Biomedical subjects

I Björkhem

Publications and source records attributed to I Björkhem.

At least 19 recordsLinked to original sources

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↗

PubMed2001

Evidence that the major oxysterols in human circulation originate from distinct pools of cholesterol: a stable isotope study.

The major oxysterols in human circulation are 7 alpha-, 27-, and (24S)-hydroxycholesterol. Two unique experiments were performed to elucidate their origin and kinetics. A volunteer was exposed to (18)O(2)-enriched air. A rapid incorporation of (18)O in both 7 alpha- and 27-hydroxycholesterol and disappearance of label after exposure were observed. The half-life was estimated to be less than 1 h. Incorporation of (18)O in (24S)-hydroxycholesterol was not significant. In the second experiment a volunteer was infused with liposomes containing 10 g of [(2)H(6)]cholesterol. This resulted in an enrichment of plasma cholesterol with (2)H of up to 13%, and less than 0.5% in cerebrospinal fluid cholesterol. The content of (2)H in circulating 7 alpha-hydroxycholesterol remained approximately equal to that of plasma cholesterol and decreased with a half-life of about 13 days. The (2)H content of circulating 27-hydroxycholesterol was initially lower than that of cholesterol but in the last phase of the experiment it exceeded that of cholesterol. No significant incorporation of (2)H in (24S)-hydroxycholesterol was observed. It is evident that 7 alpha-hydroxycholesterol must originate from a rapidly miscible pool, about 80% of 27-hydroxycholesterol from a more slowly exchangeable pool, and more than 90% of (24S)-hydroxycholesterol from a nonexchangeable pool, presumably the brain. The results are discussed in relation to the role of oxysterols in cholesterol homeostasis and their use as markers for pathological conditions. - Meaney, S., M. Hassan, A. Sakinis, D. Lütjohann, K. von Bergmann, A. Wennmalm, U. Diczfalusy, and I. Björkhem. Evidence that the major oxysterols in human circulation originate from distinct pools of cholesterol: a stable isotope study. J. Lipid Res. 2001. 42: 70;-78.

Blood Circulation↗

PubMed2001

Oxysterols in the circulation of patients with the Smith-Lemli-Opitz syndrome: abnormal levels of 24S- and 27-hydroxycholesterol.

Infants with the cholesterol synthesis defect Smith- Lemli-Opitz syndrome (SLO) have reduced activity of the enzyme 7-dehydrocholesterol-7-reductase and accumulate 7-dehydrocholesterol, with the highest concentration in the brain. As a result of the generally reduced content of cholesterol, plasma levels of oxysterols would be expected to be reduced. 24S-hydroxycholesterol is almost exclusively formed in the brain, whereas 27-hydroxycholesterol is mainly formed from extrahepatic and extracerebral cholesterol. In accordance with the expectations, sterol-correlated plasma levels of 24S-hydroxycholesterol were reduced in infants with SLO (by about 50%). In contrast, the sterol-correlated levels of 27-hydroxycholesterol in the circulation were markedly increased. No side-chain oxidized metabolites of 7-dehydrocholesterol were detected in the circulation. Recombinant human CYP27 had markedly lower 27-hydroxylase activity toward 7-dehydrocholesterol than towards cholesterol. HEK293 cells expressing 24S-hydroxylase active toward cholesterol had no significant activity towards 7-dehydrocholesterol. The plasma levels of 3 beta,7 alpha-dihydroxy-5-cholestenoic in the patients acid were reduced, suggesting a generally reduced metabolism of 27-oxygenated steroids. It is concluded that the accumulation of 7-dehydrocholesterol in the brains of patients with SLO reduces formation of 24S-hydroxycholesterol. The condition is associated with markedly increased circulating levels of 27-hydroxycholesterol, most probably due to reduced metabolism of this oxysterol. We discuss the possibility that the circulating levels of 24S-hydroxycholesterol may be used as a marker for the severity of the disease.--Björkhem, I., L. Starck, U. Andersson, D. Lütjohann, S. von Bahr, I. Pikuleva, A. Babiker, and U. Diczfaulsy. Oxysterols in the circulation of patients with the Smith-Lemli-Opitz syndrome: abnormal levels of 24S- and 27-hydroxycholesterol. J. Lipid Res. 2001. 42: 366--371.

Adolescent↗

PubMed2001

Characterization of enzymes involved in formation of ethyl esters of long-chain fatty acids in humans.

Elevated fatty acid ethyl ester (FAEE) concentrations have been detected in postmortem organs from alcoholics and patients acutely intoxicated by alcohol, and FAEE have been implicated as mediators of ethanol-induced organ damage. The formation of FAEE is catalyzed by acyl-coenzyme A:ethanol O-acyltransferase (AEAT) and by FAEE synthase, which utilize acyl-CoA and free fatty acids, respectively, as substrates. Because little is known about the capacity of various human tissues to synthesize and hydrolyze FAEE, we investigated formation of FAEE by AEAT and FAEE synthase in tissue homogenates from human gastric ventricular and duodenal mucosa, pancreas, liver, heart, lung, and adipose tissue, gallbladder mucosa, and in serum. Liver, duodenal mucosa, and pancreas were found to have the highest capacities to synthesize FAEE, mainly due to AEAT. FAEE hydrolyzing activity was highest in liver and pancreas, but hardly detectable in adipose tissue or heart. Because fatty acids and alcohol are absorbed by the intestinal mucosa, intestine may be a major site of FAEE synthesis, and FAEE may be delivered via the circulation to other organs and taken up by lipoprotein receptor-mediated uptake. A very low rate of FAEE hydrolysis was detected in heart and adipose tissue, which probably accounts for the previously observed accumulation of FAEE in these organs.

Acyltransferases↗

PubMed2001

Identification of unusual 7-oxygenated bile acid sulfates in a patient with Niemann-Pick disease, type C.

Niemann-Pick disease, type C, was diagnosed in a 3-month-old boy with hepatosplenomegaly, mild signs of cholestasis, hepatic inflammation and extramedullary erythropoiesis, together with chronic airway disease. He developed muscular hypotonia, psychomotor retardation, rickets, and signs of peripheral neuropathy. The patient was found to excrete abnormal amounts of unusual bile acids in urine at 3 and 5 months of age. These acids were shown to have a 3beta-hydroxy-Delta(5) structure and to carry an oxo or hydroxy group at C-7. They were sulfated at C-3 and nonamidated or conjugated with glycine or taurine at C-24. Part of the 7-hydroxy acids, presumably the 7beta-hydroxylated one, was also conjugated with N-acetylhexosamine, probably N-acetylglucosamine, at the 7-hydroxy group. Possible metabolic pathways for the formation of the 7-oxo and 7beta-hydroxycholenoic acids are discussed. Based on previous data concerning the effects of 3beta-hydroxy-Delta(5) bile acids on bile acid transport, it is suggested that the formation of such bile acids is responsible for the cholestasis in this patient.

Bile Acids and Salts↗

PubMed2000

Oxysterol 7 alpha-hydroxylase activity by cholesterol 7 alpha-hydroxylase (CYP7A).

A 7 alpha-hydroxylation is necessary for conversion of both cholesterol and 27-hydroxycholesterol into bile acids. According to current theories, cholesterol 7 alpha-hydroxylase (CYP7A) is responsible for the former and oxysterol 7 alpha-hydroxylase (CYP7B) for the latter reaction. CYP7A is believed to have a very high substrate specificity whereas CYP7B is active toward oxysterols, dehydroepiandrosterone, and pregnenolone. In the present study, 7 alpha-hydroxylation of various oxysterols in liver and kidney was investigated. Surprisingly, human cholesterol 7 alpha-hydroxylase, CYP7A, expressed as a recombinant in Escherichia coli and COS cells, was active toward 20(S)-hydroxycholesterol, 25-hydroxycholesterol, and 27-hydroxycholesterol. This enzyme has previously been thought to be specific for cholesterol and cholestanol. A partially purified and reconstituted cholesterol 7 alpha-hydroxylase enzyme fraction from pig liver showed 7 alpha-hydroxylase activity toward the same oxysterols as metabolized by expressed recombinant human and rat CYP7A. The 7 alpha-hydroxylase activity toward 20(S)-hydroxycholesterol, 25-hydroxycholesterol, and 27-hydroxycholesterol in rat liver was significantly increased by treatment with cholestyramine, an inducer of CYP7A. From the present results it may be concluded that CYP7A is able to function as an oxysterol 7 alpha-hydroxylase, in addition to the previously known human oxysterol 7 alpha-hydroxylase, CYP7B. These findings may have implications for oxysterol-mediated regulation of gene expression and for pathways of bile acid biosynthesis. A possible use of 20(S)-hydroxycholesterol as a marker substrate for CYP7A is proposed.

Animals↗

PubMed2000

Plasma levels of 24S-hydroxycholesterol in patients with neurological diseases.

The brain is the exclusive or almost exclusive site of formation of 24S-hydroxycholesterol and we have shown that the circulating level of 24S-hydroxycholesterol is dependent upon the relation between cerebral production and hepatic clearance. In the present work we determined plasma levels of 24S-hydroxycholesterol in patients with various neurological diseases. Eleven subjects with brain death occurring 6-10 h before collection of the plasma samples had markedly reduced circulating levels of 24S-hydroxycholesterol (-43%, P<0.001). Patients with advanced Alzheimer's disease and cerebral inflammatory diseases had slightly lower levels of 24S-hydroxycholesterol in plasma when compared to matched controls. Patients with acute ischemic stroke, multiple sclerosis and primary brain tumors had levels not significantly different from those of controls. The conditions leading to reduced plasma levels of 24S-hydroxycholesterol had no significant effect on plasma levels of another side-chain oxidized oxysterol, 27-hydroxycholesterol. Except for conditions characterized by very marked destruction of the central nervous system, different severe neurological diseases seem to have relatively small effects on the flux of 24S-hydroxycholesterol from the brain.

Adult↗

PubMed2000

Formation of oxysterols from different pools of cholesterol as studied by stable isotope technique: cerebral origin of most circulating 24S-hydroxycholesterol in rats, but not in mice.

In order to study the origin of different oxysterols in the circulation, in particular 24S-hydroxycholesterol, different pools of cholesterol in rat and mouse were labelled by feeding the animals with a diet supplemented with 0.3 or 0.5% hexadeuterium-labelled cholesterol, respectively, for 10 days. The incorporation of deuterium label in cholesterol and different oxysterols was measured by combined gas chromatography-mass spectrometry in selected tissues and in the circulation. In both rat and mouse, a high incorporation of label was found in cholesterol present in serum and liver (up to 77%). Incorporation of label was similar in 7 alpha- and 7 beta-hydroxycholesterol of the same origin. There was no significant incorporation of deuterium in brain cholesterol, and little or no incorporation in the brain oxysterols investigated, in both animals. In the testis, the incorporation of the deuterium label in cholesterol was less than half of that in the liver, with similarly reduced labelling of the testicular oxysterols. 24S-Hydroxycholesterol in the circulation contained a deuterium content that was about 50% of that of serum and liver cholesterol in the mouse experiment and about 30% in the rat experiment. Thus, about 50% of circulating 24S-hydroxycholesterol in the mouse and about 70% of this fraction in the rat must originate from pools of cholesterol that are not in equilibrium with plasma and liver cholesterol. The liver is probably responsible for a considerable part of the extracerebral formation of 24S-hydroxycholesterol, since this organ contained detectable amounts of 24S-hydroxycholesterol with a relatively high incorporation of deuterium in both animal species. The results are consistent with a cerebral origin of more than half of the 24S-hydroxycholesterol in the circulation of rats, but not in mice.

Adrenal Glands↗

PubMed2000

Plasma 24S-hydroxycholesterol: a peripheral indicator of neuronal degeneration and potential state marker for Alzheimer's disease.

The conversion of brain cholesterol into 24S-hydroxycholesterol and its subsequent release into the periphery is probably an important step for the maintenance of brain cholesterol homeostasis. Recent findings suggest that plasma 24S-hydroxycholesterol may be elevated in Alzheimer's disease (AD) and vascular dementia at least at some stage of the disease, suggesting increased brain cholesterol turnover during neurodegeneration. We investigated whether plasma 24S-hydroxycholesterol concentrations depend on the severity of AD and on the apolipoprotein E (apoE) genotype. Severity of AD and inheritance of the apoE4 allele were independently associated with reduced plasma 24S-hydroxycholesterol/cholesterol ratios. The results suggest that the decrease of plasma 24S-hydroxycholesterol/cholesterol in severely affected AD patients is a peripheral marker for loss of cholesterol 24S-hydroxylase in the CNS. Inheritance of the apoE4 allele may be associated with increased apoE-mediated transport of brain cholesterol to the periphery or with decreased activity of the 24S-hydroxylase. Longitudinal studies will assess the validity of the ratio plasma 24S-hydroxycholesterol/cholesterol as a state marker for AD.

Aged↗

PubMed2000

Regulation of sterol 12alpha-hydroxylase and cholic acid biosynthesis in the rat.

BACKGROUND & AIMS: Sterol 12alpha-hydroxylase (CYP8b1) is required for the biosynthesis of cholic acid (CA) and hence helps determine the ratio of CA to chenodeoxycholic acid (CDCA) in bile. This study examined the in vivo regulation of CYP8b1 in the rat by bile acids, cholesterol, and thyroxine. METHODS: The specific activities (SAs), messenger RNA (mRNA) levels, and transcriptional activities of CYP8b1 were determined in intact rats and rats with biliary diversion. RESULTS: CA, CDCA, and deoxycholic acid (DCA), fed as a supplement to the diet, down-regulated CYP8b1 SAs by 99% +/- 0%, 72% +/- 10%, and 98% +/- 1%, respectively. Under these same conditions, mRNA levels decreased by 93% +/- 7%, 60% +/- 11%, and 93% +/- 4%, respectively. Intraduodenal infusion of taurocholate (36 micromol/h. 100 g rat(-1)) decreased SAs and mRNA levels by 63% +/- 8% and 74% +/- 8%, respectively. Ursodeoxycholic acid (UDC) and hyocholic acid (HC) feeding increased CYP8b1 SAs by 119% +/- 21% and 65% +/- 18%, respectively. CA feeding decreased CYP8b1 transcriptional activity by 72%. Complete biliary diversion increased CYP8b1 SAs and mRNA levels by 150% +/- 30% and 287% +/- 51%, respectively. Cholesterol feeding decreased CYP8b1 mRNA by 39% +/- 8%. In intact rats, a single injection of thyroid hormone eliminated CYP8b1 activity. CONCLUSIONS: CYP8b1 is transcriptionally down-regulated by hydrophobic but not hydrophilic bile acids. Cholesterol feeding and a single thyroid hormone injection repressed CYP8b1 in the face of induction of cholesterol 7alpha-hydroxylase (CYP7a1 by the new nomenclature) SAs. These results suggest that cholesterol, thyroid hormone, and hydrophobic bile acids are important regulators of CYP8b1 and consequently of the bile acid pool composition.

Animals↗

PubMed2000

Sterol 27-hydroxylase deficiency: a rare cause of xanthomas in normocholesterolemic humans.

Cerebrotendinous xanthomatosis is characterized by the accumulation of cholestanol and cholesterol in xanthomas and brain causing a number of severe symptoms. More than 20 different mutations have been identified in the gene encoding sterol 27-hydroxylase. Defects in the gene lead to reduced bile acid biosynthesis, with accumulation of 7 alpha-hydroxylated intermediates, one of which is a precursor to cholestanol. The disease can be treated successfully with chenodeoxycholic acid, which reduces the upregulation of cholesterol 7 alpha-hydroxylase and, therefore, the formation of cholestanol. Disruption of the gene encoding sterol 27-hydroxylase in mice does not have the same metabolic consequences as in humans.

Animals↗