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Hans M.g. Princen - One of the best experts on this subject based on the ideXlab platform.

  • Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Increases Hepatic ABCA1 mRNA Expression and HDL-Cholesterol
    Arteriosclerosis Thrombosis and Vascular Biology, 2006
    Co-Authors: S.m. Post, Hans M.g. Princen, Martine Groenendijk, Caroline C. Van Der Hoogt, Catherine Fievet, Gérald Luc, Menno Hoekstra, Bart Staels, Patrick C. N. Rensen
    Abstract:

    OBJECTIVE - High-density lipoprotein (HDL) plays a key role in protection against development of atherosclerosis by reducing inflammation, protecting against LDL oxidation, and promoting reverse Cholesterol transport from peripheral tissues to the liver for secretion into bile. Cholesterol 7α-hydroxylase (Cyp7a1) catalyzes the rate-limiting step in the intrahepatic conversion of Cholesterol to bile acids that may have a role in HDL metabolism. We investigated the effect of Cyp7a1 deficiency on HDL metabolism in APOE*3-Leiden transgenic mice. METHODS AND RESULTS - Reduced bile acid biosynthesis in Cyp7a1-/-.APOE*3-Leiden mice versus APOE*3-Leiden mice did not affect total plasma Cholesterol levels, but the distribution of Cholesterol over various lipoproteins was different. Cholesterol was decreased in apoB-containing lipoproteins (ie, VLDL and IDL/LDL), whereas Cholesterol was increased in HDL. The activity of PLTP and LCAT, which play a role in HDL catabolism, were not changed, and neither was HDL clearance. However, the hepatic Cholesterol content was 2-fold increased, which was accompanied by a 2-fold elevated expression of hepatic ABCA1 and increased rate of Cholesterol efflux from the liver to HDL. CONCLUSIONS - Strongly reduced bile acid synthesis in Cyp7a1-/-.APOE*3-Leiden mice leads to increased plasma HDL-Cholesterol levels, as related to an increased hepatic expression of ABCA1. © 2006 American Heart Association, Inc. Chemicals / CAS: Cholesterol 7alpha Monooxygenase, 9037-53-0; phosphatidylcholine sterol acyltransferase, 9031-14-5; Apolipoprotein E3; ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cholesterol, HDL; Phosphatidylcholine-Sterol O-Acyltransferase, EC 2.3.1.43; phospholipid transfer protein, mouse; Phospholipid Transfer Proteins; RNA, Messenger

  • Modulating effect of the A-278C promoter polymorphism in the Cholesterol 7alpha-hydroxylase gene on serum lipid levels in normolipidaemic and hypertriglyceridaemic individuals.
    European Journal of Human Genetics, 2004
    Co-Authors: Maaike K. Hofman, Martine Groenendijk, P J J H Verkuijlen, I J A M Jonkers, M.f. Mohrschladt, Augustinus H. M. Smelt, Hans M.g. Princen
    Abstract:

    The rate-limiting enzyme in the conversion of Cholesterol into bile acids is Cholesterol 7alpha-hydroxylase (CYP7A1). An A to C substitution 278 bp upstream in the promoter of the CYP7A1 gene was found to be associated with variations in serum lipid levels in normolipidaemic populations. In the present study, we investigated the involvement of this polymorphism in four different lipid disorders: hypertriglyceridaemia (HTG), combined hyperlipidaemia (CH), familial dysbetalipoproteinaemia (FD) and familial hyperCholesterolaemia (FH). In a normolipidaemic male population, homozygous for the apoE3 isoform, an association was found between the AA genotype and higher levels of serum triglycerides (AA: + 34%, P=0.036). In HTG patients, the AA genotype was associated with significantly higher concentrations of total Cholesterol (+ 23%, P=0.005). There was a tendency towards increased levels of serum triglycerides (+ 39%, P=0.06), VLDL-triglycerides (+ 48%, P=0.053) and VLDL-Cholesterol (+ 35%, P=0.059). No significant associations were found between serum lipid levels and the CYP7A1 polymorphism in patients with CH, FD and FH. Our results show that the A-278C polymorphism in the CYP7A1 gene has an effect on triglyceride levels in normolipidaemic males and on Cholesterol levels in patients with hypertriglyceridaemia. © 2004 Nature Publishing Group All rights reserved. Chemicals / CAS: Cholesterol 7alpha Monooxygenase, 9037-53-0; Cholesterol, 57-88-5; lipid, 66455-18-3; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Triglycerides

  • Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production
    Arteriosclerosis Thrombosis and Vascular Biology, 2004
    Co-Authors: S.m. Post, Martine Groenendijk, Patrick C. N. Rensen, Karianne Solaas, Hans M.g. Princen
    Abstract:

    Objective-Cholesterol 7α-hydroxylase (cyp7a1) catalyzes the rate-limiting step in conversion of Cholesterol to bile acids. To study the relationship between bile acid biosynthesis and triglyceride metabolism, we cross-bred mice lacking cyp7a1 on a hyperlipidemic APOE*3-Leiden background. Methods and Results-Female mice received a chow or lipogenic diet. On both diets, fecal bile acid excretion was 70% decreased concomitantly with a 2-fold increased neutral sterol output. The differences in bile acid biosynthesis did not change plasma Cholesterol levels. However, plasma triglyceride levels decreased by 41% and 38% in the cyp7a1-/- APOE*3-Leiden mice as compared with APOE*3-Leiden mice on chow and lipogenic diet, respectively. Mechanistic studies showed that very-low-density lipoprotein (VLDL)-apolipoprotein B and VLDL-triglyceride production rates were reduced in cyp7a1-/-.APOE*3-Leiden mice as compared with APOE*3-Leiden mice (-34% and -35%, respectively). Cyp7a1 deficiency also increased the hepatic cholesteryl ester and triglyceride content (2.8-fold and 2.5-fold, respectively). In addition, hepatic anti-oxidative vitamin content, which can influence VLDL-production, was lower. Hepatic mRNA analysis showed decreased expression of genes involved in lipogenesis including srebf1. Conclusions-Cyp7a1 deficiency in APOE*3-Leiden mice decreases the VLDL particle production rate, as a consequence of a strongly reduced bile acid biosynthesis, leading to a decrease in plasma triglycerides. These data underscore the close relationship between bile acid biosynthesis and triglyceride levels. Chemicals / CAS: Cholesterol 7alpha Monooxygenase, 9037-53-0; Cholesterol, 57-88-5; acyltransferase, 9012-30-0, 9054-54-0; alpha tocopherol, 1406-18-4, 1406-70-8, 52225-20-4, 58-95-7, 59-02-9; diacylglycerol acyltransferase, 9029-98-5; retinol, 68-26-8, 82445-97-4; Acyltransferases, EC 2.3.-; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins B; Apolipoproteins E; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cholesterol Esters; Dgat1 protein, mouse, EC 2.3.1.20; Diacylglycerol O-Acyltransferase, EC 2.3.1.20; Ketone Bodies; Lipoproteins, VLDL; RNA, Messenger; Sterols; Triglycerides; Vitamin A, 11103-57-4; Vitamin E, 1406-18-4

  • Heterogeneous expression of Cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase genes in the rat liver lobulus.
    Journal of Clinical Investigation, 1995
    Co-Authors: J Twisk, M.f.m. Hoekman, W.h. Mager, A. F. M. Moorman, P.a.j. De Boer, L. Scheja, Hans M.g. Princen, R Gebhardt
    Abstract:

    We investigated the lobular localization and molecular level of expression of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase, two key enzymes in bile acid synthesis, in isolated periportal and pericentral hepatocytes and by in situ hybridization of rat liver. Enzyme activity, mRNA, and gene transcription of Cholesterol 7α-hydroxylase were predominant in pericentral hepatocytes of control rats, being 7.9-, 9.9-, and 4.4-fold higher than in periportal hepatocytes, respectively. Similar localization was found for sterol 27-hydroxylase: 2.9-, 2.5-, and 1.7-fold higher enzyme activity, mRNA, and gene transcription, respectively, was found in pericentral hepatocytes. Interruption of the enterohepatic circulation with colestid resulted in upregulation of these parameters for both enzymes, as a consequence of stimulated gene expression mainly in the periportal zone. In contrast, mRNA levels and gene transcription of 3-hydroxy-3-methylglutaryl CoA reductase showed opposite lobular distribution. Selective periportal expression for the latter was enhanced, but remained local, after colestid treatment. In situ hybridization showed unambiguously that Cholesterol 7α-hydroxylase mRNA is localized exclusively in the pericentral zone and that sterol 27-hydroxylase mRNA is expressed preferentially in the pericentral region, though less pronounced. Administration of colestid led to expression of both genes within a larger area of the liver lobulus. In conclusion, we suggest that Cholesterol 7α-hydroxylase and sterol 27-hydroxylase are coordinately regulated by the bile acid gradient over the lobulus, resulting in predominant expression in the pericentral zone. Opposite lobular localization of Cholesterol and bile acid synthesis provides an alternative view to interregulation of these metabolic pathways. Chemicals/CAS: 3 hydroxy 3 methylglutaryl coenzyme A, 1553-55-5; alanine aminotransferase, 9000-86-6, 9014-30-6; Cholesterol 7alpha Monooxygenase, 9037-53-0; colestipol, 25085-17-0, 37296-80-3, 50925-79-6; glutamate ammonia ligase, 9023-70-5; glyceraldehyde 3 phosphate dehydrogenase, 9001-50-7; pyruvate kinase, 9001-59-6; sterol 27 hydroxylase, 134712-57-5; Biological Markers; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Colestipol, 50925-79-6; Cytochrome P-450 Enzyme System, 9035-51-2; cytochrome P-450C27/25, EC 1.14.-; RNA, Messenger; Steroid Hydroxylases, EC 1.14.-

  • insulin suppresses bile acid synthesis in cultured rat hepatocytes by down regulation of Cholesterol 7α hydroxylase and sterol 27 hydroxylase gene transcription
    Hepatology, 1995
    Co-Authors: J Twisk, M.f.m. Hoekman, Eline M Lehmann, P Meijer, Willem H Mager, Hans M.g. Princen
    Abstract:

    Evidence from in vivo studies indicates that the bile acid pool and bile acid excretion are increased in humans with diabetes mellitus and in experimental diabetic animals, and that both parameters return to normal levels after administration of insulin. To investigate the biochemical background of these changes, the effects of insulin on bile acid synthesis and Cholesterol 7α-hydroxylase and sterel 27-hydroxylase, two key enzymes in routing of Cholesterol toward bile acids, were studied in cultured rat hepatocytes. Mass production of bile acids was dose dependently diminished, showing significant reduction (-33% to -53%) at physiological concentrations of the hormone (1.4 to 14 nmol/L) and a maximal decrease at 140 nmol/L (- 65%). The decrease of bile acid synthesis correlated well with the suppression of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase activity. The enzyme activity for Cholesterol 7α-hydroxylase, examined in more detail, was dose dependently diminished on incubation of hepatocytes with various concentrations of insulin, reaching maximal reduction at 14 nmol/L of insulin. Maximal decrease of the enzyme activity was seen after 8 hours of incubation (-70%). Insulin strongly reduced the rise in Cholesterol 7α-hydroxylase activity induced by incubation with dexamethasone. Sterol 27- hydroxylase activity was inhibited up to -58% after 24 hours of incubation with 140 nmol/L insulin. To study the mechanism of suppression of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase activity, the effects of insulin on their respective levels of messenger RNA (mRNA) and gene transcription were assessed. The decrease in enzyme activities could be explained by a concomitant reduction in the Cholesterol 7α-hydroxylase (-76%) and sterol 27-hydroxylase (-62%) mRNA level. Transcriptional activity, as assessed by nuclear runoff assays, was decreased to the same extent, i.e., -60% for Cholesterol 7α-hydroxylase and -75% for sterol 27-hydroxylase. Transient expression experiments using a construct containing the proximal 348 basepairs of the Cholesterol 7α-hydroxylase promoter fused to the chloramphenicol acetyltransferase (CAT) gene (-348Rcat) showed a significant reduction of transcriptional activity (-64%) with insulin, indicating that a sequence important for an insulin-induced transcriptional response is located within the first 348 basepairs, preceding the transcription start of the Cholesterol 7α-hydroxylase promoter. We conclude that physiological concentrations of insulin suppress bile acid synthesis by downregulation of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase gene transcription, and that this effect is mediated through a direct action of the hormone on the hepatocyte. These results may provide an explanation for the increased bile acid pool and excretion as found in humans with untreated diabetes mellitus and in experimental animals with insulin deficiency. Chemicals/CAS: Cholesterol 7alpha Monooxygenase, 9037-53-0; insulin, 9004-10-8; oxygenase, 9037-29-0, 9046-59-7; sterol 27 hydroxylase, 134712-57-5; Bile Acids and Salts; Chloramphenicol O-Acetyltransferase, EC 2.3.1.28; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cytochrome P-450 Enzyme System, 9035-51-2; cytochrome P-450C27/25, EC 1.14.-; Insulin, 11061-68-0; Membrane Glycoproteins; nuclear pore glycoprotein gp210; Nuclear Proteins; RNA, Messenger; Steroid Hydroxylases, EC 1.14.-

J Twisk - One of the best experts on this subject based on the ideXlab platform.

  • Heterogeneous expression of Cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase genes in the rat liver lobulus.
    Journal of Clinical Investigation, 1995
    Co-Authors: J Twisk, M.f.m. Hoekman, W.h. Mager, A. F. M. Moorman, P.a.j. De Boer, L. Scheja, Hans M.g. Princen, R Gebhardt
    Abstract:

    We investigated the lobular localization and molecular level of expression of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase, two key enzymes in bile acid synthesis, in isolated periportal and pericentral hepatocytes and by in situ hybridization of rat liver. Enzyme activity, mRNA, and gene transcription of Cholesterol 7α-hydroxylase were predominant in pericentral hepatocytes of control rats, being 7.9-, 9.9-, and 4.4-fold higher than in periportal hepatocytes, respectively. Similar localization was found for sterol 27-hydroxylase: 2.9-, 2.5-, and 1.7-fold higher enzyme activity, mRNA, and gene transcription, respectively, was found in pericentral hepatocytes. Interruption of the enterohepatic circulation with colestid resulted in upregulation of these parameters for both enzymes, as a consequence of stimulated gene expression mainly in the periportal zone. In contrast, mRNA levels and gene transcription of 3-hydroxy-3-methylglutaryl CoA reductase showed opposite lobular distribution. Selective periportal expression for the latter was enhanced, but remained local, after colestid treatment. In situ hybridization showed unambiguously that Cholesterol 7α-hydroxylase mRNA is localized exclusively in the pericentral zone and that sterol 27-hydroxylase mRNA is expressed preferentially in the pericentral region, though less pronounced. Administration of colestid led to expression of both genes within a larger area of the liver lobulus. In conclusion, we suggest that Cholesterol 7α-hydroxylase and sterol 27-hydroxylase are coordinately regulated by the bile acid gradient over the lobulus, resulting in predominant expression in the pericentral zone. Opposite lobular localization of Cholesterol and bile acid synthesis provides an alternative view to interregulation of these metabolic pathways. Chemicals/CAS: 3 hydroxy 3 methylglutaryl coenzyme A, 1553-55-5; alanine aminotransferase, 9000-86-6, 9014-30-6; Cholesterol 7alpha Monooxygenase, 9037-53-0; colestipol, 25085-17-0, 37296-80-3, 50925-79-6; glutamate ammonia ligase, 9023-70-5; glyceraldehyde 3 phosphate dehydrogenase, 9001-50-7; pyruvate kinase, 9001-59-6; sterol 27 hydroxylase, 134712-57-5; Biological Markers; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Colestipol, 50925-79-6; Cytochrome P-450 Enzyme System, 9035-51-2; cytochrome P-450C27/25, EC 1.14.-; RNA, Messenger; Steroid Hydroxylases, EC 1.14.-

  • insulin suppresses bile acid synthesis in cultured rat hepatocytes by down regulation of Cholesterol 7α hydroxylase and sterol 27 hydroxylase gene transcription
    Hepatology, 1995
    Co-Authors: J Twisk, M.f.m. Hoekman, Eline M Lehmann, P Meijer, Willem H Mager, Hans M.g. Princen
    Abstract:

    Evidence from in vivo studies indicates that the bile acid pool and bile acid excretion are increased in humans with diabetes mellitus and in experimental diabetic animals, and that both parameters return to normal levels after administration of insulin. To investigate the biochemical background of these changes, the effects of insulin on bile acid synthesis and Cholesterol 7α-hydroxylase and sterel 27-hydroxylase, two key enzymes in routing of Cholesterol toward bile acids, were studied in cultured rat hepatocytes. Mass production of bile acids was dose dependently diminished, showing significant reduction (-33% to -53%) at physiological concentrations of the hormone (1.4 to 14 nmol/L) and a maximal decrease at 140 nmol/L (- 65%). The decrease of bile acid synthesis correlated well with the suppression of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase activity. The enzyme activity for Cholesterol 7α-hydroxylase, examined in more detail, was dose dependently diminished on incubation of hepatocytes with various concentrations of insulin, reaching maximal reduction at 14 nmol/L of insulin. Maximal decrease of the enzyme activity was seen after 8 hours of incubation (-70%). Insulin strongly reduced the rise in Cholesterol 7α-hydroxylase activity induced by incubation with dexamethasone. Sterol 27- hydroxylase activity was inhibited up to -58% after 24 hours of incubation with 140 nmol/L insulin. To study the mechanism of suppression of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase activity, the effects of insulin on their respective levels of messenger RNA (mRNA) and gene transcription were assessed. The decrease in enzyme activities could be explained by a concomitant reduction in the Cholesterol 7α-hydroxylase (-76%) and sterol 27-hydroxylase (-62%) mRNA level. Transcriptional activity, as assessed by nuclear runoff assays, was decreased to the same extent, i.e., -60% for Cholesterol 7α-hydroxylase and -75% for sterol 27-hydroxylase. Transient expression experiments using a construct containing the proximal 348 basepairs of the Cholesterol 7α-hydroxylase promoter fused to the chloramphenicol acetyltransferase (CAT) gene (-348Rcat) showed a significant reduction of transcriptional activity (-64%) with insulin, indicating that a sequence important for an insulin-induced transcriptional response is located within the first 348 basepairs, preceding the transcription start of the Cholesterol 7α-hydroxylase promoter. We conclude that physiological concentrations of insulin suppress bile acid synthesis by downregulation of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase gene transcription, and that this effect is mediated through a direct action of the hormone on the hepatocyte. These results may provide an explanation for the increased bile acid pool and excretion as found in humans with untreated diabetes mellitus and in experimental animals with insulin deficiency. Chemicals/CAS: Cholesterol 7alpha Monooxygenase, 9037-53-0; insulin, 9004-10-8; oxygenase, 9037-29-0, 9046-59-7; sterol 27 hydroxylase, 134712-57-5; Bile Acids and Salts; Chloramphenicol O-Acetyltransferase, EC 2.3.1.28; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cytochrome P-450 Enzyme System, 9035-51-2; cytochrome P-450C27/25, EC 1.14.-; Insulin, 11061-68-0; Membrane Glycoproteins; nuclear pore glycoprotein gp210; Nuclear Proteins; RNA, Messenger; Steroid Hydroxylases, EC 1.14.-

  • Suppression of sterol 27-hydroxylase mRNA and transcriptional activity by bile acids in cultured rat hepatocytes.
    Biochemical Journal, 1995
    Co-Authors: J Twisk, E.c.m. De Wit, Hans M.g. Princen
    Abstract:

    In previous work we have demonstrated suppression of Cholesterol 7α-hydroxylase by bile acids at the level of mRNA and transcription, resulting in a similar decline in bile acid synthesis in cultured rat hepatocytes. In view of the substantial contribution of the 'alternative' or '27-hydroxylase' route to total bile acid synthesis, as demonstrated in cultured rat hepatocytes and in vivo in humans, we here evaluate the effects of various bile acids commonly found in bile of rats on the regulation of sterol 27-hydroxylase in cultured rat hepatocytes. Addition of taurocholic acid, the predominant bile acid in rat bile, to the culture medium of rat hepatocytes resulted in a 72% inhibition of sterol 27-hydroxylase activity. The effect was exerted at the level of sterol 27-hydroxylase mRNA, showing a time- and dose-dependent decline with a maximal suppression (-75%) at 50 μM taurocholic acid after 24 h of culture. The decline in mRNA followed first-order kinetics with an apparent half-life of 13 h. Under these conditions Cholesterol 7α-hydroxylase mRNA (-91%) and bile acid synthesis (i.e. chenodeoxycholic and β-muricholic acid, -81%) were also maximally suppressed. In contrast, no change was found in the level of lithocholic acid 6β-hydroxylase mRNA. Assessment of the transcriptional activity of a number of genes involved in routing of Cholesterol towards bile acids showed similar suppressive effects of taurocholate on expression of the sterol 27-hydroxylase and Cholesterol 7α-hydroxylase genes (-43% and -42% respectively), whereas expression of the lithocholic 6β-hydroxylase gene was not affected. Taurocholic acid and unconjugated cholic acid were equally as effective in suppressing sterol 27-hydroxylase mRNA. The more hydrophobic bile acids, chenodeoxycholic acid and deoxycholic acid also produced a strong inhibition of 57% and 76% respectively whereas the hydrophilic β-muricholic acid was not active. We conclude that (1) a number of bile acids, at physiological concentrations, suppress sterol 27-hydroxylase by down-regulation of sterol 27-hydroxylase mRNA and transcriptional activity and (2) co-ordinated suppression of both sterol 27-hydroxylase and Cholesterol 7α-hydroxylase results in inhibition of bile acid synthesis in cultured rat hepatocytes. Chemicals/CAS: chenodeoxycholic acid, 474-25-9; Cholesterol 7alpha Monooxygenase, 9037-53-0; cholic acid, 32500-01-9, 361-09-1, 81-25-4; deoxycholic acid, 83-44-3; lithocholic acid, 434-13-9; oxygenase, 9037-29-0, 9046-59-7; taurocholic acid, 145-42-6, 59005-70-8, 81-24-3; Adenosine Triphosphate, 56-65-5; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cytochrome P-450 Enzyme System, 9035-51-2; cytochrome P-450C27/25, EC 1.14.-; Oxidoreductases, EC 1.; RNA, Messenger; Steroid Hydroxylases, EC 1.14.-; Taurocholic Acid, 81-24-3

  • Insulin suppresses bile acid synthesis in cultured rat hepatocytes by down‐regulation of Cholesterol 7α‐hydroxylase and sterol 27‐hydroxylase gene transcription
    Hepatology, 1995
    Co-Authors: J Twisk, M.f.m. Hoekman, Eline M Lehmann, P Meijer, Willem H Mager, Hans M.g. Princen
    Abstract:

    Evidence from in vivo studies indicates that the bile acid pool and bile acid excretion are increased in humans with diabetes mellitus and in experimental diabetic animals, and that both parameters return to normal levels after administration of insulin. To investigate the biochemical background of these changes, the effects of insulin on bile acid synthesis and Cholesterol 7α-hydroxylase and sterel 27-hydroxylase, two key enzymes in routing of Cholesterol toward bile acids, were studied in cultured rat hepatocytes. Mass production of bile acids was dose dependently diminished, showing significant reduction (-33% to -53%) at physiological concentrations of the hormone (1.4 to 14 nmol/L) and a maximal decrease at 140 nmol/L (- 65%). The decrease of bile acid synthesis correlated well with the suppression of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase activity. The enzyme activity for Cholesterol 7α-hydroxylase, examined in more detail, was dose dependently diminished on incubation of hepatocytes with various concentrations of insulin, reaching maximal reduction at 14 nmol/L of insulin. Maximal decrease of the enzyme activity was seen after 8 hours of incubation (-70%). Insulin strongly reduced the rise in Cholesterol 7α-hydroxylase activity induced by incubation with dexamethasone. Sterol 27- hydroxylase activity was inhibited up to -58% after 24 hours of incubation with 140 nmol/L insulin. To study the mechanism of suppression of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase activity, the effects of insulin on their respective levels of messenger RNA (mRNA) and gene transcription were assessed. The decrease in enzyme activities could be explained by a concomitant reduction in the Cholesterol 7α-hydroxylase (-76%) and sterol 27-hydroxylase (-62%) mRNA level. Transcriptional activity, as assessed by nuclear runoff assays, was decreased to the same extent, i.e., -60% for Cholesterol 7α-hydroxylase and -75% for sterol 27-hydroxylase. Transient expression experiments using a construct containing the proximal 348 basepairs of the Cholesterol 7α-hydroxylase promoter fused to the chloramphenicol acetyltransferase (CAT) gene (-348Rcat) showed a significant reduction of transcriptional activity (-64%) with insulin, indicating that a sequence important for an insulin-induced transcriptional response is located within the first 348 basepairs, preceding the transcription start of the Cholesterol 7α-hydroxylase promoter. We conclude that physiological concentrations of insulin suppress bile acid synthesis by downregulation of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase gene transcription, and that this effect is mediated through a direct action of the hormone on the hepatocyte. These results may provide an explanation for the increased bile acid pool and excretion as found in humans with untreated diabetes mellitus and in experimental animals with insulin deficiency. Chemicals/CAS: Cholesterol 7alpha Monooxygenase, 9037-53-0; insulin, 9004-10-8; oxygenase, 9037-29-0, 9046-59-7; sterol 27 hydroxylase, 134712-57-5; Bile Acids and Salts; Chloramphenicol O-Acetyltransferase, EC 2.3.1.28; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cytochrome P-450 Enzyme System, 9035-51-2; cytochrome P-450C27/25, EC 1.14.-; Insulin, 11061-68-0; Membrane Glycoproteins; nuclear pore glycoprotein gp210; Nuclear Proteins; RNA, Messenger; Steroid Hydroxylases, EC 1.14.-

M.f.m. Hoekman - One of the best experts on this subject based on the ideXlab platform.

  • Heterogeneous expression of Cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase genes in the rat liver lobulus.
    Journal of Clinical Investigation, 1995
    Co-Authors: J Twisk, M.f.m. Hoekman, W.h. Mager, A. F. M. Moorman, P.a.j. De Boer, L. Scheja, Hans M.g. Princen, R Gebhardt
    Abstract:

    We investigated the lobular localization and molecular level of expression of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase, two key enzymes in bile acid synthesis, in isolated periportal and pericentral hepatocytes and by in situ hybridization of rat liver. Enzyme activity, mRNA, and gene transcription of Cholesterol 7α-hydroxylase were predominant in pericentral hepatocytes of control rats, being 7.9-, 9.9-, and 4.4-fold higher than in periportal hepatocytes, respectively. Similar localization was found for sterol 27-hydroxylase: 2.9-, 2.5-, and 1.7-fold higher enzyme activity, mRNA, and gene transcription, respectively, was found in pericentral hepatocytes. Interruption of the enterohepatic circulation with colestid resulted in upregulation of these parameters for both enzymes, as a consequence of stimulated gene expression mainly in the periportal zone. In contrast, mRNA levels and gene transcription of 3-hydroxy-3-methylglutaryl CoA reductase showed opposite lobular distribution. Selective periportal expression for the latter was enhanced, but remained local, after colestid treatment. In situ hybridization showed unambiguously that Cholesterol 7α-hydroxylase mRNA is localized exclusively in the pericentral zone and that sterol 27-hydroxylase mRNA is expressed preferentially in the pericentral region, though less pronounced. Administration of colestid led to expression of both genes within a larger area of the liver lobulus. In conclusion, we suggest that Cholesterol 7α-hydroxylase and sterol 27-hydroxylase are coordinately regulated by the bile acid gradient over the lobulus, resulting in predominant expression in the pericentral zone. Opposite lobular localization of Cholesterol and bile acid synthesis provides an alternative view to interregulation of these metabolic pathways. Chemicals/CAS: 3 hydroxy 3 methylglutaryl coenzyme A, 1553-55-5; alanine aminotransferase, 9000-86-6, 9014-30-6; Cholesterol 7alpha Monooxygenase, 9037-53-0; colestipol, 25085-17-0, 37296-80-3, 50925-79-6; glutamate ammonia ligase, 9023-70-5; glyceraldehyde 3 phosphate dehydrogenase, 9001-50-7; pyruvate kinase, 9001-59-6; sterol 27 hydroxylase, 134712-57-5; Biological Markers; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Colestipol, 50925-79-6; Cytochrome P-450 Enzyme System, 9035-51-2; cytochrome P-450C27/25, EC 1.14.-; RNA, Messenger; Steroid Hydroxylases, EC 1.14.-

  • insulin suppresses bile acid synthesis in cultured rat hepatocytes by down regulation of Cholesterol 7α hydroxylase and sterol 27 hydroxylase gene transcription
    Hepatology, 1995
    Co-Authors: J Twisk, M.f.m. Hoekman, Eline M Lehmann, P Meijer, Willem H Mager, Hans M.g. Princen
    Abstract:

    Evidence from in vivo studies indicates that the bile acid pool and bile acid excretion are increased in humans with diabetes mellitus and in experimental diabetic animals, and that both parameters return to normal levels after administration of insulin. To investigate the biochemical background of these changes, the effects of insulin on bile acid synthesis and Cholesterol 7α-hydroxylase and sterel 27-hydroxylase, two key enzymes in routing of Cholesterol toward bile acids, were studied in cultured rat hepatocytes. Mass production of bile acids was dose dependently diminished, showing significant reduction (-33% to -53%) at physiological concentrations of the hormone (1.4 to 14 nmol/L) and a maximal decrease at 140 nmol/L (- 65%). The decrease of bile acid synthesis correlated well with the suppression of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase activity. The enzyme activity for Cholesterol 7α-hydroxylase, examined in more detail, was dose dependently diminished on incubation of hepatocytes with various concentrations of insulin, reaching maximal reduction at 14 nmol/L of insulin. Maximal decrease of the enzyme activity was seen after 8 hours of incubation (-70%). Insulin strongly reduced the rise in Cholesterol 7α-hydroxylase activity induced by incubation with dexamethasone. Sterol 27- hydroxylase activity was inhibited up to -58% after 24 hours of incubation with 140 nmol/L insulin. To study the mechanism of suppression of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase activity, the effects of insulin on their respective levels of messenger RNA (mRNA) and gene transcription were assessed. The decrease in enzyme activities could be explained by a concomitant reduction in the Cholesterol 7α-hydroxylase (-76%) and sterol 27-hydroxylase (-62%) mRNA level. Transcriptional activity, as assessed by nuclear runoff assays, was decreased to the same extent, i.e., -60% for Cholesterol 7α-hydroxylase and -75% for sterol 27-hydroxylase. Transient expression experiments using a construct containing the proximal 348 basepairs of the Cholesterol 7α-hydroxylase promoter fused to the chloramphenicol acetyltransferase (CAT) gene (-348Rcat) showed a significant reduction of transcriptional activity (-64%) with insulin, indicating that a sequence important for an insulin-induced transcriptional response is located within the first 348 basepairs, preceding the transcription start of the Cholesterol 7α-hydroxylase promoter. We conclude that physiological concentrations of insulin suppress bile acid synthesis by downregulation of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase gene transcription, and that this effect is mediated through a direct action of the hormone on the hepatocyte. These results may provide an explanation for the increased bile acid pool and excretion as found in humans with untreated diabetes mellitus and in experimental animals with insulin deficiency. Chemicals/CAS: Cholesterol 7alpha Monooxygenase, 9037-53-0; insulin, 9004-10-8; oxygenase, 9037-29-0, 9046-59-7; sterol 27 hydroxylase, 134712-57-5; Bile Acids and Salts; Chloramphenicol O-Acetyltransferase, EC 2.3.1.28; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cytochrome P-450 Enzyme System, 9035-51-2; cytochrome P-450C27/25, EC 1.14.-; Insulin, 11061-68-0; Membrane Glycoproteins; nuclear pore glycoprotein gp210; Nuclear Proteins; RNA, Messenger; Steroid Hydroxylases, EC 1.14.-

  • Insulin suppresses bile acid synthesis in cultured rat hepatocytes by down‐regulation of Cholesterol 7α‐hydroxylase and sterol 27‐hydroxylase gene transcription
    Hepatology, 1995
    Co-Authors: J Twisk, M.f.m. Hoekman, Eline M Lehmann, P Meijer, Willem H Mager, Hans M.g. Princen
    Abstract:

    Evidence from in vivo studies indicates that the bile acid pool and bile acid excretion are increased in humans with diabetes mellitus and in experimental diabetic animals, and that both parameters return to normal levels after administration of insulin. To investigate the biochemical background of these changes, the effects of insulin on bile acid synthesis and Cholesterol 7α-hydroxylase and sterel 27-hydroxylase, two key enzymes in routing of Cholesterol toward bile acids, were studied in cultured rat hepatocytes. Mass production of bile acids was dose dependently diminished, showing significant reduction (-33% to -53%) at physiological concentrations of the hormone (1.4 to 14 nmol/L) and a maximal decrease at 140 nmol/L (- 65%). The decrease of bile acid synthesis correlated well with the suppression of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase activity. The enzyme activity for Cholesterol 7α-hydroxylase, examined in more detail, was dose dependently diminished on incubation of hepatocytes with various concentrations of insulin, reaching maximal reduction at 14 nmol/L of insulin. Maximal decrease of the enzyme activity was seen after 8 hours of incubation (-70%). Insulin strongly reduced the rise in Cholesterol 7α-hydroxylase activity induced by incubation with dexamethasone. Sterol 27- hydroxylase activity was inhibited up to -58% after 24 hours of incubation with 140 nmol/L insulin. To study the mechanism of suppression of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase activity, the effects of insulin on their respective levels of messenger RNA (mRNA) and gene transcription were assessed. The decrease in enzyme activities could be explained by a concomitant reduction in the Cholesterol 7α-hydroxylase (-76%) and sterol 27-hydroxylase (-62%) mRNA level. Transcriptional activity, as assessed by nuclear runoff assays, was decreased to the same extent, i.e., -60% for Cholesterol 7α-hydroxylase and -75% for sterol 27-hydroxylase. Transient expression experiments using a construct containing the proximal 348 basepairs of the Cholesterol 7α-hydroxylase promoter fused to the chloramphenicol acetyltransferase (CAT) gene (-348Rcat) showed a significant reduction of transcriptional activity (-64%) with insulin, indicating that a sequence important for an insulin-induced transcriptional response is located within the first 348 basepairs, preceding the transcription start of the Cholesterol 7α-hydroxylase promoter. We conclude that physiological concentrations of insulin suppress bile acid synthesis by downregulation of Cholesterol 7α-hydroxylase and sterol 27-hydroxylase gene transcription, and that this effect is mediated through a direct action of the hormone on the hepatocyte. These results may provide an explanation for the increased bile acid pool and excretion as found in humans with untreated diabetes mellitus and in experimental animals with insulin deficiency. Chemicals/CAS: Cholesterol 7alpha Monooxygenase, 9037-53-0; insulin, 9004-10-8; oxygenase, 9037-29-0, 9046-59-7; sterol 27 hydroxylase, 134712-57-5; Bile Acids and Salts; Chloramphenicol O-Acetyltransferase, EC 2.3.1.28; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cytochrome P-450 Enzyme System, 9035-51-2; cytochrome P-450C27/25, EC 1.14.-; Insulin, 11061-68-0; Membrane Glycoproteins; nuclear pore glycoprotein gp210; Nuclear Proteins; RNA, Messenger; Steroid Hydroxylases, EC 1.14.-

Patrick C. N. Rensen - One of the best experts on this subject based on the ideXlab platform.

  • Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Increases Hepatic ABCA1 mRNA Expression and HDL-Cholesterol
    Arteriosclerosis Thrombosis and Vascular Biology, 2006
    Co-Authors: S.m. Post, Hans M.g. Princen, Martine Groenendijk, Caroline C. Van Der Hoogt, Catherine Fievet, Gérald Luc, Menno Hoekstra, Bart Staels, Patrick C. N. Rensen
    Abstract:

    OBJECTIVE - High-density lipoprotein (HDL) plays a key role in protection against development of atherosclerosis by reducing inflammation, protecting against LDL oxidation, and promoting reverse Cholesterol transport from peripheral tissues to the liver for secretion into bile. Cholesterol 7α-hydroxylase (Cyp7a1) catalyzes the rate-limiting step in the intrahepatic conversion of Cholesterol to bile acids that may have a role in HDL metabolism. We investigated the effect of Cyp7a1 deficiency on HDL metabolism in APOE*3-Leiden transgenic mice. METHODS AND RESULTS - Reduced bile acid biosynthesis in Cyp7a1-/-.APOE*3-Leiden mice versus APOE*3-Leiden mice did not affect total plasma Cholesterol levels, but the distribution of Cholesterol over various lipoproteins was different. Cholesterol was decreased in apoB-containing lipoproteins (ie, VLDL and IDL/LDL), whereas Cholesterol was increased in HDL. The activity of PLTP and LCAT, which play a role in HDL catabolism, were not changed, and neither was HDL clearance. However, the hepatic Cholesterol content was 2-fold increased, which was accompanied by a 2-fold elevated expression of hepatic ABCA1 and increased rate of Cholesterol efflux from the liver to HDL. CONCLUSIONS - Strongly reduced bile acid synthesis in Cyp7a1-/-.APOE*3-Leiden mice leads to increased plasma HDL-Cholesterol levels, as related to an increased hepatic expression of ABCA1. © 2006 American Heart Association, Inc. Chemicals / CAS: Cholesterol 7alpha Monooxygenase, 9037-53-0; phosphatidylcholine sterol acyltransferase, 9031-14-5; Apolipoprotein E3; ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cholesterol, HDL; Phosphatidylcholine-Sterol O-Acyltransferase, EC 2.3.1.43; phospholipid transfer protein, mouse; Phospholipid Transfer Proteins; RNA, Messenger

  • Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production
    Arteriosclerosis Thrombosis and Vascular Biology, 2004
    Co-Authors: S.m. Post, Martine Groenendijk, Patrick C. N. Rensen, Karianne Solaas, Hans M.g. Princen
    Abstract:

    Objective-Cholesterol 7α-hydroxylase (cyp7a1) catalyzes the rate-limiting step in conversion of Cholesterol to bile acids. To study the relationship between bile acid biosynthesis and triglyceride metabolism, we cross-bred mice lacking cyp7a1 on a hyperlipidemic APOE*3-Leiden background. Methods and Results-Female mice received a chow or lipogenic diet. On both diets, fecal bile acid excretion was 70% decreased concomitantly with a 2-fold increased neutral sterol output. The differences in bile acid biosynthesis did not change plasma Cholesterol levels. However, plasma triglyceride levels decreased by 41% and 38% in the cyp7a1-/- APOE*3-Leiden mice as compared with APOE*3-Leiden mice on chow and lipogenic diet, respectively. Mechanistic studies showed that very-low-density lipoprotein (VLDL)-apolipoprotein B and VLDL-triglyceride production rates were reduced in cyp7a1-/-.APOE*3-Leiden mice as compared with APOE*3-Leiden mice (-34% and -35%, respectively). Cyp7a1 deficiency also increased the hepatic cholesteryl ester and triglyceride content (2.8-fold and 2.5-fold, respectively). In addition, hepatic anti-oxidative vitamin content, which can influence VLDL-production, was lower. Hepatic mRNA analysis showed decreased expression of genes involved in lipogenesis including srebf1. Conclusions-Cyp7a1 deficiency in APOE*3-Leiden mice decreases the VLDL particle production rate, as a consequence of a strongly reduced bile acid biosynthesis, leading to a decrease in plasma triglycerides. These data underscore the close relationship between bile acid biosynthesis and triglyceride levels. Chemicals / CAS: Cholesterol 7alpha Monooxygenase, 9037-53-0; Cholesterol, 57-88-5; acyltransferase, 9012-30-0, 9054-54-0; alpha tocopherol, 1406-18-4, 1406-70-8, 52225-20-4, 58-95-7, 59-02-9; diacylglycerol acyltransferase, 9029-98-5; retinol, 68-26-8, 82445-97-4; Acyltransferases, EC 2.3.-; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins B; Apolipoproteins E; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cholesterol Esters; Dgat1 protein, mouse, EC 2.3.1.20; Diacylglycerol O-Acyltransferase, EC 2.3.1.20; Ketone Bodies; Lipoproteins, VLDL; RNA, Messenger; Sterols; Triglycerides; Vitamin A, 11103-57-4; Vitamin E, 1406-18-4

Martine Groenendijk - One of the best experts on this subject based on the ideXlab platform.

  • Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Increases Hepatic ABCA1 mRNA Expression and HDL-Cholesterol
    Arteriosclerosis Thrombosis and Vascular Biology, 2006
    Co-Authors: S.m. Post, Hans M.g. Princen, Martine Groenendijk, Caroline C. Van Der Hoogt, Catherine Fievet, Gérald Luc, Menno Hoekstra, Bart Staels, Patrick C. N. Rensen
    Abstract:

    OBJECTIVE - High-density lipoprotein (HDL) plays a key role in protection against development of atherosclerosis by reducing inflammation, protecting against LDL oxidation, and promoting reverse Cholesterol transport from peripheral tissues to the liver for secretion into bile. Cholesterol 7α-hydroxylase (Cyp7a1) catalyzes the rate-limiting step in the intrahepatic conversion of Cholesterol to bile acids that may have a role in HDL metabolism. We investigated the effect of Cyp7a1 deficiency on HDL metabolism in APOE*3-Leiden transgenic mice. METHODS AND RESULTS - Reduced bile acid biosynthesis in Cyp7a1-/-.APOE*3-Leiden mice versus APOE*3-Leiden mice did not affect total plasma Cholesterol levels, but the distribution of Cholesterol over various lipoproteins was different. Cholesterol was decreased in apoB-containing lipoproteins (ie, VLDL and IDL/LDL), whereas Cholesterol was increased in HDL. The activity of PLTP and LCAT, which play a role in HDL catabolism, were not changed, and neither was HDL clearance. However, the hepatic Cholesterol content was 2-fold increased, which was accompanied by a 2-fold elevated expression of hepatic ABCA1 and increased rate of Cholesterol efflux from the liver to HDL. CONCLUSIONS - Strongly reduced bile acid synthesis in Cyp7a1-/-.APOE*3-Leiden mice leads to increased plasma HDL-Cholesterol levels, as related to an increased hepatic expression of ABCA1. © 2006 American Heart Association, Inc. Chemicals / CAS: Cholesterol 7alpha Monooxygenase, 9037-53-0; phosphatidylcholine sterol acyltransferase, 9031-14-5; Apolipoprotein E3; ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cholesterol, HDL; Phosphatidylcholine-Sterol O-Acyltransferase, EC 2.3.1.43; phospholipid transfer protein, mouse; Phospholipid Transfer Proteins; RNA, Messenger

  • Modulating effect of the A-278C promoter polymorphism in the Cholesterol 7alpha-hydroxylase gene on serum lipid levels in normolipidaemic and hypertriglyceridaemic individuals.
    European Journal of Human Genetics, 2004
    Co-Authors: Maaike K. Hofman, Martine Groenendijk, P J J H Verkuijlen, I J A M Jonkers, M.f. Mohrschladt, Augustinus H. M. Smelt, Hans M.g. Princen
    Abstract:

    The rate-limiting enzyme in the conversion of Cholesterol into bile acids is Cholesterol 7alpha-hydroxylase (CYP7A1). An A to C substitution 278 bp upstream in the promoter of the CYP7A1 gene was found to be associated with variations in serum lipid levels in normolipidaemic populations. In the present study, we investigated the involvement of this polymorphism in four different lipid disorders: hypertriglyceridaemia (HTG), combined hyperlipidaemia (CH), familial dysbetalipoproteinaemia (FD) and familial hyperCholesterolaemia (FH). In a normolipidaemic male population, homozygous for the apoE3 isoform, an association was found between the AA genotype and higher levels of serum triglycerides (AA: + 34%, P=0.036). In HTG patients, the AA genotype was associated with significantly higher concentrations of total Cholesterol (+ 23%, P=0.005). There was a tendency towards increased levels of serum triglycerides (+ 39%, P=0.06), VLDL-triglycerides (+ 48%, P=0.053) and VLDL-Cholesterol (+ 35%, P=0.059). No significant associations were found between serum lipid levels and the CYP7A1 polymorphism in patients with CH, FD and FH. Our results show that the A-278C polymorphism in the CYP7A1 gene has an effect on triglyceride levels in normolipidaemic males and on Cholesterol levels in patients with hypertriglyceridaemia. © 2004 Nature Publishing Group All rights reserved. Chemicals / CAS: Cholesterol 7alpha Monooxygenase, 9037-53-0; Cholesterol, 57-88-5; lipid, 66455-18-3; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Triglycerides

  • Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production
    Arteriosclerosis Thrombosis and Vascular Biology, 2004
    Co-Authors: S.m. Post, Martine Groenendijk, Patrick C. N. Rensen, Karianne Solaas, Hans M.g. Princen
    Abstract:

    Objective-Cholesterol 7α-hydroxylase (cyp7a1) catalyzes the rate-limiting step in conversion of Cholesterol to bile acids. To study the relationship between bile acid biosynthesis and triglyceride metabolism, we cross-bred mice lacking cyp7a1 on a hyperlipidemic APOE*3-Leiden background. Methods and Results-Female mice received a chow or lipogenic diet. On both diets, fecal bile acid excretion was 70% decreased concomitantly with a 2-fold increased neutral sterol output. The differences in bile acid biosynthesis did not change plasma Cholesterol levels. However, plasma triglyceride levels decreased by 41% and 38% in the cyp7a1-/- APOE*3-Leiden mice as compared with APOE*3-Leiden mice on chow and lipogenic diet, respectively. Mechanistic studies showed that very-low-density lipoprotein (VLDL)-apolipoprotein B and VLDL-triglyceride production rates were reduced in cyp7a1-/-.APOE*3-Leiden mice as compared with APOE*3-Leiden mice (-34% and -35%, respectively). Cyp7a1 deficiency also increased the hepatic cholesteryl ester and triglyceride content (2.8-fold and 2.5-fold, respectively). In addition, hepatic anti-oxidative vitamin content, which can influence VLDL-production, was lower. Hepatic mRNA analysis showed decreased expression of genes involved in lipogenesis including srebf1. Conclusions-Cyp7a1 deficiency in APOE*3-Leiden mice decreases the VLDL particle production rate, as a consequence of a strongly reduced bile acid biosynthesis, leading to a decrease in plasma triglycerides. These data underscore the close relationship between bile acid biosynthesis and triglyceride levels. Chemicals / CAS: Cholesterol 7alpha Monooxygenase, 9037-53-0; Cholesterol, 57-88-5; acyltransferase, 9012-30-0, 9054-54-0; alpha tocopherol, 1406-18-4, 1406-70-8, 52225-20-4, 58-95-7, 59-02-9; diacylglycerol acyltransferase, 9029-98-5; retinol, 68-26-8, 82445-97-4; Acyltransferases, EC 2.3.-; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins B; Apolipoproteins E; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cholesterol Esters; Dgat1 protein, mouse, EC 2.3.1.20; Diacylglycerol O-Acyltransferase, EC 2.3.1.20; Ketone Bodies; Lipoproteins, VLDL; RNA, Messenger; Sterols; Triglycerides; Vitamin A, 11103-57-4; Vitamin E, 1406-18-4