopt=Abstract cholesterol