Thesis (doctoral)--University of Helsinki, 1990. / Includes bibliographical references (p. 50-64).

Simvastatin is a cholesterol-lowering drug designed to lower cholesterol by inhibiting HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins also inhibit the production of coenzyme Q (CoQ), which shares the same biosynthetic pathway. CoQ is an essential part of the mitochondrial electron transport chain (ETC) and has antioxidant properties. In addition, statins have been shown to effect the expression of antioxidant enzymes and heat shock proteins. Aerobic exercise has also been shown to have an effect on the aforementioned proteins. Statins and aerobicexercise are often co-prescribed by physicians even though the interaction of statins and exercise in heart and skeletal muscle has not been adequately explored. Purpose: To determine the interaction of simvastatin and exercise on CoQ, catalase (CAT), glutathione peroxidase (GPx), Manganese superoxide dismutase (Mn SOD), and heat shock protein 70 (HSP70) in cardiac muscle tissue and the expression of CoQ in the plantaris. Methods: Female 4-mo-old Sprague-Dawley rats were randomly assigned to four treatment groups (N = 15-18/group): sedentary (SED), sedentary treated with simvastatin (SED+SIM), exercise trained (EX), and exercise trained treated with simvastatin (EX+SIM). Rats assigned to simvastatin treated groups received 10 mg simvastatin (Zocor®)/kg body/eight/day for four weeks. Rats assigned to exercise groups were exercised on a treadmill five days/week for four weeks at about 70% VO2max for a duration that was gradually increased to 60 minutes/day. Twenty-four hours after the last session, the animals were euthanized and the heart and both plantaris muscles were removed. Some hearts were perfused for 20 minutes to rinse away blood and others were subjected to an ischemia-reperfusion (I-R) protocol. Left ventricles of IR hearts and the left plantaris were homogenized in ddH2O and lipids were extracted and analyzed for CoQ by high performance liquid chromatography. CAT, GPx, and Mn SOD activity was measured polarographically and HSP70 expression was determined by western blotting of the supernatant of homogenate from the left ventricular tissue of rinsed hearts. Results: A simvastatin main effect was observed on CoQ expression of cardiac and skeletal muscle, and CAT activity of cardiac muscle tissue. Expression of CoQ was decreased while CAT activity was increased following statin treatment. An exercise main effect was observed on CoQ and HSP70 expression of cardiac muscle tissue. Exercise decreased CoQ expression, but increased HSP70 expression in the heart. An interaction effect was observed on both HSP70 expression and Mn SOD activity of cardiac tissue. With respect to HSP70, treatment with simvastatin slightly attenuated an exercise induced increase in HSP70 expression. With respect to Mn SOD, treatment with simvastatin or exercise decreased activity while a combined treatment restored Mn SOD activity to a level similar to that of animals who received no treatment. Conclusion: Treatment with simvastatin or exercise alone results in alterations in the expression of CoQ and HSP70 and activity of CAT, GPx, and Mn SOD. With co-administration, simvastatin and aerobic exercise interact in such a way that maintains one's antioxidant defenses despite impairment the body's ability to synthesize CoQ.

No description available.

Our laboratory has recently reported that lecithin:cholesterol acyltransferase (LCAT) deficient mice are hypersensitive to insulin and resistant to diet-induced obesity, particularly in the LDL receptor (LDLR) knockout background. These phenotypes are linked to hepatic endoplasmic reticulum (ER) stress, which we showed is elevated basally and highly inducible in LDLR deficient mice. While in LCAT/LDLR deficient mice, ER stress is normalized basally and its diet-induction is attenuated. Mechanistically, we show here that excess free cholesterol (FC), in part from the bile, accumulates in the ER membrane of LDLR deficient mice. In contrast, LCAT/LDLR deficient mice have reduced levels of ER membrane FC and are resistant to cholesterol diet-induced elevations, in part from increased INSIG-1 expression and cholesterol esterification by ACAT2. Our analysis has led to the first report of cholesterol-induced hepatic ER stress in vivo and the identification of ER FC levels as a critical indicator of ER stress susceptibility.

No description available.

Phytosterols occur naturally in the non-saponifiable material of plant oils. Sitostanol, the saturated derivative of beta-sitosterol, is found in negligible concentrations in plant sources and, hence, is almost absent from typical Western diets. Tall oil extracts, on the other hand, contain about 20% (w/w) sitostanol. Phytosterols have been shown to lower plasma total cholesterol levels in animals and humans while sitostanol exhibited stronger reducing effects. Several studies have suggested that phytosterols lower plasma total cholesterol levels by either inhibiting cholesterol absorption or altering the activities of enzymes critical in cholesterol metabolism and excretion. However, results obtained demonstrate inconsistency regarding the effects of phytosterols on cholesterol absorption rates and cholesterogenesis. In addition, few studies have determined quantitatively the changes in the rate of cholesterol absorption and biosynthesis. Hence, the objective of this thesis was to investigate further the impact of different sources of phytosterols on plasma lipid profiles and to develop a new methodology for simultaneous measurement of percent cholesterol absorption and cholesterol synthesis rates in animals and humans. The stable isotopes, 13C-, 18 O-cholesterol, and deuterium oxide were utilized for the dual isotope plasma ratio and deuterium uptake methodologies. Results from the series of animal experiments conducted demonstrate (i) a gender effect of phytosterols in modulating plasma lipid profile in hamsters, (ii) that sitostanol was more potent in lowering plasma and hepatic lipid concentrations than beta-sitosterol in hamsters and rabbits and (iii) that this lowering effect was due to a reduction in fractional cholesterol absorption and an increase in cholesterol excretion rates. Concomitantly, an up-regulation in cholesterogenesis was observed in hamsters. Furthermore, in humans tall oil phytosterols lowered total cholesterol levels in hypercholesterole

Phytosterols play an important role in nature and as synthetic supplements for the modification of cholesterol metabolism in humans. The consensus is that the primary mechanism by which phytosterols modify lipid profiles is through altering the absorption of cholesterol. This thesis examined the effects of phytosterol mixtures on (i) de novo cholesterol synthesis rates and appearance of de novo cholesterol into the cholesterol ester pool through the use of deuterium incorporation, as well as, (ii) plasma lipid and sterol concentrations in normolipidemic humans. The initial investigation of this thesis compared the effects of diets based on either corn oil, olive oil, or olive oil plus phytosterol mixture on cholesterol metabolism. Each treatment was administered for 10 days in a cross-over design to 16 normolipidemic humans. In addition to confirming prior conclusions that corn oil was more effective than olive oil at decreasing plasma total and LDL-cholesterol concentration, this study was one of the first to determine that the differential effects on cholesterol metabolism observed in humans consuming corn versus olive oil is due, in part, to the higher concentrations of plant sterols naturally found in corn oil. The second study presented in this thesis investigated the differential effects on sterol metabolism of phytosterol mixtures either enriched with sitostanol or sitostanol-free administered for 10 days in 11 normolipidemic humans. The results of this study demonstrated that only the phytosterol mixture containing low doses of sitostanol decreased plasma total and LDL-cholesterol concentrations and increased the circulating HDL/LDL ratios; thus, the sitostanol-enriched phytosterol mixture was a more effective cholesterol-lowering agent.

La synthese endogene du cholesterol (CH) a ete etudie chez 81 nouveau-nes, ages de 4 mois (BRAS 1) ou de 11 a 12 mois (BRAS2), afin d'evaluer les effets a long terme d'un supplement de CH sur l'homeostasie du CH. BRAS 1 etait compose de 32 nouveau-nes recevant soit du lait humain (HUM) (6M, 7F), une formule a base de lait de vache (VAC) (6M, 3F) contenant 3.5 mg CH/dl, ou une formule a base de lait de vache modifiee (VACM) (6M, 7F) contenant 13.5 mg CH/dl, afin d'evaluer l'effet du supplement sur les taux de synthese du CH. BRAS2 etait compose de 49 autres enfants recevant soit HUM (11M, 6F), VAC (7M, 12F) ou VACM (6M, 7F) jusqu'a l'age de 6 mois dans le but d'evaluer une hypothese d'impression genetique. Ceci a ete realise en utilisant un design "cross-over" et en montant un defi journalier de 250 g de CH a l'age de 11 mois. Le taux d'incorporation de deuterium, provenant des reserves d'eau corporelle, dans la structure du CH a servi comme indice du taux de synthese fractionnel (TSF) de ce dernier sur une periode de 48 heures. Les niveaux de CH total et LDL etaient considerablement eleves dans HUM en comparaison avec VAC et VACM a l'age de 4 mois. La concentration sanguine du CH etait semblable a 11 et 12 mois. Le TSF etait 4 fois plus eleve dans VAC et VACM relatif a HUM, mais il n'y avait pas de difference entre VAC et VACM a 11 et 12 mois. Cependant, les TSF de 4 a 12 mois ont augmente dans HUM et baisse dans VAC et VACM. Nos resultats indiquent qu'independamment du contenu des dietes, le defi journalier de CH n'as pas eu d'effet considerable ni sur les taux de synthese, ni sur les niveaux de CH sanguin. Ces resultats appuient l'idee que le CH alimentaire n'a que des effets minimes sur le metabolisme a long terme du CH.

The objective was to assess the effect of a high-monounsaturated fat (MUFA) dietary portfolio of cholesterol-lowering foods on oxidative stress and cardiovascular risk. Twenty-four hyperlipidemic subjects followed a very low-saturated-fat therapeutic control diet for 4 weeks after which they were randomized to receive the dietary portfolio, consisting of soy protein (20g/1000kcal), viscous fibre (10.3g/1000kcal), plant sterols (2-3g) and almonds (21.5g/1000kcal), in combination with high- or low-MUFA (25.9% and 12.9% MUFA, respectively) for the next 4 weeks, where MUFA replaced 13.0% of dietary carbohydrate. On high-MUFA, there were significantly greater increases in HDL-C and apoA1 and significantly greater reductions in total:high-density lipoprotein cholesterol (total:HDL-C) ratio and high-sensitivity C-reactive protein (hs-CRP) compared to the low-MUFA dietary portfolio. In all diets there were significant increases in protein thiols and reductions in conjugated dienes and thiobarbituric acid reactive substances (TBARS) measured in the LDL-fraction, however no difference between the high- and low-MUFA diets.

Graduation date: 1961