Biomedical subjects

Arnold von Eckardstein

Publications and source records attributed to Arnold von Eckardstein.

At least 19 recordsLinked to original sources

PubMed2006

Lipoprotein distribution and biological variation of 24S- and 27-hydroxycholesterol in healthy volunteers.

24S- and 27-hydroxycholesterol are obligatory intermediates of cholesterol catabolism and play an important role in the maintenance of whole-body cholesterol homeostasis. Using an HPLC-MS method for oxysterol quantification, the distribution of esterified and unesterified oxysterols in lipoprotein subfractions as well as the influence of daytime, food intake and menstrual cycle on oxysterol concentrations were investigated in healthy volunteers. Moreover, reference intervals for 24S- and 27-hydroxycholesterol in plasma as well as the corresponding levels for 27-hydroxycholesterol in the HDL subfraction were established in 100 healthy volunteers. Both circulating oxysterols are mainly transported in association with HDL and LDL--primarily in the esterified form. No significant diurnal changes and no variations during menstrual cycle of either absolute or cholesterol-related plasma levels were detected. In contrast to 24S-hydroxycholesterol in plasma and 27-hydroxycholesterol in the HDL subfraction, the 95% reference intervals of 27-hydroxycholesterol both in plasma and the non-HDL subfraction were higher in males than in females. The concentrations of 27-hydroxycholesterol in plasma and the non-HDL subfraction showed strong positive correlations with the concentrations of cholesterol, non-HDL cholesterol and triglycerides. Our data on the lipoprotein distribution of oxysterols as well as on their intra- and inter-individual variation set the stage for future clinical studies.

Adult↗

PubMed2006

ATP-Binding cassette transporter A1 modulates apolipoprotein A-I transcytosis through aortic endothelial cells.

High-density lipoproteins and their major protein constituent apolipoprotein A-I (apoA-I) possess diverse atheroprotective properties. Most of them must be exerted within the arterial wall. Actually, high-density lipoproteins are the most abundant lipoproteins within the arterial intima. We have recently reported that apoA-I is transcytosed through aortic endothelial cells. In the present study, we evaluate the role of ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor BI (SR-BI) in this process. Using pharmacological interventions and RNA interference, we investigated whether ABCA1 and SR-BI modulate apoA-I binding, internalization and transcytosis in endothelial cells. Upregulation of ABCA1 with oxysterols increased apoA-I binding and internalization. Trapping ABCA1 on the cell surface with cyclosporin A enhanced apoA-I binding but decreased its internalization and transcytosis. In addition, apoA-I binding, internalization, and transcytosis were reduced by at least 50% after silencing ABCA1 but not after knocking down SR-BI. The integrity of the endothelial cell monolayer was affected neither by cyclosporin A treatment nor by ABCA1 silencing, as controlled by measuring inulin permeability. Finally, in ABCA1-GFP-expressing cells, fluorescently labeled apoA-I colocalized intracellularly with ABCA1-GFP. However, apoA-I-containing vesicles did not colocalize with the late endosome marker LAMP-1 (lysosome-associated membrane protein-1). In conclusion, ABCA1, but not SR-BI, modulates the transcytosis of apoA-I through endothelial cells.

ATP Binding Cassette Transporter 1↗

PubMed2006

Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase.

Serine-palmitoyltransferase (SPT) catalyzes the rate-limiting step of the de novo synthesis of sphingolipids. SPT is considered to be a heterodimer composed of two subunits, SPTLC1 and SPTLC2. Here we report the identification of a novel, third, SPT subunit (SPTLC3) that shows 68% homology to the SPTLC2 subunit. Quantitative real-time PCR revealed that SPTLC3 expression is highly variable between different human tissues and cell lines. The highest expression was observed in placenta tissue and human trophoblast cell lines. The overexpression of SPTLC3 in Hek293 cells, which otherwise have very little endogenous SPTLC3, led to a 2- to 3-fold increase in cellular SPT activity. Silencing of SPTLC3 expression in HepG2 cells or human trophoblast cells by transfecting SPTLC3-specific siRNA resulted in a significant reduction of cellular SPT activity. The expression of two SPT isoforms could be a cellular mechanism to adjust SPT activity to tissue-specific requirements of sphingolipid synthesis.

Acyltransferases↗

PubMed2006

Relation of plasma thyroid-stimulating hormone levels to vascular lesions and atrophy of the brain in the elderly.

CONTEXT: Recent studies suggest that thyroid disease is associated with cardiovascular and peripheral vascular disease. However, little is known about the underlying pathophysiology and the relation with cerebrovascular disease or brain atrophy in the elderly. OBJECTIVE: To determine if plasma thyroid-stimulating hormone (TSH) levels are associated with vascular brain changes and cortical atrophy in the elderly. DESIGN: Community based, cross-sectional study. PARTICIPANTS AND SETTING: 268 participants of the Memory and Morbidity in Augsburg Elderly Study, 65-83 years of age and without contraindications for magnetic resonance imaging (MRI) of the brain. MAIN OUTCOME MEASURES: The presence of brain lesions and atrophy was determined using a standardized MRI protocol, an established rating scale and a single rater. Plasma TSH levels were assessed using standard laboratory methods. The association between plasma TSH levels and MRI findings was analyzed using logistic and linear regression models. RESULTS: Higher TSH levels within the normal clinical range were significantly associated with severer cortical atrophy (p = 0.04) and a higher proportion of infarct-like vascular lesions (p = 0.005) in men. These associations were independent of potential confounders, including thyroid hormone therapy, in multivariable regression analysis. No association between plasma TSH levels and both MRI outcomes were observed in women. In addition, neither in men nor in women was an association between TSH levels and white-matter lesions found. CONCLUSIONS: Increasing TSH levels even within the normal clinical range are associated with severer brain atrophy and infarct-like vascular lesions in elderly men.

Aged↗

PubMed2006

Evidence for oxidative stress at elevated plasma thiol levels in chronic exposure to carbon disulfide (CS2) and coronary heart disease.

OBJECTIVES: Oxidative stress in plasma may be promoted by plasma thiols such as homocysteine. However, other thiols such as glutathione may also exert antioxidant effects in vitro and in vivo. To further investigate whether plasma thiols act as prooxidants or antioxidants, we compared plasma oxidative status in patients with coronary heart disease (CHD) and in subjects occupationally exposed to carbon disulfide (CS(2)). METHODS: Fifty-five subjects chronically exposed to CS(2), 53 CHD patients, and 52 healthy controls were examined. To assess plasma oxidative status, concentrations of thiobarbituric reactive substances (TBARS) and total antioxidative capacity (TAC), as well as ferritin and ceruloplasmin were determined. Antioxidative reserve was assessed by the determination of vitamine E, uric acid, superoxide dismutase, catalase, and glutathion peroxidase. In addition, protein and non-protein plasma thiol levels were measured. RESULTS: Patients in both groups had increased levels of plasma thiols as compared to controls: CS(2)-exposed subjects presented with increased levels of thiols associated with plasma proteins, whereas CHD patients presented with elevated total homocysteine and cysteine levels. TBARS were significantly increased and TAC was significantly decreased both in CS(2)-exposed subjects and in CHD patients. In addition decreased activity of glutathione peroxidase, an antioxidative enzyme inhibited by thiol-containing compounds, was noted in both groups. CONCLUSION: These results demonstrate that regardless of their metabolic origin increased thiols are associated with increased oxidative stress in plasma.

Adult↗

PubMed2006

Ethnicity-dependent genetic association of ABCA2 with sporadic Alzheimer's disease.

A recent study demonstrated a significant genetic association between the ATP-binding cassette transporter A2 (ABCA2) and the risk for Alzheimer's disease (AD) in a large Caucasian sample. The rare T allele of the synonymous exonic single nucleotide polymorphism (SNP) rs908832 was overrepresented in early-onset AD patients as compared to cognitively healthy controls. Here we confirm the association of rs908832 with AD in a Western European population (n = 291, P = 0.008). In a second sample from Southern Europe, rs908832 was not associated with AD. Interestingly, rs908832 was not polymorphic in a Japanese sample. Furthermore, rs908832 was not associated with either serum cholesterol levels or with the risk for coronary artery disease, but seemed to be related to cholesterol levels in the cerebrospinal fluid. These data suggest that ABCA2 may exert population-dependent effects on the genetic risk for sporadic AD and support a role of ABC lipid transporters in the pathogenesis of this disease.

ATP-Binding Cassette Transporters↗

PubMed2006

Role of the kidney in the metabolism of apolipoprotein A-IV: influence of the type of proteinuria.

Increased plasma concentrations of apolipoprotein A-IV (apoA-IV) in chronic renal disease suggest a metabolic role of the kidney for this antiatherogenic protein. Therefore, we investigated patients with various forms of proteinuria and found increased serum concentrations of apoA-IV in 124 nephrotic patients compared with 274 controls (mean 21.9 +/- 9.6 vs. 14.4 +/- 4.0 mg/dl; P < 0.001). Decreasing creatinine clearance showed a strong association with increasing apoA-IV levels. However, serum albumin levels significantly modulated apoA-IV levels in patients with low creatinine clearance, resulting in lower levels of apoA-IV in patients with low compared with high albumin levels (21.4 +/- 8.6 vs. 29.2 +/- 8.4 mg/dl; P = 0.0007). Furthermore, we investigated urinary apoA-IV levels in an additional 66 patients with a wide variety of proteinuria and 30 controls. Especially patients with a tubular type of proteinuria had significantly higher amounts of apoA-IV in urine than those with a pure glomerular type of proteinuria and controls (median 45, 14, and 0.6 ng/mg creatinine, respectively). We confirmed these results in affected members of a family with Dent's disease, who are characterized by an inherited protein reabsorption defect of the proximal tubular system. In summary, our data demonstrate that the increase of apoA-IV caused by renal impairment is significantly modulated by low levels of serum albumin as a measure for the severity of the nephrotic syndrome. From this investigation of apoA-IV in urine as well as earlier immunohistochemical studies, we conclude that apoA-IV is filtered through the normal glomerulus and is subsequently reabsorbed mainly by proximal tubular cells.

Adult↗

PubMed2006

Unsaturated fatty acids suppress the expression of the ATP-binding cassette transporter G1 (ABCG1) and ABCA1 genes via an LXR/RXR responsive element.

ATP-binding cassette transporters (ABC) G1 and ABCA1 are membrane cholesterol transporters and have been implicated to mediate cholesterol efflux from cells in the presence of high density lipoproteins and its major protein constituent apolipoprotein A-I, respectively. We previously demonstrated that unsaturated fatty acids suppress the stimulatory effects of oxysterols and retinoids on ABCA1 gene transcription. We here demonstrate that unsaturated fatty acids significantly suppress the stimulatory effects of oxysterols and retinoids on the expression of ABCG1 mRNA and protein and the activity of the wild-type human ABCG1 promoter as well as ABCA1. Mutation or deletion of the DR4 element within the ABCG1 or ABCA1 promoters, to which the transcriptional inducers LXR and RXR bind, abolished the suppressive effects of unsaturated fatty acids. Our observations provide the first evidence that unsaturated fatty acids suppress ABCG1 gene expression by a mechanism which involves the binding of LXR/RXR to the promoters. Suppression of both the ABCA1 and ABCG1 genes may indicate that unsaturated fatty acids suppress not only cholesterol efflux to apoA-I and thereby nascent HDL formation but also HDL-dependent cholesterol efflux from vascular cells.

ATP Binding Cassette Transporter 1↗

PubMed2006

Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1.

Plasma levels of high-density lipoproteins (HDL) and apolipoprotein A-I (apoA-I) are inversely correlated with the risk of cardiovascular disease. One major atheroprotective mechanism of HDL and apoA-I is their role in reverse cholesterol transport, i.e., the transport of excess cholesterol from foam cells to the liver for secretion. The ATP-binding cassette transporters ABCA1 and ABCG1 play a pivotal role in this process by effluxing lipids from foam cells to apoA-I and HDL, respectively. In the liver, ABCA1 activity is one rate-limiting step in the formation of HDL. In macrophages, ABCA1 and ABCG1 prevent the excessive accumulation of lipids and thereby protect the arteries from developing atherosclerotic lesions. However, the mechanisms by which ABCA1 and ABCG1 mediate lipid removal are still unclear. Particularly, three questions remain controversial and are discussed in this review: (1) Do apoA-I and HDL directly interact with ABCA1 and ABCG1, respectively? (2) Does cholesterol efflux involve retroendocytosis of apoA-I or HDL? (3) Which lipids are directly transported by ABCA1 and ABCG1?

ATP Binding Cassette Transporter 1↗

PubMed2006

Binding, internalization and transport of apolipoprotein A-I by vascular endothelial cells.

High density lipoproteins (HDL) and their main protein constituent, apolipoprotein A-I (apoA-I), exert potentially anti-atherogenic properties within the arterial wall. However, it is unknown how they are transported from the blood stream into the vascular wall. Here we investigated the interaction of apoA-I with endothelial cells. At 4 degrees C endothelial cells bound 125I-apoA-I with high affinity, Kd = 2.1 microg/ml and in a saturable manner (Bmax of 35 ng/mg cell protein). At 37 degrees C, the cell association of apoA-I revealed similar affinity as at 4 degrees C (Kd = 2.2 microg/ml) but the maximum specific cell association was much enhanced (Bmax = 360 ng/mg cell protein). Binding and cell association was competed by excess unlabeled apoA-I and HDL but not by albumin. Biotinylation experiments and electron microscopy studies showed that endothelial cells internalize labeled apoA-I. Only minor amounts of the internalized apoA-I were degraded. Cultivated in a Transwell system, the cells transported a fraction of 125I-apoA-I from the apical to the basolateral compartment in a competable and temperature-sensitive manner. Furthermore, after specific transport the originally prebeta-mobile and lipid-free apoA-I was recovered as particles which have electrophoretic alpha-mobility. We conclude that endothelial cells transcytose and lipidate lipid-free apoA-I.

Animals↗

PubMed2006

Apolipoprotein A-I activates Cdc42 signaling through the ABCA1 transporter.

It has been suggested that the signal transduction initiated by apolipoprotein A-I (apoA-I) activates key proteins involved in cholesterol efflux. ABCA1 serves as a binding partner for apoA-I, but its participation in apoA-I-induced signaling remains uncertain. We show that the exposure of human fibroblasts to ABCA1 ligands (apolipoproteins and amphipathic helical peptides) results in the generation of intracellular signals, including activation of the small G-protein Cdc42, protein kinases (PAK-1 and p54JNK), and actin polymerization. ApoA-I-induced signaling was abrogated by glyburide, an inhibitor of the ABC transporter family, and in fibroblasts from patients with Tangier disease, which do not express ABCA1. Conversely, induction of ABCA1 expression with the liver X receptor agonist, T0901317, and the retinoid X receptor agonist, R0264456, potentiated apoA-I-induced signaling. Similar effects were observed in HEK293 cells overexpressing ABCA1-green fluorescent protein (GFP) fusion protein, but not ABCA1-GFP (K939M), which fails to hydrolyze ATP, or a nonfunctional ABCA1-GFP with a truncated C terminus. We further found that Cdc42 coimmunoprecipitates with ABCA1 in ABCA1-GFP-expressing HEK293 cells exposed to apoA-I but not in cells expressing ABCA1 mutants. We conclude that ABCA1 transduces signals from apoA-I by complexing and activating Cdc42 and downstream kinases and, therefore, acts as a full apoA-I receptor.

ATP Binding Cassette Transporter 1↗

PubMed2006

Prevalence of renal impairment and its association with cardiovascular risk factors in a general population: results of the Swiss SAPALDIA study.

BACKGROUND: Impaired renal function is evolving as an independent marker of the risk of cardiovascular morbidity and mortality. Little is known about the prevalence of impaired renal function and its relationship to cardiovascular risk factors in the Swiss general population. METHODS: SAPALDIA comprises a random sample of the Swiss population established in 1991, originally to investigate the health effects of long-term exposure to air pollution. Participants were reassessed in 2002/3 and blood measurements were obtained (n = 6317). Renal function was estimated using the Cockcroft-Gault equation and the modified MDRD (four-component) equation incorporating age, race, gender and serum creatinine level. RESULTS: The estimated prevalence of impaired renal function [estimated glomerular filtration rate <60 ml/min/1.73 m(2)] differed substantially between men and women, particularly at higher ages, and amounted to 13% [95% confidence interval (CI) 10-16%] and 36% (95% CI 32-40%) in men and women, respectively, of 65 years or older. Smoking, obesity, blood lipid levels, high systolic blood pressure and hyperuricaemia were all more common in men when compared with women. These cardiovascular risk factors were also associated independently with creatinine in both women and men. Women were less likely to receive cardiovascular drugs, in particular angiotensin-converting enzyme inhibitors and beta-blockers, when compared with men of the same age. CONCLUSION: Moderate renal impairment seems to be prevalent in the general population, with an apparent excess in females which is not explained by conventional cardiovascular risk factors. The unexpected finding questions the validity of the prediction equations, in particular in females.

Aged↗

PubMed2006

Prognostic value of plasma N-terminal pro-brain natriuretic peptide in children with congenital heart defects and open-heart surgery.

OBJECTIVE: To assess whether preoperative and postoperative plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) predict postoperative outcome of open-heart surgery in children. STUDY DESIGN: A prospective observational study was conducted with 40 children with congenital heart defects who were undergoing elective open-heart surgery. Plasma levels of NT-proBNP, troponin T, lactate, C-reactive protein, and total neutrophil cell counts were measured before, during, and 1 and 3 hours after the end of cardiopulmonary bypass grafting (CPB). Outcomes were assessed by means of the kind, dosage, and duration of inotropic drug use during the postoperative period, lactate concentrations, and the duration of mechanical ventilation. RESULTS: Preoperative levels of NT-proBNP were significantly increased irrespective of the type of congenital heart defect and the age of the patient. Preoperative NT-proBNP levels were higher in patients receiving prolonged postoperative inotropic drug therapy (r = 0.56, P = .0003). By means of multivariate analysis with the duration of inotropic therapy as the dependent variable, a significant impact of preoperative NT-proBNP levels, the presence of a cyanotic heart defect, the risk adjustment for congenital heart surgery score, duration of CPB time, and postoperative lactate levels were demonstrated (R squared = 76.8%, P <.0001). CONCLUSION: Preoperative NT-proBNP levels were associated with complicated postoperative outcome in children who underwent low-risk open-heart surgery. This marker may therefore be a useful tool in risk stratification of patients with congenital heart defects.

Biomarkers↗

PubMed2006

Heart rate variability in an ageing population and its association with lifestyle and cardiovascular risk factors: results of the SAPALDIA study.

AIMS: (i) To report associations between cardiovascular risk factors and heart rate variability (HRV) in a general population and (ii) to provide normal values for various HRV measurements in a healthy European general population sample aged >or=50. METHODS AND RESULTS: Twenty-four-hour electrocardiograms were recorded in 1742 randomly selected SAPALDIA (Swiss cohort study on Air Pollution and Lung Diseases in Adults) participants aged >or=50. In multivariate regression analyses, women (n=895) had a 6.1% lower standard deviation of all normal RR (NN) intervals (SDNN), a 11.4% lower total power (TP), and a 27.2% lower low-frequency (LF) power than men (n=847). Per unit increase in BMI, SDNN decreased by 0.7% and TP decreased by 1.2%. Persons with high blood pressure had a 9.2% lower LF than normotensive persons and current smokers a 15.5% lower LF than never smokers. Each hour of heavy physical exercise was associated with a 2.0% increase in SDNN, a 3.6% increase in the high frequency (HF) range power and a 4.2% increase in LF power. Higher levels of uric acid, high-sensitive C-reactive protein and non-HDL-cholesterol were associated with lower TP, HF and LF. Percentiles of TP and LF/HF as a function of age were calculated for an asymptomatic subsample of participants (n=499) free of cardioactive medications. CONCLUSION: Heart rate variability in a general population sample shows expected associations with all known cardiovascular risk factors, although not identically for all HRV domains. Together with our percentile estimates for HRV as a function of age, these findings could assist scientists in interpreting 24 h HRV values and factors influencing them in an ageing population.

Aging↗

PubMed2006

Comparable increase of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide levels in patients with severe sepsis, septic shock, and acute heart failure.

OBJECTIVE: B-type natriuretic peptide (BNP) and N-terminal pro-BNP measurements are used for the diagnosis of congestive heart failure (HF). However, the diagnostic value of these tests is unknown under septic conditions. We compared patients with severe sepsis or septic shock and patients with acute HF to unravel the influence of the underlying diagnosis on BNP and N-terminal pro-BNP levels. DESIGN: Prospective, clinical study. SETTING: Academic medical intensive care unit (ICU). PATIENTS: A total of 249 consecutive patients were screened for the diagnosis of sepsis or HF. Sepsis was defined according to published guidelines. HF was diagnosed in the presence of an underlying heart disease and congestive HF, pulmonary edema, or cardiogenic shock. INTERVENTIONS: BNP and N-terminal pro-BNP were measured from blood samples that were drawn daily for routine analysis. MEASUREMENTS AND MAIN RESULTS: We identified 24 patients with severe sepsis or septic shock and 51 patients with acute HF. At admission, the median (range) BNP and N-terminal pro-BNP levels were 572 (13-1,300) and 6,526 (198-70,000) ng/L in patients with sepsis and 581 (6-1,300) and 4,300 (126-70,000) ng/L in patients with HF. The natriuretic peptide levels increased during the ICU stay, but the differences between the groups were not significant. Nine patients with sepsis and eight patients with HF were monitored with a pulmonary artery catheter. Mean (sd) pulmonary artery occlusion pressure were 16 (4.2) and 22 (5.3) mm Hg (p = .02), and cardiac indexes were 4.6 (2.8) and 2.2 (0.6) L/min/m (p = .03) in patients with sepsis and HF, respectively. Despite these clear hemodynamic differences BNP and N-terminal pro-BNP levels were not statistically different between the two groups. CONCLUSION: In patients with severe sepsis or septic shock, BNP and N-terminal pro-BNP values are highly elevated and, despite significant hemodynamic differences, comparable with those found in acute HF patients. It remains to be determined how elevations of natriuretic peptide levels are linked to inflammation and sepsis-associated myocardial dysfunction.

Acute Disease↗

PubMed2005

Differential diagnosis of familial high density lipoprotein deficiency syndromes.

Monogenic high density lipoprotein (HDL) deficiency, because of defects in the genes of apolipoprotein A-I (apoA-I), adenosine triphosphate binding cassette transporter A1 (ABCA1) or lecithin:cholesterol acyltransferase (LCAT), can be assumed in patients with HDL cholesterol levels below the fifth percentile within a given population. As in a first step underlying diseases should be excluded. Patients with a virtual absence of HDL must undergo careful physical examination to unravel the clinical hallmarks of certain HDL deficiency syndromes. In addition, family studies should be initiated, to demonstrate the vertical transmission of the low HDL cholesterol phenotype. Definitive diagnosis requires specialized biochemical tests and the demonstration of a functionally-relevant mutation in one of the three discussed candidate genes. As yet no routinely used drug is able to increase HDL cholesterol levels in patients with familial low HDL cholesterol so that prevention of cardiovascular disease in these patients must be focused on the avoidance and treatment of additional risk factors.

Cholesterol, HDL↗

PubMed2005

Brain cholesterol synthesis in mice is affected by high dose of simvastatin but not of pravastatin.

On a global scale, there is an increasing tendency for a more aggressive treatment of hypercholesterolemia. Minor effects of statins on brain cholesterol metabolism have been reported in some in vivo animal studies, and it seems that this is due to a local effect of the drug. We treated male mice of the inbred strain C57/BL6 with a high daily dose of lipophilic simvastatin (100 mg/kg b.wt.) or hydrophilic pravastatin (200 mg/kg b.wt.) or vehicle (controls) by oral gavage for 3 days. To compare the impact of both statins on brain cholesterol synthesis and degradation, levels of cholesterol, its precursor lathosterol, and its brain metabolite 24(S)-hydroxycholesterol as well as statin concentrations were determined in whole-brain lipid extracts using mass spectrometry. The expression of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase mRNA and of other target genes were evaluated using real-time reverse transcription-polymerase chain reaction. In addition, analysis of liver and serum samples was performed. Similar levels of simvastatin and pravastatin were detected in whole-brain homogenates. Cholesterol contents in the brain, liver, and serum were not affected by high-dose statin treatment. Whereas brain cholesterol precursor levels were reduced in simvastatin-treated animals only, no effect was observed on the formation of the brain cholesterol metabolite, 24(S)-hydroxycholesterol. Polymerase chain reaction analysis revealed that mRNA expression of HMG-CoA reductase and ATP-binding cassette transporter A1 in the brain was significantly up-regulated in simvastatin-treated animals compared with pravastatin-treated or control animals. We conclude that, under the present experimental conditions, brain cholesterol synthesis is significantly affected by short-term treatment with high doses of lipophilic simvastatin, whereas whole-brain cholesterol turnover is not disturbed.

Animals↗

PubMed2005

Differentiated quantification of human bile acids in serum by high-performance liquid chromatography-tandem mass spectrometry.

Determination of quantitative changes in the pattern of serum bile acids is important for the monitoring of diseases affecting bile acid metabolism. A sensitive and specific high-performance liquid chromatography (HPLC)-MS/MS method was developed for the differentiated quantification of unconjugated as well as glycine- and taurine-conjugated cholic, chenodeoxycholic (CDCA), deoxycholic (DCA), ursodeoxycholic (UDCA) and lithocholic acid (LCA) in serum samples. After solid-phase extraction and reversed-phase HPLC separation, detection of the conjugated bile acids was performed using electrospray ionization (ESI)-MS/MS and selected reaction monitoring mode, whereas unconjugated bile acids were determined by ESI-MS and selected ion monitoring mode. The within-day and between-day coefficients of variation were below 7% for all bile acids and the recovery rates of the extraction procedure were between 84.9 and 105%. The developed method was applied to a group of 21 healthy volunteers and preliminary reference intervals in serum were established. In patients with drug-induced cholestasis, an elevation of primary bile acids has been shown.

Adult↗