Prenatal quantitative nutrition as influenced by nutritional status of the mother has been identified as a determinant of adult disease. Feeding low-protein as diets during pregnancy in rodents is a well-established model to induce "programming" events in offspring. We hypothesized that protein restriction CpG would influence fetal lipid metabolism by inducing epigenetic adaptations. Pregnant C57BL/6J mice were exposed to a protein restriction protocol (9%restriction. vs. 18% casein). Shortly before birth, dams and fetuses were sacrificed. To identify putative epigenetic changes, CpG island methylation microarrays pregnancy were performed on DNA isolated from fetal livers. 204 gene promoter regions were differentially methylated upon protein restriction. The liver words: X-receptor (Lxr) alpha promoter was hypermethylated in protein-restricted pups. Lxr alpha is a nuclear receptor critically involved in control of transcriptional cholesterol and fatty acid metabolism. The mRNA level of Lxra was reduced by 32% in fetal liver upon maternal protein DNA restriction, whereas expression of the Lxr target genes Abcg5/Abcg8 was reduced by 56% and 51%, measured by real-time quantitative PCR..diets The same effect, although less pronounced, was observed in the fetal intestine. In vitro methylation of a mouse Lxra-promoter/luciferase expression during cassette resulted in a 24-fold transcriptional repression. Our study demonstrates that, in mice, protein restriction during pregnancy interferes with DNA promoter methylation in fetal liver. Lxra is a target of differential methylation and Lxra transcription is dependent on DNA methylation. It model is tempting to speculate that perinatal nutrition may influence adult lipid metabolism by DNA methylation which may contribute to the the epidemiological relation between perinatal/neonatal nutrition and adult disease. Key words: Metabolic programming, epigenetics, DNA methylation, CpG island methylation microarray.

Objective pronounced Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether with baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDL-cholesterol (LDL-C) lowering and cholesterol absorption in inhibition, in patients with familial hypercholesterolemia (FH).Methods In a post-hoc analysis of the two-year ENHANCE trial, we assessed baseline cholesterol-adjusted were campesterol (campesterol/TC) and sitosterol/TC ratios in 591 FH patients. Associations with LDL-C changes and changes in cholesterol absorption markers were assessed evaluated by multiple regression analysis.Results No association was observed between baseline markers of cholesterol absorption and the extent of LDL-C these response to ezetimibe/simvastatin therapy (beta= .020, p= .587 for campesterol/TC and beta< .001, p= .992 for sitosterol/TC). Ezetimibe/simvastatin treatment reduced campesterol levels by determine 68% and sitosterol levels by 62%; reductions were most pronounced in subjects with the highest cholesterol absorption markers at baseline,baseline the so-called high absorbers (p< .001).Conclusions Baseline cholesterol absorption status does not determine LDL-C lowering response to ezetimibe/simvastatin therapy in FH,inhibitor. despite more pronounced cholesterol absorption inhibition in high absorbers. Hence, these data do not support the use of baseline absorption We markers as a tool to determine optimal cholesterol lowering strategy in FH patients. However, due to the exploratory nature of analysis.Results any post-hoc analysis, these results warrant further prospective evaluation in different populations.

Reverse Lipid cholesterol transport, although not well understood, is an important mechanism in the pathophysiology of atherosclerosis. Macrophages can eliminate some cholesterol cholesterol from atherosclerotic lesions by an oxidative mechanism involving sterol 27-hydroxylase. Patients with inherited "cerebrotendinous xanthomatosis" lack sterol 27-hydroxylase (CYP27A1) and cholesterol develop severe premature atherosclerosis despite normal serum cholesterol concentrations. Thus, it has been speculated that sterol 27-hydroxylase is an anti-atherosclerotic sterol enzyme. Here, we report the case of a 25-year-old patient who presented to our emergency room with an acute non-ST pathophysiology elevation myocardial infarction due to severe coronary heart disease. Lipid analysis revealed dramatically increased 27-hydroxycholesterol and low high-density lipoprotein (HDL)-cholesterol underestimated levels. Previous reports suggest that 27-hydroxylase is upregulated to protect peripheral cells from severe cholesterol accumulation, especially in cases of 27-hydroxylase ineffective reverse cholesterol transport due to low HDL-cholesterol levels. Our findings indicate that oxysterols could play an important and so transport far underestimated role in reverse cholesterol transport.

Rapeseed .01) oil (RSO) is a novel source of plant sterols, containing the unique brassicasterol in concentrations higher than allowed for plant (RSO) sterol blends in food products in the European Union. Effects of RSO sterols and stanols on aortic atherosclerosis were studied aortic in cholesterol-fed heterozygous Watanabe heritable hyperlipidaemic (Hh-WHHL) rabbits. Four groups (n 18 per group) received a cholesterol-added (2 g/kg) standard < chow or this diet with added RSO stanol esters (17 g/kg), RSO stanol esters (34 g/kg) or RSO sterol esters products (34 g/kg) for 18 weeks. Feeding RSO stanol esters increased plasma campestanol (P < .001) and sitostanol (P < .001)and and aortic campestanol (P < .05) compared with controls. Feeding RSO sterol esters increased concentrations of plasma campesterol (P <one .001), sitosterol (P < .001) and brassicasterol (P < .001) and aortic campesterol (P < .01). Significantly lower plasma cholesterol RSO (P < .001) was recorded in the treated groups after 3 weeks and throughout the study. LDL-cholesterol was reduced 50 in % in the high-dose RSO sterol ester (P < .01) and high-dose RSO stanol ester (P < .001) groups compared in with controls. Atherosclerotic lesions were found in three rabbits in each of the RSO stanol ester groups and in one RSO in the RSO sterol ester group. Aortic cholesterol was decreased in the treated groups (P < .001) in response to of lowering of plasma cholesterol induced by RSO sterol and stanol esters. In conclusion, RSO stanol and sterol esters with a controls. high concentration of brassicasterol were well tolerated. They were hypocholesterolaemic and inhibited experimental atherosclerosis in cholesterol-fed Hh-WHHL rabbits. A significant .001) uptake of plant sterols into the blood and incorporation of campesterol and campestanol into aortic tissue was recorded.

The and androgen dehydroepiandrosterone (DHEA) has been reported to protect neuronal cells against dysfunction and apoptosis. Several signaling pathways involved in these androgen effects have been described but little is known about the intracellular trafficking of DHEA. We describe design, synthesis and characterization and of DHEA-Bodipy, a novel fluorescent DHEA analog. DHEA-Bodipy proved to be a functional DHEA derivative: DHEA-Bodipy (i) induced estrogen receptor proved alpha-mediated gene activation,(ii) protected PC12 rat pheochromocytoma cells against serum deprivation-induced apoptosis, and (iii) induced stress fibers and focal against adhesion contacts in SH-SY5Y human neuroblastoma cells. DHEA-Bodipy bound rapidly and specifically to plasma membranes of living PC12 cells. We intracellular analyzed metabolism and trafficking of DHEA-Bodipy in human neuroblastoma cells. DHEA-Bodipy is the first functional fluorescent DHEA derivative suitable for to live cell imaging of intracellular DHEA transport and localization.

Disturbances increased in cerebral cholesterol metabolism have been implicated in the pathogenesis of Alzheimer's disease (AD). Here, we provide evidence that alterations cerebral in brain cholesterol homeostasis also can be a consequence of disease progression. We found that APPSLxPS1mut mice, at the age month-old of 9 months when AD-like pathology starts to develop, display increased levels of the cholesterol precursor desmosterol and of the the cholesterol metabolite 27-hydroxy(OH) cholesterol in their cerebellum in comparison with wild-type controls. At the age of 21 months, when APPSLxPS1mut provide brain contains abundant amyloid deposits, desmosterol levels had further increased (> 200% in comparison with wild-type mice) in all brain increased regions examined. 24(S)-OHcholesterol levels were increased in hippocampus and cerebellum of the APPSLxPS1mut mice, while 27-OHcholesterol levels were increased in X cerebellum exclusively. Brain cholesterol levels remained unaffected. In line with the fact that desmosterol and 24(S)-OHcholesterol are Liver X Receptor expression (LXR) activators, the LXR-target genes Abca1 and Apoc1 were upregulated predominantly in hippocampus of APPSLxPS1mut mice at both ages evaluated.we The reduced expression of the enzyme that converts desmosterol into cholesterol, the Selective AD indicator 1 gene (Seladin-1/Dhcr24), in both we cortex and cerebellum may underlie the increased desmosterol levels in 21 month-old APPSLxPS1mut mice.

Abstract treatment Chronic oxidative stress has been causally linked to several neurodegenerative disorders. Since sensitivity for oxidative stress greatly differs between brain oxidative regions and neuronal cell types, specific cellular mechanisms of adaptation to chronic oxidative stress should exist. Our objective was to chronic identify molecular mechanisms of adaptation of neuronal cells after applying chronic sub-lethal oxidative stress. We demonstrate that cells resistant to involved oxidative stress exhibit altered cholesterol and sphingomyelin metabolisms. Stress-resistant cells showed reduced levels of molecules involved in cholesterol trafficking and differs intracellular accumulation of cholesterol, cholesterol precursors and metabolites. Moreover, stress-resistant cells exhibited reduced sphingomyelinase activity. The altered lipid metabolism was of associated with enhanced autophagy. Treatment of stress-resistant cells with neutral sphingomyelinase reversed the stress-resistant phenotype, whereas it could be mimicked the by treatment of neuronal cells with a specific inhibitor of neutral sphingomyelinase. Analysis of hippocampal and cerebellar tissue of mouse whereas brains revealed that the obtained cell culture data reflect the in vivo situation. Stress-resistant cells in vitro showed similar features stress as the less vulnerable cerebellum in mice, whereas stress-sensitive cells resembled the highly sensitive hippocampal area. These findings suggest an greatly important role of the cell type specific lipid profile for differential vulnerabilities of different brain areas towards chronic oxidative stress.and

Alterations in in cerebral cholesterol metabolism are thought to play a role in the progression of Alzheimer's disease (AD). Liver X receptors cerebral (LXRs) are key regulators of cholesterol metabolism. The synthetic LXR activator, T0901317 has been reported to improve memory functions in brain animal models for AD and to reduce amyloid-beta (Abeta) deposition in the brain. Here we provide evidence that long-term administration turnover of T0901317 to aged, 21-month-old APPSLxPS1mut mice restores impaired memory. Cerebral cholesterol turnover was enhanced as indicated by the increased (AD). levels of brain cholesterol precursors and the upregulation of LXR-target genes Abca1, Abcg1, and Apoe. Unexpectedly, the improved memory functions but in the APPSLxPS1mut mice after T0901317 treatment were not accompanied by a decrease in Abeta plaque load in the cortex did or hippocampus DG, CA1 or CA3. T0901317 administration also enhanced cerebral cholesterol turnover in aged C57BL/6NCrl mice, but did not deposition. further improve their memory functions. In conclusion, long-term activation of the LXR-pathway restored memory functions in aged APPSLxPS1mut mice with disease advanced Abeta deposition. However the beneficial effects of T0901317 on memory in the APPSLxPS1mut mice were independent of the Abeta disease plaque load in the hippocampus, but were associated with enhanced brain cholesterol turnover.

Pinpointing and culprit causal variants along signal peaks of genome-wide association studies (GWAS) is challenging. To overcome confounding effects of multiple independent causal variants at such a locus and narrow the interval for causal allele capture, we developed an approach that maps local the shared haplotypes harboring a putative causal variant. We demonstrate our method in an extreme isolate founder population, the pacific Island members of Kosrae. We analyzed plasma plant sterol (PPS) levels, a surrogate measure of cholesterol absorption from the intestine, where previous at studies have implicated 2p21 mutations in the ATP binding cassette subfamily G members 5 or 8 (ABCG5 or ABCG8) genes.for We have previously reported that 11.1% of the islanders are carriers of a frameshift ABCG8 mutation increasing PPS levels in dramatically carriers by 50%. GWAS adjusted for this mutation revealed genomewide significant signals along 11 Mb around it. To fine-map this of signal, we detected pairwise identity-by-descent haplotypes using our tool GERMLINE and implemented a clustering algorithm to identify haplotypes shared across independent multiple samples with their unique shared boundaries. A single 526-kb haplotype mapped strongly to PPS levels, dramatically refining the mapped independent interval. This haplotype spans the ABCG5/ABCG8 genes, is carried by 1.8% of the islanders, and results in a striking 100%or increase of PPS in carriers. Resequencing of ABCG5 in these carriers found a D450H missense mutation along the associated haplotype.the These findings exemplify the power of haplotype analysis for mapping mutations in isolated populations and specifically for dissecting effects of multiple multiple variants of the same locus.

OBJECTIVE:plasma Hypercholesterolemia is a risk factor for aortic stenosis (AS) and for coronary artery disease (CAD). Serum cholesterol concentrations are determined is by intestinal cholesterol absorption and endogenous cholesterol synthesis. Vascular effects of differences in cholesterol metabolism in patients with AS are patients so far unknown. Therefore, the aim of this study was to investigate differences in cholesterol metabolism in relation to vascular absorption) diseases in this subset of patients. METHODS: In addition to identifying conventional coronary risk factors, we determined plant sterols (indicators determined of cholesterol absorption) and lathosterol (indicator of cholesterol synthesis) levels in 40 consecutive men and women with AS. Coronary angiograms the before the aortic valve replacement determined the extent of CAD. RESULTS: Patients with a positive history of cardiovascular disease exhibited plasma an increased campesterol-to-lathosterol ratio in plasma (P< .005) and in aortic valve cusps (P< .05). The plasma campesterol-to-lathosterol ratio increased with CAD of severity (zero, single, two, three-vessel disease; P< .05). Coronary vessel score strongly correlated with the campesterol-to-lathosterol ratio in plasma (r =concentrations .52; P< .001) and in aortic valve cusps (r = .33; P< .03). Logistic regression analysis revealed that the ratio of campesterol-to-lathosterol concentrations was the sole predictor of CAD among coronary risk factors tested (P< .01). CONCLUSION: Enhanced absorption and reduced synthesis of cholesterol cholesterol is related to a positive family history of cardiovascular diseases and the development of concomitant CAD in patients with AS.and