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Biomedical subjects

I Björkhem

Publications and source records attributed to I Björkhem.

At least 19 recordsLinked to original sources
PubMed2006

Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain.

A normal brain function requires constant levels of cholesterol, and the need for constancy seems to be higher here than in any other organ. Nature has met this need by isolation of brain cholesterol by a highly efficient blood-brain barrier. As a low synthesis of cholesterol is present in the brain, a mechanism for compensatory elimination is required. A decade ago we made the unexpected finding that the favoured mechanism for this involves conversion into 24S-hydroxycholesterol, followed by diffusion over the blood-brain barrier. Recent studies by us and others on this new pathway have given new insights into the mechanisms by which cholesterol homeostasis is maintained in the brain. We recently demonstrated a flux of another oxygenated product of cholesterol, 27-hydroxycholesterol, in the opposite direction. The latter flux may be important for neurodegeneration, and may be the link between hypercholesterolaemia and Alzheimer's disease. An overview of the above studies is presented and the possibility that the cholesterol 24S-hydroxylase in the brain may be important for memory and learning and that it may be a new drug target is discussed.

Alzheimer Disease↗
PubMed2006

Oxysterols and Alzheimer's disease.

There is a clear link between cholesterol turnover and neurodegenerative diseases and hypercholesterolemia is an established risk factor for Alzheimer's disease (AD). The failure to demonstrate a transfer of cholesterol from the circulation into the brain in humans and experimental animals makes it difficult to explain the link between hypercholesterolemia and AD. In contrast to cholesterol itself, side-chain oxidized cholesterol metabolites such as 24S-hydroxycholesterol and 27-hydroxycholesterol are able to pass the blood-brain barrier (BBB). Formation of 24S-hydroxycholesterol is the quantitatively most important mechanism for elimination of cholesterol from the brain and we recently demonstrated a significant net uptake of 27-hydroxycholesterol by the brain from the circulation. We have also shown that patients with AD have increased brain levels of 27-hydroxycholesterol, which may affect the production of beta-amyloid in the brain. The levels of 27-hydroxycholesterol in the circulation are correlated with the levels of cholesterol and the possibility must be considered that the flux of 27-hydroxycholesterol into the brain is the missing link between hypercholesterolemia and Alzheimer's disease. Current knowledge about the role of the two oxysterols for cholesterol homeostasis in the brain as well as their diagnostic potential are reviewed.

Alzheimer Disease↗
PubMed2005

Studies on LXR- and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice.

As previously reported by us, mice with targeted disruption of the CYP8B1 gene (CYP8B1-/-) fail to produce cholic acid (CA), upregulate their bile acid synthesis, reduce the absorption of dietary cholesterol and, after cholesterol feeding, accumulate less liver cholesterol than wild-type (CYP8B1+/+) mice. In the present study, cholesterol-enriched diet (0.5%) or administration of a synthetic liver X receptor (LXR) agonist strongly upregulated CYP7A1 expression in CYP8B1-/- mice, compared to CYP8B1+/+ mice. Cholesterol-fed CYP8B1-/- mice also showed a significant rise in HDL cholesterol and increased levels of liver ABCA1 mRNA. A combined CA (0.25%)/cholesterol (0.5%) diet enhanced absorption of intestinal cholesterol in both groups of mice, increased their liver cholesterol content, and reduced their expression of CYP7A1 mRNA. The ABCG5/G8 liver mRNA was increased in both groups of mice, but cholesterol crystals were only observed in bile from the CYP8B1+/+ mice. The results demonstrate the cholesterol-sparing effects of CA: enhanced absorption and reduced conversion into bile acids. Farnesoid X receptor (FXR)-mediated suppression of CYP7A1 in mice seems to be a predominant mechanism for regulation of bile acid synthesis under normal conditions and, as confirmed, able to override LXR-mediated mechanisms. Interaction between FXR- and LXR-mediated stimuli might also regulate expression of liver ABCG5/G8.

ATP Binding Cassette Transporter 1↗
PubMed2005

Polymorphism in the coding part of the sterol 12alpha-hydroxylase gene does not explain the marked differences in the ratio of cholic acid and chenodeoxycholic acid in human bile.

OBJECTIVE: In humans, two primary bile acids are synthesized: cholic acid (CA) and chenodeoxycholic acid (CDCA), the first and rate-limiting enzyme being cholesterol 7alpha-hydroxylase (CYP7A1). CA has one more hydroxyl group at position 12alpha. This hydroxylation is carried out by the sterol 12alpha-hydroxylase (CYP8B1). Earlier, we and others have noticed a marked variation in the ratio between CA and CDCA in human bile. The aim of this study was to investigate whether this marked difference could be due to a genetic polymorphism in the gene of the CYP8B1. MATERIAL AND METHODS: Screening for genetic polymorphisms was carried out in a 2.4-kb-long area including the exon and part of the promoter region in subjects who had undergone cholecystectomy earlier, and where bile acid analysis had been performed. Among these subjects those with very high or low CA/CDCA ratios (ranging from 0.9 to 6.8) were investigated. The subjects were all female, normolipidaemic, having normal weight and a normal thyroid function. RESULTS: No polymorphisms were found in the investigated sequence. However, a statistically significant correlation was found between the activity of the CYP7A1 and the ratio between CA and CDCA. The difference in ratio could, at least in part, be explained by the difference in rate of bile acid synthesis. CONCLUSION: The difference in ratio between CA and CDCA cannot be explained by a polymorphism in the coding area of the CYP8B1.

Adult↗
PubMed2005

Patients with atherosclerosis may have increased circulating levels of 27-hydroxycholesterol and cholestenoic acid.

Extrahepatic sterol 27-hydroxylase (CYP27) appears to have a role in the elimination of excess cholesterol from various cells, particularly macrophages, and there is a net flux of 27-hydroxyycholesterol and its metabolites from different extrahepatic sources to the liver. In this study we tested the hypothesis that patients with advanced atherosclerosis may have higher levels of 27-oxygenated products in the circulation than control subjects. Concordant with previous studies, a strong correlation was observed between circulating levels of 27-hydroxycholesterol and cholesterol, in both healthy subjects and subjects with hypercholesterolemia and documented atherosclerosis. A group of male subjects with normal or only slightly elevated serum cholesterol and rapidly progressing carotid atherosclerosis (n = 20) had serum levels of 27-oxygenated cholesterol not statistically different from those of a matched group of subjects with little or no development of atherosclerosis (n = 20). The situation was similar in a group of patients (n = 20) with advanced general atherosclerosis associated with severe clinical symptoms. Among the two groups of patients with atherosclerosis, a few patients had relatively high levels of 27-oxygenated products. Among the healthy controls, two healthy volunteers (brother and sister) were found to have high levels of 27-hydroxycholesterol, most probably due to genetic reasons. The possibility is discussed that the high levels of 27-oxygenated products in the circulation of a few patients with atherosclerosis may be related to high amounts of active macrophages present in atherosclerotic lesions. In view of the number of factors that could affect the levels in the circulation, other explanations cannot be ruled out. At the present state of knowledge, measurements of circulating levels of 27-oxygenated metabolites do not seem to add useful information about the atherosclerotic process.

Arteriosclerosis↗
PubMed2002

Effects of combined treatment with pravastatin and ursodeoxycholic acid on hepatic cholesterol metabolism.

BACKGROUND: Treatment with ursodeoxycholic acid and also, to some degree, statins reduces cholesterol saturation of bile. The present study aimed [1] to study the effects of combined treatment with ursodeoxycholic acid and pravastatin on hepatic cholesterol metabolism and [2] to evaluate if the addition of pravastatin to ursodeoxycholic acid treatment has beneficial effects on the lipid composition of gallbladder bile in gallstone patients. MATERIALS AND METHODS: Nineteen patients with cholesterol gallstones were subjected to combined treatment with ursodeoxycholic acid (500 mg bid) and pravastatin (20 mg bid) for three weeks before cholecystectomy. Eleven patients received ursodeoxycholic acid only and 20 untreated gallstone patients served as controls. Gallbladder bile was collected, and for both the patients receiving combined treatment and the controls a liver biopsy was also obtained peroperatively. RESULTS: The cholesterol saturation of bile averaged 59% in the patients on combined treatment, 60% in the ursodeoxycholic acid-treated patients, and 130% in the untreated controls. In the patients receiving ursodeoxycholic acid, this bile salt constituted approximately 60% of all bile salts. The patients receiving combined treatment had reduced cholesterol synthesis, as reflected by a 45% reduction in serum lathosterol. The activity and the mRNA levels of cholesterol 7 alpha-hydroxylase and the mRNA levels for the low density lipoprotein-receptor were not significantly affected. CONCLUSIONS: Pravastatin does not further reduce the cholesterol saturation of bile in gallstone patients treated with ursodeoxycholic acid, although hepatic cholesterol synthesis is inhibited. The study supports the important concept that de novo synthesized cholesterol is not particularly important for biliary cholesterol secretion in humans.

Adult↗
PubMed2002

Cerebrotendinous xanthomatosis: molecular characterization of two Scandinavian sisters.

Cerebrotendinous xanthomatosis (CTX) is a hereditary disorder, which is inherited as an autosomally recessive disease, causing production of cholesterol and cholestanol xanthomas and mental retardation. The disease is caused by mutations in the gene for sterol 27-hydroxylase (CYP27A1). The only CTX patients diagnosed in Scandinavia are two Norwegian sisters from a consanguineous marriage. Here we have characterized the mutation and its functional consequences for the enzyme. Analysis of genomic DNA from cultured fibroblasts identified a base exchange C > T in position 1441, causing arginine at amino acid position 441 to be replaced by tryptophan. The same mutation was introduced by mutagenesis in the complimentary DNA (cDNA) for CYP27, ligated into the expression vector pcDNA4/HisMax and transfected into HEK293 cells. The mutated enzyme had less than 5% of the enzyme activity compared with the native enzyme. No abnormal catalytic products could be identified in the cell culture medium. Probably the mutation affects the haem binding within the holoenzyme. The mutation has also previously been reported in a Japanese family. This is the second example of a CTX-causing mutation that has been recognized in more than one population.

Adult↗
PubMed2002

Cholesterol treatment forever? The first Scandinavian trial of cholesterol supplementation in the cholesterol-synthesis defect Smith-Lemli-Opitz syndrome.

OBJECTIVES: To investigate if exogenous cholesterol affects sterol turnover in the cholesterol-synthesis defect Smith-Lemli-Opitz syndrome (SLOS) and if clinical effects justify long-time supplementation. The SLOS is caused by a deficiency of the enzyme 7-dehydrocholesterol-7-reductase with markedly reduced cholesterol levels and greatly increased levels of 7-dehydrocholesterol (7-DHC). DESIGN: Treatment with dietary cholesterol in patients with SLOS in a case series study. SETTING: All biochemical analyses were performed in one laboratory. The clinical follow-up was carried out by one of the authors (LS), a paediatric neurologist. SUBJECTS: Seven patients with biochemically verified SLOS have been diagnosed in Sweden and all of them are included in the study. INTERVENTIONS: Six patients were treated for 0.5-6 years orally with cholesterol and the bile acid taurocholate and one patient was supplemented with cholesterol only. MAIN OUTCOME MEASURES: In addition to cholesterol, 7- and 8-DHC, lathosterol was used as a marker of endogenous cholesterol synthesis and the patients were followed clinically. Nerve conduction velocities (NCV) were measured before treatment in all patients and a UVA-light test was performed in one of them. RESULTS: Lathosterol was initially increased by cholesterol supply in subjects with very low cholesterol levels with subsequent rise of 7- and 8-DHC. Photosensitivity clinically improved in all, verified by UVA-light testing in one. Progressive polyneuropathy improved, whilst stationary forms did not. CONCLUSION: Dietary cholesterol can up-regulate sterol turnover in severely affected patients. Although some specific features are treatable and verifiable by objective methods, data supporting life-long treatment dietary cholesterol in all SLO patients are still lacking.

Age Factors↗
PubMed2002

Post-occlusive reactive hyperemia in single nutritive capillaries of the nail fold: methodological considerations.

Endothelial function at the arterial level has been extensively assessed by a non-invasive method using flow-mediated dilatation (FMD) of the brachial artery. Early disturbances have been found in patient groups prone to later development of manifest macrovascular atherosclerosis. A possible non-invasive means of studying blood-flow regulation and function at the microcirculatory level is through videophotometric capillaroscopy. The most stable variable in such an investigation is the time-to-peak (TtP) flow after a brief arterial occlusion. The short-term reproducibility of such assessments is excellent but the coefficient of variation (CV) in long-term studies is reported to be in the order of slightly less than 20%. The aim of the present methodological study was to evaluate different sources of variations in such microcirculatory assessments in order to be able to propose design recommendations that minimize the number of patients and recordings needed to achieve sufficient statistical power in longitudinal studies. We used a symmetric design with 144 recordings of TtP after a one-minute arterial occlusion in healthy volunteers. We did six occlusions each time in the capillaries of two fingers on each occasion, and repeated the procedure three times with an interval of at least one week between each investigation. All recordings were analyzed off-line using a cross-correlation technique with the Capiflow system. Each analysis was performed at least three times, giving a total of slightly less than 500 assessments. In our material (n = 10) TtP had a mean of 6.3 s (95% confidence interval 5.2-7.4). The correlation between repeated measurements in a single capillary during a single session was r > 0.91 (CV 6%). The between-finger CV was 8% (r = 0.84). The CV of measurements between different days was about 20% when single measurements were compared. However, the CV decreased to less than 13% when the mean of at least two time-to-peak assessments on each occasion was used. In conclusion, the methodological error including day-to-day variation could be minimized using the mean of at least two repeated assessments of post-occlusive hyperemia at each time point in a longitudinal study. This finding should be taken into consideration in the design of future longitudinal studies.

Blood Flow Velocity↗
PubMed2001

On the anti-atherogenic effect of the antioxidant BHT in cholesterol-fed rabbits: inverse relation between serum triglycerides and atheromatous lesions.

We have shown that inclusion of the antioxidant butylated hydroxytoluene (BHT) in the diet protects against development of atherosclerotic lesions in cholesterol-fed rabbits. In parallel, BHT treatment results in increased plasma triglyceride levels. The present study explores the relationship between the triglyceride-inducing and protective effects of BHT in two different studies. The combined material contains 22 rabbits fed cholesterol and 18 rabbits fed cholesterol in combination with 1% BHT. In the BHT group there was an inverse relationship between triglyceride exposure/cholesterol exposure and extent of lesions with r=0.74 (P=0.0005). Our results show that increased triglyceride exposure parallels the anti-atherogenic effect of BHT. There was no significant correlation between atheromatosis and serum BHT levels. beta-very low density lipoprotein (beta-VLDL) from cholesterol and BHT animals was triglyceride-enriched and smaller compared to beta-VLDL from cholesterol-fed animals, but there was no significant association between the anti-atherogenic effect of BHT and particle size or apolipoprotein pattern of LDL or beta-VLDL. LDL isolated from rabbits treated with cholesterol and BHT was less sensitive to oxidative modification than LDL isolated from rabbits treated with cholesterol only. In conclusion, our results demonstrate that the degree of triglyceride exposure may be an important modulator of the anti-atherogenic effect of an antioxidant.

Animals↗
PubMed2001

On the turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells.

Evidence is accumulating for a link between cerebral cholesterol metabolism and Alzheimer's disease (AD). Here we focus on a possible relationship between AD and a newly discovered mechanism for cholesterol efflux from the brain, involving conversion of brain cholesterol into 24S-hydroxycholesterol by the neuronal oxidative enzyme CYP46. There was a marked difference in the distribution of CYP46 in brains of control and AD patients. The neuronal cells were less stained in AD brains than in controls while marked positive staining was found in glial cells in AD but not in controls. The dynamic changes in the mechanisms for cholesterol efflux from the brain are of interest in relation to the link between brain cholesterol and amyloid beta-protein in AD.

Aged↗
PubMed2001

Putative helix F contributes to regioselectivity of hydroxylation in mitochondrial cytochrome P450 27A1.

On the basis of alignment with structurally characterized cytochromes P450 (P450s), we have identified the putative F and G helices of mitochondrial P450s 27A1 and 11A. We introduced substitutions at Phe-207, Ile-211, and Phe-215 within putative helix F and at Trp-235 and Tyr-238 within putative helix G in P450 27A1 and compared wild type and mutants with respect to catalytic activity, product pattern, substrate binding, formation of hydrogen peroxide, and interaction with redox partner. Results indicate that the mutated residues are important for delivery of the correctly oriented substrate to the P450 active site. The I211K and F215K mutations, for example, affected the regioselectivity of P450 27A1-dependent hydroxylation reactions and conferred the P450 capacity to cleave the C-C bond of the substrate during the catalytic cycle. Studies of P450 11A1 indicate that Phe-202 has functions similar to those of its counterpart in P450 27A1 (Phe-215). We propose that putative helices F and G form the sides of the substrate-access channel, thus providing the additional mechanism to control regioselectivity of hydroxylation in mitochondrial P450s.

Amino Acid Sequence↗
PubMed2001

N-acetylcysteine improves microcirculatory flow during smoking: new effects of an old drug with possible benefits for smokers.

BACKGROUND: Cigarette smoking provokes marked acute changes in the microcirculatory vasculature, including a reduced blood flow velocity. In accordance with the hypothesis that the reduced blood flow is due to an imbalance between pro-oxidants and oxidants, we recently showed that most of the reduction could be reversed by a high dose of vitamin C. HYPOTHESIS: In the present work we tested the hypothesis that N-acetylcysteine, a mucolyticum and an antioxidant, may have an effect on the smoking-induced changes observed by vital capillary microscopy of the nailfold. METHODS: In all, 37 healthy volunteers of both genders and with varied smoking habits were treated with N-acetylcysteine 200 mg t.i.d. for 2 weeks. In vivo investigation of the microcirculation by capillaroscopy was performed before and after treatment. RESULTS: Treatment with N-acetylcysteine significantly reduced the smoking-induced relative decrease in capillary blood flow velocity in a group of volunteers with varied smoking habits (p = 0.0016). The preventive effect was clearly significant in smokers (p = 0.003). CONCLUSION: Treatment with N-acetylcysteine has a positive impact on microcirculatory flow during smoking, particularly in habitual smokers.

Acetylcysteine↗
PubMed2001

Expression of sterol 12alpha-hydroxylase alters bile acid pool composition in primary rat hepatocytes and in vivo.

BACKGROUND & AIMS: The rate of 12alpha-hydroxylation of bile acid intermediates is believed to determine the ratio of cholic acid (CA) to chenodeoxycholic acid (CDCA) biosynthesis and the overall hydrophobicity of the bile acid pool. The aim of this study was to determine the effects of the level of expression of sterol 12alpha-hydroxylase (CYP8b1) and cholesterol 7alpha-hydroxylase (CYP7a1) on rates of CA biosynthesis and bile acid pool composition. METHODS: Expression of CYP8b1 and CYP7a1 was accomplished through infection of primary rat hepatocytes (PRH) or intact male SD rats with replication-defective recombinant adenoviruses encoding either CYP8b1 or CYP7a1. RESULTS: Increased expression of CYP7a1 over basal levels in PRH dramatically increased bile acid biosynthesis (586% +/- 82%, P < 0.001) but did not alter the ratio of CA to CDCA. Conversely, increased expression of CYP8b1 in vitro had no significant effect on the rates of total bile acid synthesis but significantly increased (4.1-fold) the rates of CA biosynthesis, resulting in an increase in the CA-CDCA ratio from 1:6.6 to 2.8:1. In whole rats, increased CYP8b1 expression over basal levels markedly increased the CA in the bile acid pool from 36% +/- 3.4% to 50% +/- 2.9% in 5 days. CDCA and its muricholic acid derivatives decreased from 64% +/- 3.4% to 50% +/- 2.9%. CONCLUSIONS: Increased expression of CYP8b1 led to a marked increase in CA biosynthesis both in PRH and in whole animals. CYP8b1 is capable of 12alpha-hydroxylating bile acid intermediates from both the classic and acidic pathways.

Animals↗
PubMed2001

Cholesterol dynamics in the foetal and neonatal brain as reflected by circulatory levels of 24S-hydroxycholesterol.

UNLABELLED: Oxysterols, particularly those hydroxylated in the steroid side-chain, are formed from cholesterol by specific cytochrome P450 enzymes and may facilitate elimination of cholesterol from extrahepatic sources. In humans, the greatest portion of circulating 24S-hydroxycholesterol (24S-OH-Chol) is derived from the brain and the absolute concentration depends on age. In the present study, concentrations of 24S-OH-Chol and for comparison 27-OH-Chol were determined by a highly sensitive isotope dilution method using gas chromatography-mass spectrometry in serum samples from normal preterm and term neonates and those with Rhesus haemolytic disease, taken serially for diagnostic purposes. Serum concentrations of cholesterol, 24S-OH-Chol and 27-OH-Chol were similar in venous versus arterial cord blood of 6 term neonates. Serum concentrations of 24S-OH-Chol and 27-OH-Chol in 12 small for gestational age (SGA) preterm neonates were significantly lower than those in 12 appropriate for gestational age (AGA) preterm neonates (p < 0.001), and also lower than those in 12 SGA (0 < 0.001) and 12 AGA term neonates (p < 0.05). Serum cholesterol was significantly higher in preterm than in term neonates (p < 0.001). 24S-OH-Chol serially determined in 8 infants with Rhesus haemolytic disease increased 5-6-fold during the first 3 mo after birth (from 42 +/- 20 ng ml(-1) to 227 +/- 71 ng ml(-1)). 27-OH-Chol increased simultaneously from 30 +/- 14 ng ml(-1) to 100 +/- 39 ng ml(-1). CONCLUSION: Serum concentrations of 24S-OH-Chol increased 5-6-fold after birth. This could be an indication of normal cholesterol metabolism in the developing neonatal brain.

Brain↗
PubMed2001

Genes involved in initial steps of bile acid synthesis.

The mechanism and regulation of the degradation of cholesterol into bile acids has attracted increased interest, in particular after the recent discovery that nuclear receptors (farnesoid X receptor and liver X receptor) are involved in the regulation of bile acid synthesis. Recently, it has also been shown that the biosynthesis of bile acids is not exclusively restricted to the liver, and that degradation may start by a hydroxylation of cholesterol in the brain or in other extrahepatic organs. During the past 2 years the genes coding for three of the six enzymes catalysing the first steps in bile acid biosynthesis have been cloned and characterized. These genes and their gene products will be described here.

3-Hydroxysteroid Dehydrogenases↗
PubMed2001

Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRbeta-deficient mice.

The nuclear oxysterol-receptor paralogues LXRalpha and LXRbeta share a high degree of amino acid identity and bind endogenous oxysterol ligands with similar affinities. While LXRalpha has been established as an important regulator of cholesterol catabolism in cholesterol-fed mice, little is known about the function of LXRbeta in vivo. We have generated mouse lines with targeted disruptions of each of these LXR receptors and have compared their responses to dietary cholesterol. Serum and hepatic cholesterol levels and lipoprotein profiles of cholesterol-fed animals revealed no significant differences between LXRbeta(-/-) and wild-type mice. Steady-state mRNA levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl diphosphate synthase, and squalene synthase were increased in LXRbeta(-/-) mice compared with LXRbeta(+/+) mice, when fed standard chow. The mRNA levels for cholesterol 7alpha-hydroxylase, oxysterol 7alpha-hydroxylase, sterol 12alpha-hydroxylase, and sterol 27-hydroxylase, respectively, were comparable in these strains, both on standard and 2% cholesterol chow. Our results indicate that LXRbeta(-/-) mice - in contrast to LXRalpha(-/-) mice - maintain their resistance to dietary cholesterol, despite subtle effects on the expression of genes coding for enzymes involved in lipid metabolism. Thus, our data indicate that LXRbeta has no complete overlapping function compared with LXRalpha in the liver.

Alanine Transaminase↗