Although the clinical efficacy of statins has been well established, there is a wide inter-individual variation in the lipid responses to statins. Pharmacogenetic studies have identified some genetic differences that contribute to the variation, but overall the results have been disappointing. The studies described in this thesis were performed to examine whether certain genetic variants predicted the lipid responses to rosuvastatin in Chinese patients. Over 400 Chinese patients with increased risk of cardiovascular disease (CVD) who were treated with rosuvastatin 10 mg daily for at least 4 weeks (more than 97% of patients had at least 6 weeks treatment) were studied, including 166 having familial hypercholesterolaemia (FH) and 36 having rheumatoid arthritis (RA). They were genotyped for 135 polymorphisms in 62 candidate genes/loci potentially related to pharmacokinetics or pharmacodynamics of statins and lipid metabolism. Associations between genetic polymorphisms and the lipid responses to rosuvastatin were analyzed in 386 patients with good compliance. The associations between genetic polymorphisms and some risk factors for CVD including baseline lipid levels, high-sensitivity C-reactive protein (hsCRP), uric acid and bilirubin levels were also analyzed. / Some novel genetic determinants of the LDL-C response to rosuvastatin treatment have been identified in this study. The responses in HDL-C and triglycerides were related more closely to the baseline levels of these lipids than to any of the polymorphisms examined. Genetic associations with baseline lipid parameters, hsCRP, uric acid and bilirubin were identified and generally correspond with some of the previous reports of studies in Chinese and other ethnic groups. / The key findings of the study are as follows: 1. The polymorphisms most highly associated with the low-density lipoprotein cholesterol (LDL-C) response were 421C>A in the ATP-binding cassette G2 (ABCG2) gene (P=9.2x10 -7), followed by 18281G>A (V257M) in the flavin-containing monooxygenase 3 (FMO3) gene (P=0.0002), 1421C>G in the lipoprotein lipase (LPL) gene (P=0.002), and rs4420638 in the apolipoprotein E/C-I/C-IV/C-II (APOE/C1/C4/C2) gene cluster (P=0.004). These genetic polymorphisms and having FH totally explained 13.6% of the variance in percentage change in LDL-C in response to rosuvastatin. The greater percentage reduction in LDL-C in patients with the ABCG2 421AA genotype compared to those with the ABCG2 421CC genotype was equivalent to at least doubling the dose of rosuvastatin. 2. Three SNPs (glucokinase regulator [ GCKR] rs1260326, apolipoprotein AS [APOA5] -1131T>C and the solute carrier organic anion transporter 1B1 [SLCO1B1] 521T>C) tended to be associated with percentage changes in high-density lipoprotein cholesterol (HDL-C) (P<0.05), but none of these reached the overall significance level. In multivariate stepwise regression analysis, baseline HDL-C (P=1.6x10 -6), having diabetes (P=0.0004) or RA (P=0.002) and the SLCO1B1 521T>C polymorphism (P=0.03) were determinants of HDL-C responses, contributing 9.9% of the variance in percentage change in HDL-C, but the genetic factors only contributed to 0.8% of the variance. 3. The triglyceride response to rosuvastatin was highly variable and was strongly related to baseline levels. The diacylglycerol acyltransferase-2 (DGAT2) rs10899113 C>T polymorphism tended to be associated with reduced triglyceride response in a gene-dose dependent manner. However, in multivariate stepwise regression analysis, baseline triglyceride level was the only factor that strongly related to the triglyceride response, explaining 14.4% of the variance. 4. This study has also analyzed relationships between on-treatment plasma hsCRP concentrations and cardiovascular risk factors and 14 single nucleotide polymorphisms in CRP and other candidate genes, which showed that central obesity, low HDL-C and CRP polymorphisms are major determinants of higher hsCRP levels in Chinese patients on treatment with rosuvastatin. 5. The association between genetic polymorphisms and lipid traits were analyzed in FH and non-FH patients separately due to their different lipid profiles. The analysis has shown that there were different genetic predictors of lipid levels in patients with and without FH and that more genetic factors appeared to affect the baseline lipid levels in patients with FH compared to non-FH patients, suggesting complex interactions between genetic and environmental factors and plasma cholesterol levels in patients with and without FH. 6. The SLC2A9 (solute carrier family 2, member 9) rs1014290 T>C was significantly associated with plasma uric acid levels in a gene-dose dependent manner (P=1.0x10-5) and the relationship was more pronounced in women or in patients without hypertension than in men or patients with hypertension. The ABCG2 421 C>A did not show a significant effect on uric acid levels. 7. The UGT1A1 (uridine diphosphate glucuronosyltransferases family, polypeptide A1) variants *28 (P=1.5x10 -9) and *6 (P=2.2x10-7) were independently associated with increased baseline bilirubin levels. Polymorphisms in SLCO1B1 did not appear to affect bilirubin levels in this study. / Hu, Miao. / Adviser: Brian Tomlinson. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 230-264). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Abstract not available

Diss. (sammanfattning) Linköping : Linköpings universitet, 2010. / Härtill 4 uppsatser.

Current feed formulations within the aquaculture industry have tended to rely on high dietary lipid thus offsetting relatively expensive protein as a source of energy. In this way, protein can be ‘spared’ for synthesis of new tissue and the high lipid content can also fulfil both fish and consumer essential fatty acid (EFA) requirements. However, the main disadvantage of feeding high lipid levels to farmed fish is a surplus of fat deposition in the flesh and other important tissues, which can detrimentally impact on quality characteristics central to the human consumer. However, based on previous work in other animal models, it is entirely feasible that supplementation of the diet with bioactive fatty acids such as conjugated linoleic acid (CLA) and tetradecylthioacetic acid (TTA) may mitigate the deleterious effects of feeding farmed fish high fat diets by reducing fat deposition in particular. The general objective of this research work was to test the hypothesis that CLA and/or TTA could augment growth, reduce fat deposition and enhance fatty acid composition via incorporation of these bioactive fatty acids, and increase n-3 highly unsaturated fatty acid (HUFA) levels in the flesh of commercially important fish species such as Atlantic salmon (Salmo salar), Atlantic cod (Gadus morhua L.) and rainbow trout (Oncorhynchus mykiss). This project also considered the influence of CLA and TTA on enzymes and transcription factors thought to be pivotal in lipid metabolism and fatty acid oxidation in particular. A subsidiary aim of this research work was to investigate the immunological impact of dietary CLA and TTA administration in these fish. The results of this project have revealed that the hypothesis was only partly proved. There was no effect in growth or biometry after either CLA or TTA supplementation in any of the fish species investigated. Additionally, there were few physiologically significant effects on fat levels on fish as a result of TTA or CLA administration. However, there were a number of effects on fatty acid metabolism including inhibition of steroyl coenzyme desaturase (SCD) in cod and trout in particular and also enhancement of hepatic n-3 HUFA levels in trout. Importantly, it was determined that both TTA and CLA could be incorporated into the flesh thus providing a vehicle through which these bioactive fatty acids can be delivered to the consumer. There were also a number of beneficial effects on activity and gene expression of a number of enzymes and transcription factors thought to be fundamental to the modulation of fatty acid oxidation in particular. However, the effects on gene transcription and biochemistry had little impact at the whole body level. This research work also showed that there were no detrimental effects on immune status after supplementation with dietary CLA or TTA. Conclusively, this thesis has contributed to the overall understanding of the influence of dietary CLA and TTA in farmed fish.

Tyrimo tikslas buvo nustatyti sumažinto kaloringumo dietos poveikį kai kuriems kūno kompozicijos rodikliams ir lipidų koncentracijai. Tyrime siekta įvertinti kai kuriuos kūno kompozicijos rodiklius (riebalines raukšles, procentinį riebalų kiekį, kūno masės indeksą(KMI)), nustatyti liemens ir klubų apimčių santykį ir įvertinti kraujo lipidų koncentraciją prieš ir po sumažinto kaloringumo dietos. Tyrime dalyvavo aštuonios sveikos moterys nuo 28 iki 46 metų. Prieš tyrimą visos tiriamosios pildė anketą apie gyvenimo būdą, žalingus įpročius, fizinį aktyvumą. Visos tiriamos moterys buvo sveikos, nerūkančios, nesportuojan��ios bei nevartojusios alkoholio tyrimo metu. Tyrimo metu, pusantro mėnesio tris kartus per savaitę, jos laikėsi sumažinto kaloringumo dietos, kitomis savaitės dienomis maitinosi įprastai. Tyrimo metu moterys registravo savo įprastą mitybos racioną. Kūno kompozicijos rodikliai (KMI, riebalinės raukšlės, liemens, klubų apimtis), bendrojo cholesterolio (Bch), didelio tankio lipoproteinų cholesterolio (DTL-ch) ir triacilglicerolių (TAG) koncentracijos kraujyje buvo išmatuoti prieš tyrimą ir po pusantro mėnesio trukusios sumažinto kaloringumo dietos. Po eksperimento nustatyta, kad dėl sumažinto kaloringumo dietos patikimai sumažėjo moterų KMI, procentinis riebalų kiekis ir riebalinės raukšlės. Taikant sumažinto kaloringumo dietą, per pusantro mėnesio kraujo lipidų (DTL-ch; Bch; TAG) koncentracija nepakito. Liemens ir klubų apimties santykio pokyčiai po sumažinto... [toliau žr. visą tekstą] / The aim of this research was to measure the effect of calorie restricted diet on some indexes of body composition and lipoprotein concentration. This research was carried out to estimate indexes of body composition (skinfold thickness, the percentage of body fat, body mass index), waist-to-hip ratio, and the concentration of blood lipoproteins before and after calorie restricted diet. Eight healthy women aged from 28 to 46 participated in the research. All participants filled in the questionnaire about their life style, harmful habits and physical activity. Participating women were healthy, non-smoking, sedentary and sober during the research. They were on calorie restricted diet for one and a half months, three times a week, the other days they took an usual nourishment. During the research, women registered their usual nutrition ration. The indexes of body composition (body mass index, skinfold thickness, waist-to-hip ratio), serum total cholesterol (Tchol), high density lipoprotein cholesterol (HDL), triglyceride (TG) concentration was estimated before the research and after one and a half months lasting calorie restricted diet. It was found that because of calorie restricted diet women‘s body mass index, percentage body fat, and skinfold thickness decreased (p < 0,05). After practising calorie restricted diet for one and a half months, blood lipoprotein (HDL, Tchol, TG) concentration did not change (p > 0,05). Waist-to-hip ratio change after calorie restricted diet was... [to full text]

Mirtingumas nuo lėtinių neinfekcinių ligų (koronarinės širdies ligos, cukrinio diabeto, lėtinių kepenų ligų) yra gerokai didesnis Lietuvoje palyginus su Europos Sąjungos vidurkiu. 2007 metais pagal 20 – 64 metų vyrų mirtingumo nuo širdies ir kraujagyslių ligų rodiklį tarp Europos Sąjungos šalių Lietuva užėmė trečiąją vietą. Dažniausiai pasitaikanti širdies ir kraujagyslių ligų pasireiškimo forma – koronarinė širdies liga (KŠL). Epidemiologiniai tyrimai atskleidė svarbiausius lėtinių neinfekcinių ligų rizikos veiksnius. Be to, nustatyti nauji aterosklerozės patogenezės elementai - oksiduoti mažo tankio lipoproteinai, vitaminai antioksidatoriai, riebalų rūgštys. Riebalų rūgštys (RR) yra oksidacijos žymenys, nes dalyvauja lipidų peroksidacijoje, kaip substratai. Jautriausios peroksidacijai – polinesočiosios riebalų rūgštys (PNRR). Žmogaus organizmui yra svarbios nepakeičiamos PNRR, kurias būtina gauti su maistu. Jos yra panaudojamos eikozanoidų sintezei.Gaunant su maistu per daug arba per mažai RR, atsiranda tam tikrų sveikatos sutrikimų. Dažnai RR disbalanso priežastimi tampa per gausus gyvūninių ir nepakankamas augalinių riebalų vartojimas. Dėl to gali išsivystyti lėtinės neinfekcinės ligos. Žmogaus organizmo RR turi įtakos kitų medžiagų apykaitai, todėl tokių sąsajų tyrimas tampa aktualus nagrinėjant cukraligės, kepenų ir inkstų ligų patogenezės kelius. Šio darbo tikslas yra ištirti ir įvertinti riebalų rūgštis, kaip biožymenis ir jų reikšmę lėtinių neinfekcinių ligų... [toliau žr. visą tekstą] / Mortality rate from chronic non-infectious diseases (coronary heart diseases, diabetes mellitus, and chronic liver disease) in Lithuania is far higher as compared to the European Union average. In 2007, Lithuania ranked third among EU member states according to mortality rate indicator for cardiovascular diseases of males aged 20–64. The most frequent manifestation of cardiovascular diseases is the coronary heart disease (CHD). Epidemiological studies revealed the most important risk factors of chronic non-infectious diseases. Moreover, new elements in the pathogenesis of atherosclerosis have been identified, i.e. oxidized low-density lipoproteins, antioxidant vitamins and fatty acids. Fatty acids (FA) are oxidation markers, since they participate in lipid peroxidation as substrates. The most sensitive to peroxidation are the polyunsaturated fatty acids (PUFA). On the contrary, essential PUFA are important for synthesis of eicosanoids. When too little or too much of fatty acids are consumed with food, certain health disorders arise. A common cause of FA imbalance is too abundant consumption of animal fats and insufficient consumption of vegetable fats. This may cause chronic non-infectious diseases. The FA of human body influences the metabolism of other substances, therefore, the study of such metabolic correlations comes of relevance in exploring the pathogenesis pathways of diabetes mellitus, liver and kidney diseases. The purpose of the present review is to evaluate... [to full text]

In the last decades our knowledge concerning cardiovascular risk factors has grown rapidly through results from longitudinal studies. However, despite new treatment, in Western countries coronary heart disease remains the leading cause of death and stroke is still the leading cause of severe disability. The studies reported in these papers examine the relationships between stroke/transient ischaemic attack (TIA) and a number of different factors measured on two different occasions in men born in Uppsala 1920-1924 and are epidemiological in their character. The findings indicate that in addition to already established risk factors, indices of an unhealthy dietary fat intake and high serum lipoprotein(a) are independent predictors of stroke/TIA. Among different glucometabolic variables a low insulin sensitivity index derived from the euglycaemic insulin clamp and proinsulin carries a high predictive value for later stroke, independently of diabetes. Moreover, cognitive test performance measured with Trail Making Test B at age 70 is a strong and independent predictor of brain infarction, indicating that the risk is already increased in the subclinical phase of milder cognitive dysfunction. Performance at a pre-stroke Trail Making Test is also of predictive value for mortality after first-ever stroke/TIA, but none of the studied pre-stroke variables or cognitive tests was found to be related to dependency after an event. In summary these studies provide further knowledge about predictors of stroke and of mortality after first-ever stroke. They also indicate the possible importance of new markers of risk, such as the level of lipoprotein(a), profile of fatty acids in the diet, low insulin sensitivity derived from clamp investigations, level of proinsulin, and cognitive performance measured with Trail Making Tests.

[Formulae and special characters can only be approximated here. Please see the pdf version of the abstract for an accurate reproduction.] Atherosclerosis is a common degenerative disease in which the clinical manifestations are often through stroke or myocardial infarction. Some of the established risk factors for atherosclerosis include elevated plasma low-density lipoprotein (LDL)-cholesterol levels, obesity, diabetes mellitus (DM) and cigarette smoking. Of the risk factors, an elevation in plasma LDL is one of the most established and the most researched. This is partly a consequence of the deposition of cholesterol within arterial intima being a crucial step in the progression of atherosclerosis, combined with the finding that LDL particles are a major transporter of cholesterol in circulation. Recently there is increasing evidence showing a role of the other major transporter of cholesterol in circulation, chylomicron remnants, in the progression of atherosclerosis. The notion of atherosclerosis as a postprandial phenomenon has been further substantiated by the emergence of evidence showing a direct role of chylomicron remnants in arterial cholesterol deposition. Based on evidence that chylomicron remnants are proatherogenic, the suggestion arises that accumulation of postprandial lipoproteins in plasma may add another dimension of risk to the development of coronary artery disease (CAD). This thesis tests the general hypothesis that individuals with or at high risk of CAD have postprandial dyslipidaemia and that this metabolic abnormality is correctable with a class of lipid-lowering drugs called statins. To test the hypothesis, clinical studies were conducted in normolipidaemic CAD patients, heterozygous familial hypercholesterolaemia (FH) and postmenopausal women with type 2 DM. Determination of postprandial dyslipidaemia by comparison with control populations were conducted initially in each patient group (Studies 1, 3 and 5), followed by intervention studies investigating possible modulation of the dyslipidaemia with a statin (Studies 2, 4 and 6). Six observation statements based on case-control comparisons of postprandial lipaemia in patients with or at risk of CAD and the effects of statins on postprandial dyslipidaemia in the patient groups were derived from the general hypothesis. The observation statements were examined in the individual studies described below. Postprandial lipoprotein metabolism was assessed using a number of methods. For comparison of postprandial lipaemia in Studies 1 and 2, a classic oral fat challenge was utilised. As markers of chylomicrons and chylomicron remnants, retinyl palmitate and triglyceride were measured postprandially as well as apolipoprotein (apo) B48 concentrations, a specific marker of intestinal lipoproteins. ApoB48 was also measured in the fasting state and found to predict the postprandial responses of retinyl palmitate, triglyceride and apoB48. This suggested that fasting measurement of apoB48 could be used as a simple indicator of postprandial dyslipidaemia. Consequently for Studies 3 - 6, fasting apoB48 measurements were used as primary markers of postprandial dyslipidaemia. Other markers for chylomicrons and their remnants utilised were fasting plasma concentrations of remnant-like particle-cholesterol (RLP-C) and apoC-III. As well as these static markers, chylomicron remnant catabolism was measured using a stable isotope breath test. The breath test involves the intravenous injection of a chylomicron remnant-like emulsion labelled with ¹³C-oleate and measurement of enriched ¹³CO2 in expired breath by isotope ratio mass spectrometry. The fractional catabolic rate (FCR) of the injected emulsion was subsequently calculated using multi-compartmental modeling (SAAM II). The studies are presented in this thesis as published and unpublished works. In Study 1, postprandial lipoprotein metabolism was compared between 18 normolipidaemic CAD patients (cholesterol 4.54 ± 0.12 mmol/L, triglyceride 1.09 ± 0.16) with 13 asymptomatic healthy controls using an oral fat challenge. Normolipidaemic CAD patients had higher postprandial area-under-curve (AUC) for triglyceride (+34%, p=0.019), retinyl palmitate (+74%, p=0.032) and apoB48 (+36%, p<0.001). Fasting apoB48 was also higher (+41%, p=0.001) and found to correlate significantly with AUC of triglyceride (p=0.017), retinyl palmitate (p=0.001) and apoB48 (p<0.001). The data suggest that normolipidaemic CAD patients have increased concentrations of intestinal lipoproteins in the fasting and postprandial state. In addition to these findings, significant correlations of fasting apoB48 with postprandial markers (p<0.02) suggests the fasting marker to be a simpler surrogate marker for the degree of total postprandial lipaemia. Study 2 investigated the effect of atorvastatin treatment on postprandial dyslipidaemia found in the 18 near-normolipidaemic CAD patients from Study 1. The trial was conducted in a randomised, placebo-controlled design, using oral fat challenges before and after 12-weeks atorvastatin/placebo treatment. Compared with the placebo group, atorvastatin decreased the total postprandial AUC for iii triglyceride (-22%, p=0.05) and apoB48 (-34%, p=0.013). Fasting markers of apoB48 (-35%, p=0.019) and RLP-C (-36%, p=0.032) also decreased significantly. Atorvastatin was also found to increase LDL-receptor activity by +218% (p<0.001) as reflected in binding studies. The data suggest atorvastatin reduces the fasting levels of intestinal lipoproteins as well as total postprandial lipaemia, but without acute dynamic changes in postprandial lipaemia. The reduction in fasting and total postprandial lipoprotein levels could be partly attributed to an increase in LDL-receptor mediated removal from circulation. In Study 3, postprandial lipaemia was compared in 15 heterozygous FH patients with 15 healthy controls. FH patients had higher fasting concentrations of apoB48 (+56%, p<0.001) and RLP-C (+48%, p=0.003). The elevation in these fasting markers of chylomicrons and their remnants suggests FH patients have postprandial dyslipidaemia due to an accumulation of these particles in plasma. Study 4 examined the effects of long- (> 6 months) and short-term (4 weeks) simvastatin treatment on modulating postprandial dyslipidaemia found in the 15 FH patients from Study 3. Short- and long-term simvastatin treatment decreased the fasting concentrations of apoB48 (-29% and 15% respectively, p<0.05) and RLP-C (both -38%, p<0.001), but did not significantly alter the FCR of the injected chylomicron remnant-like emulsion. The data suggest that in heterozygous FH both long- and short-term simvastatin treatments decrease the fasting markers of postprandial lipoproteins by mechanisms that may not be mediated via processes differentiated by the 13CO2 breath test. This implies that the effect on postprandial lipaemia may be from a decrease in production and/or a possible increase in catabolism of triglyceride-rich lipoproteins (TRLs). In Study 5, postprandial lipaemia was compared in 24 postmenopausal women age and body mass index matched with 14 postmenopausal women with type 2 DM. Postmenopausal diabetic women were found to have higher fasting concentrations of apoB48 (+21%, p=0.021) and apoC-III (+16%, p=0.042) as well as lower FCR of the chylomicron remnant-like emulsion (-50%, p<0.001). The data suggest that postmenopausal diabetic women have postprandial dyslipidaemia, and that this is due to delayed catabolism of chylomicron remnants. Study 6 was an hypothesis-generating exercise examining the effects of 4-weeks pravastatin treatment on postprandial dyslipidaemia found in 7 postmenopausal women with type 2 DM from Study 5. Although plasma LDL-cholesterol was reduced (-19%, p=0.028), there were no significant effects found on fasting apoB48 concentrations (-12%, p=0.116) or the FCR of the chylomicron remnant-like emulsion (+38%, p=0.345). A larger sample size of patients and/or treatment with a more potent statin at a dosage known to affect chylomicron remnant metabolism would be required to demonstrate a significant reduction in postprandial dyslipidaemia in postmenopausal women with type 2 DM. The results of the above mentioned studies combined support the general hypothesis that postprandial dyslipidaemia is a feature of patients with or at risk of CAD. This defect may be demonstrated using fasting apoB48 as an indicator of the degree of postprandial lipaemia. Postprandial dyslipidaemia may reflect a reduction in catabolism, as suggested with the breath test in type 2 DM, and/or an over overproduction of chylomicrons. Both these mechanisms would also increase competition for lipolysis and clearance pathways between hepatically and intestinally-derived lipoproteins. The exact mechanisms by which postprandial dyslipidaemia occurs are yet to be determined. Statins appear to improve defective postprandial lipaemia in patients with or at risk of CAD, which is in agreement with the general hypothesis. The effectiveness of a statin is dependant on their potency in inhibiting cholesterol biosynthesis and increasing receptor mediated clearance of LDL and chylomicron remnants. The studies conducted in this thesis show that postprandial dyslipidaemia can be reduced by statins but not to the extent demonstrated in controls. However, the demonstrated reduction in fasting and total postprandial lipaemia translates to a lowering in overall arterial exposure to circulating proatherogenic particles. The elevation in fasting and postprandial levels of proatherogenic chylomicron remnants found in the patient groups described in this thesis indicates another dimension to their risk of coronary disease. The reductions in the overall levels of proatherogenic particles in patients with or at high CAD risk, infers a possible reduction in the risk of coronary disease in these patients.

[Truncated abstract] The low density lipoprotein receptor-related protein (LRP), a member of the low-density lipoprotein (LDL) receptor gene family is involved in numerous biological processes including lipoprotein metabolism. This thesis concerns investigations into some aspects of LRP metabolism/regulation and possible roles in coronary artery disease (CAD). Specific aims were: to investigate the association between polymorphisms in the LRP gene and in its associated protein, the lipoprotein receptor-associated protein (RAP), with the risk of CAD; to extensively examine the influence of the LRP exon 22 C200T polymorphism on lipid metabolism; to develop and characterise assays for the mRNA expression of LRP and 2 other genes relevant to lipid metabolism, the LDL receptor (LDLR), and HMG CoA reductase (HMGCR); and finally, to apply the latter techniques to studies on the influence of genetic variation in LRP, and dietary and drug interventions, on LRP, LDLR and HMGCR mRNA expression in nucleated blood cells from healthy human subjects. Six hundred CAD subjects and 700 similarly aged controls were genotyped for 8 LRP gene polymorphisms as well as for the RAP V311M polymorphism. ... In the final phase of my studies, I examined the influence of 4 weeks therapy with a cholesterol lowering drug, an HMGCR inhibitor, atorvastatin (20mg daily), on the mRNA expression of LDLR, LRP and HMGCR in human nucleated blood cells. Twelve normal Caucasian male subjects aged 49 ? 5 (SD) years were studied. Plasma total cholesterol and LDL-C decreased by averages of 29 % and 41 % after the 4 week period. This was accompanied by an elevation in LDLR mRNA expression by approximately 30 35 %. In contrast, there was no significant effect on LRP and HMGCR mRNA expression. In conclusion, the original findings in this thesis included: demonstration of a strong influence of the LRP exon 22 C200T polymorphism on coronary artery disease and LDLR expression, but without a clear effect on fasting or postprandial lipid levels; data on the biological variation in LDLR and LRP gene expression in nucleated blood cells from normal subjects; the influence of an oral fat load on the expression viii of these genes, finding that LDLR was significantly depressed; and finally, the observation that statin therapy upregulated LDLR in nucleated blood cells.

Introduction: Cardiovascular disease affects a greater proportion of females than it does males, and is responsible for an estimated 52 percent of female deaths per annum, globally. Due to the loss of oestrogen associated with the menopause, post-menopausal females are at elevated risk for hypercholesterolaemia which is a primary risk factor for cardiovascular disease. It has not yet been conclusively established whether resistance training can be used to ameliorate hypercholesterolaemia. Aim: This randomized controlled trial investigated what effect 12 weeks of progressive resistance training would have on plasma lipoproteins in a sample of post-menopausal females. Methods: Caucasian women (n=30 intervention and n=18 control) between the ages of 55 and 65 years who were not taking hormone replacement therapy were recruited. Participants did not smoke, were sedentary, were not taking any form of cholesterol-lowering medication, had at least one cholesterol abnormality at baseline but were otherwise healthy and able to participate in a strength training programme. Following extensive medical pre-screening, information dissemination and voluntary consent, the sample was divided into two groups. The exercise sample undertook 12 weeks of resistance training on five days of the week. The control group received no intervention. Measurements were obtained at baseline and every four weeks thereafter and included measures of strength, biochemistry (oestradiol, testosterone, full blood lipid profile, glycated haemoglobin and sex hormone binding globulin), anthropometry, morphology and self-reports (dietary intake, energy expenditure and the profile of mood states questionnaire). Results: There was no change to low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglyceride content or total cholesterol as a result of the intervention. Back, chest and leg strength increased significantly (p<0.01) (increases of 51 percent, 35 percent and 43 percent respectively from baseline); waist circumference dropped (p<0.01) by 5 percent overall and diastolic blood pressure decreased significantly (-9 percent, p<0.01) in the exercise cohort but no change was noted in the matched control. Dietary intake, energy expenditure and body mass remained unchanged in both samples. Morphology (sum of skinfolds, estimated body fat content and girth measures) did not change and nor did other biochemical measures (HbA1c and sex hormone binding globulin) or hormone levels (oestradiol and testosterone). Despite the lack of overall change, an important finding was noted in individual results where a clear indication of ‘responders’ and ‘non-responders’ emerged. Conclusion: Overall mean results suggest that 12 weeks resistance training undertaken five days of the week was ineffective in reducing hypercholesterolaemia in this sample. Despite there being no identifying characteristics determined in this sample, evidence of responders and non-responders to the intervention indicates that reliance on mean data may not be sufficient when analysing data from exercise interventions. Therefore, while progressive resistance training had a positive effect on strength, waist circumference and diastolic blood pressure, it did not positively influence the plasma lipoproteins in this cohort of post-menopausal women. / Maiden name: Kelly, Janet Erica