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PubMed2001

cyp7b1 catalyses the 7alpha-hydroxylation of dehydroepiandrosterone and 25-hydroxycholesterol in rat prostate.

Dehydroepiandrosterone (DHEA) is the most prominent circulating steroid in humans, and it is a precursor for sex-steroid synthesis in peripheral tissues, including the prostate. Recently, enzyme-mediated pre-receptor metabolism has been recognized as a key step in determining steroid action in vivo. Hydroxylation of 3beta-steroids at the 7alpha-position has been reported in rat and human prostate to be a major inhibitory pathway to sex-steroid synthesis/action. However, the molecular identity of the enzyme responsible is so far unknown. We recently described a novel cytochrome P450 enzyme, cyp7b1, strongly expressed in the hippocampus of rodent brain, which catalyses the metabolism of DHEA, pregnenolone and 25-hydroxycholesterol to 7alpha-hydroxy products. In the light of this new enzyme, we have examined its possible role in 7alpha-hydroxylation conversion in rat prostate. NADPH-dependent 7alpha-hydroxylation was confirmed for 3beta-hydroxysteroids including DHEA and androstenediol, as well as 25-hydroxycholesterol. Kinetic analysis yielded an apparent K(m) of 14+/-1 microM for 7alpha-hydroxylation of DHEA in the prostate gland, a value similar to that recorded for recombinant cyp7b1 enzyme [13.6 microM; Rose, Stapleton, Dott, Kieny, Best, Schwarz, Russell, Bjoorkheim, Seckl and Lathe (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 4925-4930]. The V(max) value of the prostate was 46+/-2 pmol/min per mg, and this activity was inhibited by clotrimazole, a P450-enzyme blocker. Moreover, RNA analysis (reverse-transcription PCR, Northern blotting and in situ hybridization) revealed a high expression of cyp7b1 mRNA in the rat prostate, restricted to the epithelium, suggesting that cyp7b1 catalyses oxysterol 7alpha-hydroxylation in the prostate gland.

Animals↗
PubMed2002

Oxysterol-binding-protein (OSBP)-related protein 4 binds 25-hydroxycholesterol and interacts with vimentin intermediate filaments.

Oxysterol-binding protein (OSBP) is the prototypical member of a class of phospholipid and oxysterol-binding proteins that interacts with the Golgi apparatus and regulates lipid and cholesterol metabolism. As a result of recent sequencing efforts, eleven other OSBP-related proteins (ORPs) have been identified in humans. We have investigated the structure, oxysterol-binding activity, cellular localization and function of ORP4 (also designated OSBP2 or HLM), a homologue that shares the highest degree of similarity with OSBP. Two ORP4 cDNAs were identified: a full-length ORP4 containing a pleckstrin homology (PH) domain and an oxysterol-binding region (designated ORP4-L), and a splice variant in which the PH domain and part of the oxysterol-binding domain were deleted (designated ORP4-S). ORP4 mRNA and protein expression overlapped partially with OSBP and were restricted to brain, heart, muscle and kidney. Like OSBP, ORP4-L bound [3H]25-hydroxycholesterol with high affinity and specificity. In contrast, ORP4-S did not bind [3H]25-hydroxycholesterol or [3H]7-ketocholesterol. Immunofluorescence localization in stably transfected Chinese hamster ovary cells showed that ORP4-S co-localized with vimentin and caused the intermediate filament network to bundle or aggregate. ORP4-L displayed a diffuse staining pattern that did not overlap with vimentin except when the microtubule network was disrupted with nocodazole. Oxysterols had no effect on the localization of either ORP4. Cells overexpressing ORP4-S had a 40% reduction in the esterification of low-density-lipoprotein-derived cholesterol, demonstrating that ORP4 interaction with intermediate filaments inhibits an intracellular cholesterol-transport pathway mediated by vimentin. These studies elucidate a hitherto unknown relationship between OSBPs and the intermediate filament network that influences cholesterol transport.

Alternative Splicing↗
PubMed2003

22R-hydroxycholesterol and 9-cis-retinoic acid induce ATP-binding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid beta secretion.

The ATP-binding cassette transporter A1 (ABCA1) is a major regulator of peripheral cholesterol efflux and plasma high density lipoprotein metabolism. In adult rat brain we found high expression of ABCA1 in neurons in the hypothalamus, thalamus, amygdala, cholinergic basal forebrain, and hippocampus. Large neurons of the cholinergic nucleus basalis together with CA1 and CA3 pyramidal neurons were among the most abundantly immunolabeled neurons. Glia cells were largely negative. Because cholesterol homeostasis may have an essential role in central nervous system function and neurodegeneration, we examined ABCA1 expression and function in different brain cell types using cultures of primary neurons, astrocytes, and microglia isolated from embryonic rat brain. The basal ABCA1 mRNA and protein levels detected in these cell types were increased markedly after exposure to oxysterols and 9-cis-retinoic acid, which are ligands for the nuclear hormone liver X receptors and retinoic X receptors, respectively. Functionally, the increased ABCA1 expression caused by these ligands was followed by elevated apoA-I- and apoE-specific cholesterol efflux in neurons and glia. In non-neuronal and neuronal cells overexpressing a human Swedish variant of amyloid precursor protein, 22R-hydroxycholesterol and 9-cis-retinoic acid induced ABCA1 expression and increased apoA-I-mediated cholesterol efflux consequently decreasing cellular cholesterol content. More importantly, we demonstrated that these ligands alone or in combination with apoA-I caused a substantial reduction in the stability of amyloid precursor protein C-terminal fragments and decreased amyloid beta production. These effects of 22R-hydroxycholesterol may provide a novel strategy to decrease amyloid beta secretion and consequently reduce the amyloid burden in the brain.

ATP Binding Cassette Transporter 1↗
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↗
PubMed2006

24S-hydroxycholesterol induces cholesterol release from choroid plexus epithelial cells in an apical- and apoE isoform-dependent manner concomitantly with the induction of ABCA1 and ABCG1 expression.

The release of cholesterol from choroid plexus epithelial cells (CPE) plays an important role in cholesterol homeostasis in the CSF. The purpose of this study was to clarify the molecules involved in cholesterol release in CPE and the regulation mechanisms of the cholesterol release by the liver X receptor (LXR) using a conditionally immortalized CPE line (TR-CSFB3). The mRNA expression of LXRalpha, LXRbeta and their target genes, ATP-binding cassette transporter (ABC)A1, ABCG1, ABCG4 and ABCG5, were detected in rat choroid plexus. ABCA1 and ABCG1 protein were detected in the plasma membrane of TR-CSFB3 cells. Following treatment with 24S-hydroxycholesterol, an endogenous LXR ligand, the expression of ABCA1 and ABCG1 were induced in TR-CSFB3 cells. Moreover, apolipoprotein (apo)AI- and high-density lipoprotein (HDL)-mediated cholesterol release to the apical side of TR-CSFB3 cells was facilitated by this treatment, whereas that to the basal side was not affected. Following 24S-hydroxycholesterol treatment, apoE3-dependent cholesterol release from TR-CSFB3 cells was enhanced more than the apoE4-dependent release. These results suggest that LXR activation facilitates cholesterol release into the CSF from CPE through the functional induction of ABCA1 and ABCG1. The difference between apoE3 and apoE4 suggests that the cholesterol release from CPE is related to the development of neurodegenerative diseases.

ATP Binding Cassette Transporter 1↗
PubMed1998

Macrophage inhibition of lymphocyte and tumor cell growth is mediated by 25-hydroxycholesterol in the cell membrane.

We have previously reported that a lipid molecule in the membrane fraction of cloned macrophage hybridomas inhibited the growth of lymphocytes and several tumor cell lines. In this study, the inhibitory lipid molecule in the membrane fraction of macrophages was analyzed by thin-layer chromatography and identified as 25-hydroxycholesterol, a family of oxysterols. This conclusion was confirmed by analysis using gas chromatography-mass spectrometry. In addition, both 25-hydroxycholesterol and the lipid molecule recovered from macrophage cell membrane induced apoptosis of the murine T cell lymphoma, BW-5147. These results suggest that an oxysterol expressed in the macrophage cell membrane may participate in the regulation of cell growth through cell contact.

Animals↗
PubMed1994

Cytotoxicity of oxidized LDL to porcine aortic smooth muscle cells is associated with the oxysterols 7-ketocholesterol and 7-hydroxycholesterol.

The cytotoxicity of oxidized low-density lipoprotein (Ox-LDL) to arterial smooth muscle cells (SMCs) may contribute to atherogenesis by causing cell death in core regions of plaques. The aim of the present study was to identify the components of copper-oxidized LDL responsible for its toxicity to porcine aortic SMCs. Toxicity to SMCs was assessed as the decrease in viable cell counts after 3-day cell incubation. Extracts of LDL were tested for toxicity at concentrations equivalent to that derived from 100 micrograms LDL protein per milliliter. Lipid extracts of Ox-LDL but not native-LDL were toxic to SMCs. When separated into neutral and polar lipid classes, only the neutral lipids were toxic (89.7 +/- 0.7% cell loss). The neutral lipids were fractionated further by use of solid-phase extraction and high-performance liquid chromatography (HPLC). Two toxic fractions, causing 93.3% and 60.3% cell loss, were isolated from HPLC and analyzed by gas chromatography/mass spectrometry. The most toxic of these fractions contained 7-ketocholesterol, and the other contained 7 alpha- and 7 beta-hydroxycholesterol. Quantification of these unesterified oxysterols in LDL extracts and comparison with the toxicity of authentic standards indicate that 7-ketocholesterol and 7-hydroxycholesterol are present in Ox-LDL at levels sufficient to account for its toxicity to SMCs.

Animals↗
PubMed2004

Determination of 24S- and 27-hydroxycholesterol in plasma by high-performance liquid chromatography-mass spectrometry.

24S-Hydroxycholesterol (24S-OH-Chol) and 27-hydroxycholesterol (27-OH-Chol) are oxidized derivatives of cholesterol and of potential diagnostic interest because their circulating levels may reflect the cholesterol metabolism of the brain and macrophages, respectively. We developed a sensitive and specific HPLC-MS method for the quantification of 24S-OH-Chol and 27-OH-Chol in human plasma. In contrast to currently available procedures based on gas chromatography-mass spectrometry, this methodology offers the advantage that no time-consuming derivatization is needed. After saponification, solid-phase extraction, and HPLC separation under reversed-phase column conditions, detection by MS was performed using atmospheric pressure chemical ionization and selected ion monitoring mode. The standard curves were linear throughout the calibration range for both oxysterols. Within-day and between-day coefficients of variation were less than 9%, and the recoveries ranged between 98% and 103%. The quantification limits were 40 and 25 microg/l for 24S-OH-Chol and 27-OH-Chol, respectively. Mean values for both oxysterols were determined in plasma from 22 healthy volunteers. The sensitive and selective HPLC-MS method described here combined with the appropriate workup procedure allow the quantification of 24S-OH-Chol and 27-OH-Chol in plasma samples, for example in clinical studies to elaborate the clinical usefulness of these two oxysterols.

Chromatography, High Pressure Liquid↗
PubMed1998

25-Hydroxycholesterol is not a ligand for the orphan nuclear receptor steroidogenic factor-1 (SF-1).

The orphan nuclear receptor steroidogenic factor-1 (SF-1) is involved in the transcriptional regulation of all the steroid hydroxylase genes, and also regulates the transcription of the genes for Müllerian Inhibitory substance (MIS), alpha subunit of glycoprotein hormone, LHbeta, oxytocin, GnRH receptor, ACTH receptor, prolactin receptor, DAX-1, and steroidogenic acute regulatory protein. Other members of the nuclear receptor gene family, including steroid hormone, thyroid hormone, retinoic acid, PPAR, and vitamin D receptors must bind ligand to activate transcription, but SF-1 has been considered to be an orphan nuclear receptor because, when identified, it had no known ligand. A recent publication suggested that transcriptional regulation by SF-1, expressed in a non-steroidogenic CV-1 cells, could be activated by oxysterols suggesting that these compounds could serve as natural ligands for SF-1. We now demonstrate that 25-hydroxycholesterol, either added exogenously or synthesized endogenously in steroidogenic mouse Leydig MA-10 cells, did not act as a ligand for SF-1, as it did not increase transcription from six different SF-1-dependent DNA sequences. Furthermore, the abundance of these oxysterols in MA-10 cells was much less than concentrations needed for activation of SF-1 in CV-1 cells, indicating that SF-1 is not constitutively bound by ligand in MA-10 cells. Thus, in steroidogenic cells, transcriptional regulation of the steroid hydroxylase genes by SF-1 does not depend upon the presence of 25-hydroxycholesterol, and is not modified by its presence.

Animals↗
PubMed2000

Anti-tumor effects of 25-hydroxycholesterol and low-dose recombinant tumor necrosis factor-alpha on rat liver tumorigenesis: modulated differentiation therapy for hepatocellular carcinoma.

Previously, we have demonstrated that treatment of rat AH136B ascites hepatoma cells with 25-hydroxycholesterol (25-OH) induces apoptosis. In this study, to elucidate whether modulated differentiation therapy may be useful in treating patients with hepatoma, we assayed the effects of 25-OH and/or tumor necrosis factor-alpha (TNF) on rat AH136B ascites hepatoma cells in vivo. Here we show that a high concentration of TNF (250 U/ml) mediated a stronger cytocidal effect than a low concentration of TNF (25 U/ml) in vitro. Flow cytometric DNA analysis also showed that treatment of cells with the high concentration of TNF (250 U/ml) increased the percentage of AH136B cells in the G0/G1 phase, while 25 U/ml of TNF did not cause any marked change in cell kinetics. In in vivo experiments, 25-OH (80 microg/rat) and TNF (500 U/rat) were administered after transplanting AH136B cells into Donryu rats intraperitoneally. We found that tumor development was completely inhibited by this treatment in 3 of 9 rats, and their 40-day survival rate was 44%; in contrast, rats administered 25-OH (80 microg/rat) alone or TNF (500 U/ml) alone developed peritonitis carcinomatosa, and died within 13 days of inoculation. These findings suggest that local combined treatment with 25-hydroxycholesterol and low-dose TNF can induce synergistic anti-tumor effects.

Animals↗
PubMed2000

Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients.

Alzheimer's disease (AD) is characterized by the presence of senile plaques, neurofibrillary tangles, and neuronal cell loss associated with membrane cholesterol release. 24S-hydroxycholesterol (24S-OH-Chol) is an enzymatically oxidized product of cholesterol mainly synthesized in the brain. We tested the hypothesis that plasma levels of this oxysterol could be used as a putative biochemical marker for an altered cholesterol homeostasis in the brain of AD patients. Thirty patients with clinical criteria for AD, 30 healthy volunteers, 18 depressed patients, and 12 patients with vascular dementia (non-Alzheimer demented) were studied. Plasma concentrations of 24S-OH-Chol were assayed by isotope dilution;-mass spectrometry, cholesterol was measured enzymatically, and apolipoprotein E (apoE) was genotyped by polymerase chain reaction and restricted fragment length polymorphism. The concentration of 24S-OH-Chol in AD and non-Alzheimer demented patients was modestly but significantly higher than in healthy controls and in depressed patients. There was no significant difference in the concentrations of 24S-OH-Chol between depressed patients and healthy controls nor between AD and non-Alzheimer demented patients. The apoE straightepsilon4 allele influences plasma 24S-OH-Chol. However, this influence could be completely accounted for by the elevated plasma cholesterol in apoE4 hetero- or homozygotes. Plasma 24S-OH-Chol levels correlated negatively with the severity of dementia. AD and vascular demented patients appear to have higher circulating levels of 24S-OH-Chol than depressed patients and healthy controls. We speculate that 24S-OH-Chol plasma levels may potentially be used as an early biochemical marker for an altered cholesterol homeostasis in the central nervous system. 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients.

Aged↗
PubMed1975

Conversion of 7alpha-hydroxycholesterol and 7alpha-hydroxy-beta-sitosterol to 3alpha, 7alpha-dihydroxy- and 3alpha, 7alpha, 12alpha-trihydroxy-5beta-steroids in vitro.

The metabolism of 7alpha-hydroxycholesterol and 7alpha-hydroxy-beta-sitosterol (24alpha-ethyl-5-cholestene-3beta,7alpha-diol) has been compared in rat liver subcellular fractions. 7alpha-Hydroxy-beta-sitosterol was shown to be metabolized in the same manner as 7alpha-hydroxycholesterol. Thus, the following C29 metabolites have been identified: 24alpha-ethyl-7alpha-hydroxy-4-cholesten-3-one, 24alpha-ethyl-7alpha,12alpha-dihydroxy-4-cholesten-3-one, 24alpha-ethyl-7alpha-hydroxy-5beta-cholestan-3-one, 24alpha-ethyl-5beta-cholestane-3alpha,7alpha-diol, 24alpha-ethyl-7alpha,12alpha-dihydrozy-5beta-cholestan-3-one, and 24alpha-ethyl-5beta-cholestane-3alha,7alpha,12alpha-triol. The C29 compounds were generally less efficient substrates. The most pronounced difference was noted for the delta4-3-oxosteroid 5beta-reductase. Thus, 7alpha-hydroxy-4-cholesten-3-one was three to four times as efficiently reduced as the C29 analog. The oxidation of the 3beta,7alpha-dihydroxy-delta5-steroid to the 7alpha-hydroxy-delta4-3-oxosteroid, the 12alpha-hydroxylation of the 7alpha-hydroxy-delta4-3-oxosteroid, and the reduction of the 7alpha-hydroxy-5beta-3-oxosteroid to the 3alpha,7alpha-dihydroxy-5beta-steroid occurred in up to two times better yields for the C27 steroids.

Animals↗
PubMed2002

25R,26-Hydroxycholesterol revisited: synthesis, metabolism, and biologic roles.

The CYP27 gene is expressed in arterial endothelium, macrophages, and other tissues. The gene product generates sterol intermediates that function as ligands for nuclear receptors prior to their transport to the liver for metabolism, mostly to bile acids. Most attention has been given to 27-hydroxycholesterol as a ligand for LXR activated receptors and to chenodeoxycholic acid as a ligand for farnesoid X activated receptors (FXRs). Expression of the pathway in macrophages is essential for normal reverse cholesterol transport. Thus, ABC transporter activity is upregulated, which enhances cholesterol efflux. Absence of these mechanisms probably accounts for the accelerated atherosclerosis that occurs in cerebrotendinous xanthomatosis. Accumulation of 27-hydroxycholesterol in human atheroma is puzzling and may reflect low levels of oxysterol 7alpha-hydroxylase activity in human macrophages. The same enzyme determines the proportion of mono-, di-, and tri-hydroxy bile acids synthesized in the liver. Oxysterol 7alpha-hydroxylase deficiency is a molecular basis for cholestatic liver disease. Chenodeoxycholic acid, the major normal end product, downregulates expression of cholesterol 7alpha-hydroxylase via the FXR/short heterodimer protein nuclear receptor and thus limits total bile acid production. The challenge is to quantify in a physiologic setting the magnitude of the pathway in different tissues and to further evaluate the biologic roles of all the intermediates that may function as ligands for orphan nuclear receptors or via other regulatory mechanisms.

Animals↗
PubMed1976

A sterospecific synthesis of 7alpha-hydroxycholesterol.

The five step synthesis of 7alpha-hydroxycholesterol utilizes the solvolysis of 7alpha-bromocholesterol benzoate with potassium acetate in acetic acid as the key step in controlling the stereospecificity of the reaction sequence. This reaction yields 7alpha-acetoxycholesterol benzoate with retention of configuration at position seven. The diester is readily reduced with lithium aluminum to 7alpha-hydroxycholesterol.

Hydroxycholesterols↗
PubMed1986

Comparative effects of 7 beta-hydroxycholesterol towards murine lymphomas, lymphoblasts and lymphocytes: selective cytotoxicity and blastogenesis inhibition.

The effects of 7 beta-hydroxycholesterol on lymphoma cells in culture, on lymphocytes entering blastic transformation and on quiescent murine spleen lymphocytes have been investigated. The early events of blastogenesis as well as YAC-1, RDM-4 and EL-4 cells were shown to be very sensitive to this sterol at microM concentration, whereas constituted lymphoblasts and normal lymphocytes remained insensitive at 50 times higher concentration. The effect of some classical antitumor drugs (Adriamycin, Mitomycin-C, Methotrexate) on these lymphoma cells were of the same order of magnitude. However, the activity of 7 beta-hydroxycholesterol was closely related to the composition of the culture medium. Indeed, the cytotoxic effects of this compound were less in medium supplemented with foetal calf serum than in lipoprotein poor, Ultroser-G supplemented medium. The possible impairment of the same, or closely related, events occurring in blastic transformation and in rapid proliferation of cells is pointed out. Our results raise the question of the possible use of these compounds for an antitumor strategy.

Animals↗
PubMed1985

[In vivo antitumor activity of hydrosoluble derivatives of 7-hydroxycholesterols].

Sodium bis-hemisuccinates of 7 beta- and 7 alpha-hydroxycholesterols are moderately water-soluble. They have been tested intraperitoneally against the murine Krebs-II carcinoma, grown as an ascitic tumour, and their action has been compared with that of usual chemotherapeutic drugs, cyclophosphamide, 5-fluoro-uracil, and methotrexate. The hydroxycholesterol derivatives show a faster and stronger activity (life prolongation), and lead to the complete disappearance of the tumour in about 1/3 of the cases, even with one single injection. Similar results have been obtained (on fewer cases) with two other experimental ascitic tumours, the S-180 sarcoma and the ZHC hepatoma. The mechanism of action is not known; it appears to be very different from that of the usual anti-cancer chemotherapeutic agents.

Animals↗
PubMed1985

Identification of regulatory oxysterols, 24(S),25-epoxycholesterol and 25-hydroxycholesterol, in cultured fibroblasts.

Biosynthetically tritiated sterols from Chinese hamster lung (Dede) cells were fractionated by high performance liquid chromatography, and fractions were assayed for their ability to repress 3-hydroxy-3-methylglutaryl-CoA reductase in L cell cultures. Most of the activity found was associated with two oxysterols, 24(S),25-epoxycholesterol and 25-hydroxycholesterol. The identities of the two sterols were established by co-chromatography with authentic samples and by isotopic dilution and recrystallization. Only low levels of repressor activity were found in other fractions of the sterol extract. The endogenous concentrations of 24(S),25-epoxycholesterol (7.2 fg/cell) and 25-hydroxycholesterol (1.5 fg/cell) appear to be within the ranges required for the regulation of HMG-CoA reductase.

Animals↗
PubMed1995

7 Alpha-hydroxylation of 27-hydroxycholesterol in rat brain microsomes.

27-hydroxycholesterol is shown to be 7 alpha-hydroxylated by microsomal preparations of rat brain. The apparent Km was about 2 microM and Vmax about 15 pmol/min x mg protein. The reaction might modulate biological functions of 27-hydroxycholesterol, such as its suppressive effect on the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and supports the possibility of bile acid formation in the brain.

Animals↗