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Background Many patients suffering from premature coronary artery disease report a family history for such events. A mutation in a particular gene, which confers susceptibility for atherosclerosis, will be found more frequently in individuals suffering from coronary atherosclerosis than in the general population. We have recently reported the identification of an Asp 9 Asn substitution in the lipoprotein lipase (LPL) enzyme. We analyzed the impact of this mutation on the progression of coronary atherosclerosis and the effect of pravastatin in both carriers and noncarriers. Methods and Results All patients were enrolled in the quantitative coronary angiographic clinical trial REGRESS, which studied the impact of pravastatin therapy on coronary atherosclerosis. The Asp 9 Asn mutation was identified in 38 of 819 (4.8%) patients. Carriers of the mutation more often had a positive family history of cardiovascular disease and lower HDL cholesterol levels than noncarriers. In the placebo group, carriers showed more progression of coronary atherosclerosis than noncarriers: mean reduction of the minimum obstruction diameter of −0.25 mm versus −0.12 mm ( P =.029) and increase of percentage diameter stenosis of 6.4% versus 1.4% ( P =.004). Moreover, the adjusted relative risk for a clinical event for carriers was calculated at 2.16 (95% CI, 1.09 to 4.29; P =.027). Although the lipid-lowering effect of pravastatin was attenuated in carriers, it appeared that these patients showed a response similar to noncarriers in terms of less progression of atherosclerosis and event-free survival. Conclusions This study shows that heterozygosity for a mutation in the LPL gene, which causes only subtle changes in fasting plasma lipids, may promote the progression of coronary atherosclerosis and diminish clinical event–free survival.

Hypercholesterolemia, although a modifiable risk factor for cardiovascular disease, is still one of the leading causes of death among older people in western countries. The use of statins among cholesterol reducing agents in both primary and secondary prevention has not been extensively studied in older patients in contrast to middle-aged patients. Despite a growing body of evidence in secondary prevention, statins are still under utilized in older patients with established vascular disease. On the other hand, the benefits of statins in primary prevention are not so clear. Therefore, the systematic use of statins in older patients with hypercholesterolemia needs to be further investigated.

Background Our objective was to find single nucleotide polymorphisms (SNPs), within transcriptional pathways of glucose and lipid metabolism, which are related to multiple features of the metabolic syndrome (MetS). Methods 373 SNPs were measured in 3575 subjects of the Doetinchem cohort. Prevalence of MetS features, i.e. hyperglycemia, abdominal obesity, decreased HDL-cholesterol levels and hypertension, were measured twice in 6 years. Associations between the SNPs and the individual MetS features were analyzed by log-linear models. For SNPs related to multiple MetS features (P < 0.01), we investigated whether these associations were independent of each other. Results Two SNPs, CETP Ile405Val and APOE Cys112Arg, were associated with both the prevalence of low HDL-cholesterol level (Ile405Val P = < .0001; Cys112Arg P = 0.001) and with the prevalence of abdominal obesity (Ile405Val P = 0.007; Cys112Arg P = 0.007). For both SNPs, the association with HDL-cholesterol was partly independent of the association with abdominal obesity and vice versa. Conclusion Two SNPs, mainly known for their role in lipid metabolism, were associated with two MetS features i.e., low HDL-cholesterol concentration, as well as, independent of this association, abdominal obesity. These SNPs may help to explain why low HDL-cholesterol levels and abdominal obesity frequently co-occur.

Background: The possible association between depressive symptoms and metabolic syndrome (MetS) has recently become an important topic of discussion. There is some limited and inconsistent evidence in the literature concerning whether or not depression and metabolic syndrome are associated. The aim of this study was to examine the association between depressive symptoms and metabolic syndrome. Methods: This is a cross-sectional community-based study. The setting is a family practice unit in an urban area which serves about 3,600 people. The participants were 250 individuals aged 18 and over, selected randomly from all enrolled patients in this family practice unit. National Cholesterol Education Program (NCEP- ATP-III) criteria were used for the classification of metabolic myndrome (MetS). The Beck Depression Inventory was filled out by the participants for the evaluation of depressive symptoms. Results: The prevalence of MetS was similar for men (48.8%) and women (48.1%) and increased with age in both sexes. Participants with only primary education were found to be 2.2 times more at risk of developing MetS than participants with a higher education. The prevalence of depressive symptoms was higher among women (31.0%) than men (9.9%). Statistical analyses revealed no statistically significant association between MetS and depressive symptoms. Conclusion: The prevalence of MetS was found to be high in both sexes. Women had a 3.8 times higher risk of developing depressive symptoms than men. We found no association of depressive symptoms with MetS or with any of the MetS criteria. Depresif semptomlar ve metabolik sendrom (MetS) arasındaki muhtemel ilişki son dönemde önemli bir tartışma konusudur. Bu ilişkinin varlığı konusunda sınırlı veri vardır. Bu çalışmanın amacı depresyon ve MetS arasındaki ilişkiyi incelemektir. Yöntem: Bu çalışma toplum kökenli kesitsel bir çalışmadır. Çalışma 3600 kişiden sorumlu kentsel bir aile hekimliği biriminde yürütülmüştür. Çalışmaya katılanlar bu aile hekimliği ünitesine başvuran 18 yaş ve üzeri 250 kişiden oluşmuştur. MetS (MetS) sınıflaması NCEP-ATPIII kriterleri kullanılarak yapılmıştır. Beck Depresyon Ölçeği depresyon değerlendirmesi için tüm katılımcılar tarafından doldurulmuştur. Bulgular: MetS prevalansı her iki cinsiyet için benzerdi (%48.8 erkek ve %48.1 bayan) ve yaş ilerledikçe artmaktaydı. İlkokul mezunları yüksekokul mezunlarına göre 2.2 kez daha fazla MetS riskine sahipti. Depresif şikayet prevalansı kadınlarda (%31) erkeklere (%9.9) oranla daha fazlaydı. İstatistik analizlerle MetS ve depresif semptomlar arasında anlamlı bir ilişki tespit edilemedi. Sonuç: MetS prevalansı her iki cinsiyet içinde yüksek bulundu. Depresif semptomlar açısından kadınlar erkeklere kıyasla 3.8 kat daha fazla risk altındaydı. Depresyon semptomları ile hem MetS hemde MetS kriterleri arasında ilişki bulamadık.

Findings from numerous studies suggest an association between low cholesterol levels and suicidal behavior in patients with different psychiatric diagnoses. The aims of this case-control study were to test whether cholesterol levels in male suicidal patients (N=20) with borderline personality disorder (BPD) are lower than in male non-suicidal patients (N=20) with BPD and male healthy control group (N=20), and to evaluate the influence of structured individual psychoanalytic psychotherapy on suicidal behavior. The groups were matched for age and body mass index (BMI). Results showed that serum cholesterol levels did not differ significantly between suicidal and non-suicidal BPD patients and healthy controls. The level of psychopathology (measured by Brief Psychiatric Rating Scale and Hamilton Depression Rating Scale) was significantly higher in the group of suicidal patients, which indicates the importance of evaluating particular clinical symptoms in BPD, in order to prevent suicidal behavior. Non-suicidal male patients suffering from BPD received more frequently structured individual psychoanalytic psychotherapy prior to the hospitalization than suicidal group. These results emphasized the role of this type of psychotherapy in preventing suicidal behavior in BPD patients.

We present an approach to association studies involving a dozen or so 'response' variables and a few hundred 'explanatory' variables which emphasizes transparency, simplicity, and protection against spurious results. The methods proposed are largely non-parametric, and they are systematically rounded-off by the Benjamini-Hochberg method of multiple testing. An application to the detection of associations between risk factors of heart disease and genetic polymorphisms using the REGRESS dataset provides ample illustration of our approach. Special attention is paid to book-keeping and information-management aspects of data analysis, which allow the creation of an informative and reasonably digestible 'map of relationships' - the end-product of an association study as far as statistics is concerned.

OBJECTIVE To explore the prevalence of lipid abnormalities and their relationship with albumin excretion and microalbuminuria in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS The study population comprised 895 young subjects with type 1 diabetes (490 males); median age at the baseline assessment was 14.5 years (range 10–21.1), and median diabetes duration was 4.8 years (0.2–17). A total of 2,194 nonfasting blood samples were collected longitudinally for determination of total cholesterol, LDL cholesterol, HDL cholesterol, TG, and non-HDL cholesterol. Additional annually collected data on anthropometric parameters, A1C, and albumin-to-creatinine ratio (ACR) were available. RESULTS Total cholesterol, LDL cholesterol, HDL cholesterol, and non-HDL cholesterol were higher in females than in males (all P < 0.001). A significant proportion of subjects presented sustained lipid abnormalities during follow-up: total cholesterol >5.2 mmol/l (18.6%), non-HDL cholesterol >3.4 mmol/l (25.9%), TG >1.7 mmol/l (20.1%), and LDL cholesterol >3.4 mmol/l (9.6%). Age and duration were significantly related to all lipid parameters (P < 0.001); A1C was independently related to all parameters (P < 0.001) except HDL cholesterol, whereas BMI SD scores were related to all parameters (P < 0.05) except total cholesterol. Total cholesterol and non-HDL cholesterol were independently related to longitudinal changes in ACR (B coefficient ± SE): 0.03 ± 0.01/1 mmol/l, P = 0.009, and 0.32 ± 0.014/1 mmol/l, P = 0.02, respectively. Overall mean total cholesterol and non-HDL cholesterol were higher in microalbuminuria positive (n = 115) than in normoalbuminuric subjects (n = 780): total cholesterol 4.7 ± 1.2 vs. 4.5 ± 0.8 mmol/l (P = 0.04) and non-HDL cholesterol 3.2 ± 1.2 vs. 2.9 ± 0.8 mmol/l (P = 0.03). CONCLUSIONS In this longitudinal study of adolescents with type 1 diabetes, sustained lipid abnormalities were related to age, duration, BMI, and A1C. Furthermore, ACR was related to both total cholesterol and non-HDL cholesterol, indicating a potential role in the pathogenesis of diabetic nephropathy.

We conducted an in-depth investigation of the effects of conjugated linoleic acid (CLA) on the expression of key metabolic genes and genes of known importance in intestinal lipid metabolism using the Caco-2 cell model. Cells were treated with 80 mu mol/L of linoleic acid (control), trans-10, cis-12 CLA or cis-9, trans-11 CLA. RNA was isolated from the cells, labelled and hybridized to the Affymetrix U133 2.0 Plus arrays (n = 3). Data and functional analysis were preformed using Bioconductor. Gene ontology analysis (GO) revealed a significant enrichment (P

Objectives High serum total cholesterol and low-density lipoprotein (LDL) levels have been demonstrated to increase the probability of a sustained viral response (SVR) in chronic hepatitis C. Conversely, insulin resistance reduces SVR rates. We investigated the influence of baseline glucose and lipid values on the outcome of hepatitis C virus (HCV) treatment in HIV-1 infected subjects. Methods We retrospectively reviewed the charts of HIV/HCV-coinfected patients treated with an interferon-based regimen from 2002 to 2008. Fasting glucose levels and total cholesterol, LDL and triglyceride levels were recorded prior to the initiation of treatment. Results Of the 96 patients enrolled in the study, 36 (37.5%) had genotype 1, 48 (50%) genotype 2 or 3 and 12 (12.5%) genotype 4. SVR was obtained in 25% (nine of 36) and 70% (42 of 60) of patients with genotype 1 and other genotypes, respectively. In the multivariate analysis, the independent predictors of SVR were: genotype other than genotype 1 [adjusted odds ratio 9.64, confidence interval (CI) 2.7–34.3; P

Objective: To assess the effect of rimonabant, micronised fenofibrate and their combination on anthropometric and metabolic parameters in overweight/obese patients with dyslipidaemia. Methods: All patients (n = 30) received a hypocaloric diet (similar to 600 kcal/day deficit) and were randomly allocated to receive open-label rimonabant (R) 20 mg/day (n = 10), micronised fenofibrate (F) 200 mg/day (n = 10) or rimonabant 20 mg/day plus fenofibrate 200 mg/day (RF) (n = 10). Anthropometric and metabolic parameters were assessed at baseline and 3 months after treatment initiation. Results: Compared with baseline similar significant reductions in body weight, body mass index and waist circumference were observed in the R (-6, -5 and -5%, respectively; p < 0.01) and RF group (-5% for all, p < 0.05), while improvements in these parameters were smaller in the F group (-2, -2.5 and -2%, respectively; p < 0.05). Triglycerides were reduced by 18% in the R group (p = NS), by 39% in the F group (p < 0.001) and by 46% in the RF group (p < 0.05). Importantly, combination treatment resulted in a 42% increase in high-density lipoprotein cholesterol (HDL-C) levels (p < 0.05), while HDL-C was not significantly altered in the two monotherapy groups. Subsequently, a more pronounced increase in apolipoprotein A-I (ApoA-I) levels (+25%) was observed in the RF group compared with changes in both monotherapy groups (p < 0.0001 vs R and p < 0.005 vs F group). Low-density lipoprotein cholesterol (LDL-C) levels were not significantly altered in any group. Apolipoprotein B (apoB) levels were reduced in all groups and this reduction was significantly more pronounced in the RF group (p < 0.05 vs baseline as well as p < 0.005 and p < 0.01 for RF vs R and F groups, respectively). ApoB/apoA-I ratio decreased by 3% with R (p = NS), by 18% with F (p < 0.05) and by 40% with RF treatment (p < 0.01). Total cholesterol to HDL-C ratio decreased by 20% with F (p < 0.0001) and by 33% with RF therapy (p < 0.005), while it was not significantly altered in R group. Conclusion: The combination of rimonabant and fenofibrate may further improve metabolic parameters in overweight/obese patients with dyslipidaemia compared with each monotherapy. This improvement is particularly pronounced for HDL-C levels. Expert Opinion on Pharmacotherapy

BACKGROUND: Patients with systolic heart failure have generally been excluded from statin trials. Acute coronary events are uncommon in this population, and statins have theoretical risks in these patients. METHODS: A total of 5011 patients at least 60 years of age with New York Heart Association class II, III, or IV ischemic, systolic heart failure were randomly assigned to receive 10 mg of rosuvastatin or placebo per day. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included death from any cause, any coronary event, death from cardiovascular causes, and the number of hospitalizations. RESULTS: As compared with the placebo group, patients in the rosuvastatin group had decreased levels of low-density lipoprotein cholesterol (difference between groups, 45.0%; P

The Hyplip2 congenic mouse strain contains part of chromosome 15 from MRL/MpJ on the BALB/cJ background. Hyplip2 mice show increased plasma levels of cholesterol and predominantly triglycerides (TGs) and are susceptible to diet-induced atherosclerosis. This study aimed at elucidation of the mechanism(s) explaining the hypertriglyceridemia. Hypertriglyceridemia can result from increased intestinal or hepatic TG production and/or by decreased LPL-mediated TG clearance. The intestinal TG absorption and chylomicron formation were studied after intravenous injection of Triton WR1339 and an intragastric load of olive oil containing glycerol tri[3H]oleate. No difference was found in intestinal TG absorption. Moreover, the hepatic VLDL-TG production rate and VLDL particle production, after injection of Triton WR1339, were also not affected. To investigate the LPL-mediated TG clearance, mice were injected intravenously with glycerol tri[3H]oleate-labeled VLDL-like emulsion particles. In Hyplip2 mice, the particles were cleared at a decreased rate (half-life of 25 ± 6 vs. 11 ± 2 min; P < 0.05) concomitant with a decreased uptake of emulsion TG-derived 3H-labeled fatty acids by the liver and white adipose tissue. The increased plasma TG levels in Hyplip2 mice do not result from an enhanced intestinal absorption or increased hepatic VLDL production but are caused by decreased LPL-mediated TG clearance. Copyright © 2007 by the American Society for Biochemistry and Molecular Biology, Inc.

The effect of statins to reduce mortality and morbiditiy in primary and secondary prevention as well as in acute coronary syndroms is well established. Recent data show that pleiotropic effects might also have direct effects on the myocardial cell. However, in chronic heart failure the outcome is inversely related to LDL-plasma concentrations and other pleiotropic effects might impair mitochondrial function. Since there are no safety data on the use of statins in chronic heart failure, a controlled randomized and placebo-controlled trial is urgently needed.

ObjectivesWe tested the hypothesis that CD40 ligand (CD40L) induces a prothrombotic state by enhancing oxidative stress.BackgroundPatients with hypercholesterolemia show an ongoing prothrombotic state, but the underlying mechanism is still unclear.MethodsCirculating levels of the soluble form of CD40L (sCD40L), prothrombin fragment (F1+2, a marker of thrombin generation), and 8-hydroxy-2′-deoxyguanosine (8-OHdG, a marker of oxidative stress) were measured in 40 patients with hypercholesterolemia and in 20 age- and gender-matched healthy subjects.ResultsPatients with hypercholesterolemia showed significantly higher levels of sCD40L (p < 0.005), 8-OHdG (p < 0.005), and prothrombin F1+2 (p < 0.005), as compared with control subjects. Soluble CD40L significantly correlated with 8-OHdG (r = 0.85, p < 0.0001) and prothrombin F1+2 (r = 0.83, p < 0.0001); a significant correlation between 8-OHdG and prothrombin F1+2 was also observed (r = 0.64, p < 0.0001). An in vitro study demonstrated that CD40L-stimulated monocytes from patients with hypercholesterolemia expressed more tissue factor (TF) and prothrombin F1+2 than monocytes from controls; co-incubation of monocytes with either an inhibitor of NADPH oxidase or an inhibitor of phosphatidylinositol-3-kinase significantly reduced CD40L-mediated clotting activation. A marked inhibition of CD40L-mediated clotting activation was also observed in two male patients with hereditary deficiency of gp91 phox, the central core of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Finally, we demonstrated that CD40L-mediated clotting activation was significantly inhibited by vitamin C, a known antioxidant.ConclusionsThis study indicates that in patients with hypercholesterolemia, CD40L over-expresses TF and increases the thrombin generation rate by an oxidative stress-mediated mechanism that requires the activation of NADPH oxidase.

In the present study, we sought to evaluate the role of three polymorphisms in the ecNOS (endothelial constitutive nitric oxide synthase) gene in relation to the existence, severity and progression of CAD (coronary artery disease), MI (myocardial infarction) and the occurrence of ischaemia in a predominantly Caucasian population. Patients with CAD (n = 760) and age- and sex-matched population-based controls (n = 691) were genotyped for the -786T/C, E/D298 and 4a/b polymorphisms. Patients were randomized to pravastatin (40 mg) or placebo. Progression of atherosclerosis was evaluated by sequential angiography. Functionality was assessed by ST segment analysis of ambulant ECGs. The E298 (P = 0.003) and 4a (P = 0.001) alleles were associated with CAD. Furthermore, E298 (P = 0.009) and -786T (P = 0.022) alleles were associated with previous MI among patients, predominantly smokers. D/D298 homozygotes, but not -786T/C or 4a/4b mutants, had longer-lasting ischaemia than others (P < 0.05). We found no differences in progression of atherosclerosis, irrespective of pravastatin use. We conclude that the E/D298 polymorphism is most consistently associated with CAD, but not with progression of atherosclerosis. The E allele is associated with CAD and MI, whereas the D allele is associated with ischaemia. Chemicals / CAS: endothelial nitric oxide synthase, 503473-02-7; pravastatin, 81131-74-0; Anticholesteremic Agents; Nitric Oxide Synthase Type III, EC 1.14.13.39; Nitric Oxide Synthase, EC 1.14.13.39; NOS3 protein, human, EC 1.14.13.39; Pravastatin, 81093-37-0

OBJECTIVE - Endothelial dysfunction is considered an important early marker of atherosclerosis and cardiovascular risk and is currently used as a surrogate end point for cardiovascular at risk in clinical trials. Type 2 diabetic patients show a characteristic dyslipidemia. Aggressive lipid lowering might he an effective method to improve endothelial function in these patients. RESEARCH DESIGN AND METHODS - A randomized, double-blind, placebo-controlled trial was completed to study the effect of 30 weeks' administration of atorvastatin 10 rug and 80 rug on endothelial function, as assessed by B-mode ultrasound of the brachial artery, in 133 patients with type 2 diabetes without a history of cardiovascular disease. RESULTS- patients with diabetes and diabetic dyslipidemia had considerable endothelium-dependent and endothelium-independent dysfunction; mean flow-mediated vasodilation (SD) was 3.16% (3.56), and mean response on sublingual nitroglycerin was 6.58% (6.04). Despite su stantia owering of all atherogenic lipid parameters, no improvement of endotheliumdependent vasodilatation was found (P > 0.8). CONCLUSIONS - We observed considerable baseline endothelium-dependent and endothelium-independent dysfunction in patients with diabetes and diabetic dyslipidemia without a history of cardiovascular disease. Aggressive lipid lowering by administration of atorvastatin, resulting in substantial improvement of the lipid profile, did not reverse endothelial dysfunction.

The aim of the present case-control study was to estimate, by density gradient ultracentrifugation, LDL heterogeneity in myocardial infarction, and to evaluate the effect of smoking and beta-blocker treatment on LDL subfraction profile. Our results show that patients who survive myocardial infarction have an abundance of small, dense LDL in their plasma, compared with controls. Patients who were on beta-blockers and those who smoked showed a more atherogenic LDL subfraction profile than the rest. In patients on beta-blocker treatment, the proportion of LDL3 was positively correlated with triglyceride concentration and body mass index. Dense LDL predominates in patients irrespective of smoking or beta-blocker treatment. The relative risk, calculated by logistic regression as the odds ratio of high LDL3, was 75 (95% confidence interval 2.5-22.1) and was not significantly influenced when smoking, beta-blocker treatment, triglycerides or the other parameters of the study were included in the statistical model. Ann Clin Biochem

Lipid-lowering therapy now has undoubtedly proven to be an effective therapeutic modality to retard the progression of coronary atherosclerosis, An additional approach for prevention of the progression of atherosclerosis is calcium channel blocker (CCB) treatment. Evidence indicating that CCBs inhibit atherosclerosis is less unequivocal than the clear evidence for lipid-lowering therapy, Many investigations support the view that a number of key processes in atherosclerosis may be influenced by CCBs. From the "negative" and "positive" studies with CCBs performed in animals and humans we must conclude that apparently some, but not all, types or stages of the atherosclerotic process are inhibited by CCBs, To assess whether lipid-lowering therapy and CCB treatment may have an additive or synergistic beneficial effect on human atherosclerosis, which is conceivable because their antiatherosclerotic properties differ, data fi om the angiographic Lipid-lowering trial REGRESS (pravastatin vs. placebo) were reviewed. In REGRESS, patients in the pravastatin group had significantly less progression if cotreated with CCBs as compared with those with no CCB cotreatment, whereas in the placebo (no pravastatin) group no effect of CCB treatment was observed, With respect to angiographic new lesion formation, in the pravastatin group there were 50% less patients with new angiographic lesions if cotreated with CCBs as compared with no CCB cotreatment, whereas in the placebo (no pravastatin) group, again, no significant effect of CCB treatment was observed. No beneficial effects of CCB treatment on clinical events mere observed during the a-year study follow-up. In view of the correlation between angiographic progression and subsequent clinical events as demonstrated in several large trials, it is not unrealistic to also anticipate in this population, a beneficial effect on clinical events with longer follow-up. Although the REGRESS trial was not designed to evaluate combination therapy, the results suggest that addition of CCBs to HMG-CoA reductase inhibitor therapy (pravastatin) acts synergistically in retarding the progression of established coronary atherosclerosis, These results appear to warrant prospective randomized trials to determine in a more definitive manner the merits of this combination in the prevention of progression of coronary atherosclerosis. Currently a number of studies in these fields are being designed or are already underway.

Recent studies have shown that vascular dementia (VD) and Alzheimer's dementia (AD) might overlap in many aspects. Also it was suggested that elevated cholesterol levels could have some influence on AD onset and progression. The aim of this study was to evaluate the levels of cholesterol in patients with both types of dementia. Sixty-six patients with dementia were enrolled in this study. AD was diagnosed in 43 and VAD in 23 patients. In a group of 43 AD patients (22 males, mean age 72.79 +/-8.19) plasma values of cholesterol were analyzed. In AD group, 18 patients had normal, and 25 had elevated plasma cholesterol levels, while in VAD group 12 patients had elevated and 11 had normal plasma cholesterol levels. Mean plasma level of total cholesterol was 5.39 +/-1.05, LDL 3.33 +/- 0.95, and HDL 1.41 +/- 0-34 in patients with AD. In patients with VAD mean plasma level of total cholesterol was 5.78 +/-1.06, HDL 1.44 +/- 0.57, LDL 3.72 +/- 0.85. The levels of total cholesterol, LDL, HDL were higher in a group of patients with VAD, but the difference did not reach statistical significance. Vascular risk factors are known to be associated with VAD. Our data, however, show that patients with AD also have elevated plasma levels of cholesterol. Our results support the idea that cholesterol could have some influence on etiology, onset and progression of both AD and VAD, thus implying similarities in pathogenesis of both diseases.

Background and purpose: Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved. Experimental approach: We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis. Key results: Activation of PXR induced cholesterogenesis both in pre-clinical and clinical settings. In human volunteers, rifampicin increased intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and total cholesterol and lathosterol–cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Experiments in mice indicated that PXR activation causes widespread induction of the cholesterol synthesis genes including the rate-limiting Hmgcr and upregulates the intermediates in the Kandutsch–Russell cholesterol synthesis pathway in the liver. Additionally, PXR activation induced plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL uptake, in both mice and humans. We propose that these effects were mediated through increased proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2) in response to PXR activation. Conclusions and implications: PXR activation induces cholesterol synthesis, elevating LDL and total cholesterol in humans. The PXR–SREBP2 pathway is a novel regulator of the cholesterol and PCSK9 synthesis and a molecular mechanism for drug- and chemical-induced hypercholesterolemia.

Over an 18-year period, beginning in 1955, a group of subjects has been studied six times to determine if any relationship exists among serum cholesterol levels, body weight, health status, diet quality and stress or anxiety. For the first four test periods, extending through ages 7 to 16 years, there were 321 subjects. Later, in 1968, 86 of the original 321 subjects, now aged 19-22 years, were able to participate in a follow-up study. The 1974 study was able to involve 30 of the original 321 subjects now aged 26-29 years. Findings show that from approximately the fifteenth year onward serum cholesterol levels in males continue to rise in an almost linear fashion, whereas females experienced a drop in serum cholesterol levels at ages 19-22 years which was followed by a rise when they reached 26-29 years. Persons who were classified as overweight in the sixth test period had higher serum cholesterol levels than persons classified as either desirable weight or under-weight for both sexes. Anxiety levels as determined by the IPAT anxiety scale questionnaire in the sixth test period showed that for males there was a positive relationship between serum cholesterol and anxiety but for women a negative relationship was shown. Subjects with serum cholesterol levels above 250 mg/100 ml consumed diets higher in saturated fats than the subjects with serum cholesterol levels below 250 mg/100 ml. In males a significant positive correlation was shown between serum cholesterol levels and smoking.

Fifty eight male and 10 female free living volunteers were paired in two groups based on similar cholesterol levels. Each individual in one group ate 43 g of oatmeal daily in the form of porridge, over the period January 31 to March 15, while the corresponding individuals in a control group ate 43 g of cornflakes daily. Serum cholesterol levels and ∝-lipoprotein fractions were measured twice at 3-week intervals during the experiment and no significant differences were found between the groups. Gain in weight of volunteers was minimal during the experiment with an increase of 0.5 kg per person for males on cornflakes, and 1 to 1.5 kg per person for females on porridge. The results suggest that porridge did not have a hypocholesterolaemic effect in the quantities consumed for the time period of this experiment. Deposited by bulk import