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W2077885768 abstract "As previously reported by us, mice with targeted disruption of the CYP8B1 gene (CYP8B1−/−) fail to produce cholic acid (CA), upregulate their bile acid synthesis, reduce the absorption of dietary cholesterol and, after cholesterol feeding, accumulate less liver cholesterol than wild-type (CYP8B1+/+) mice. In the present study, cholesterol-enriched diet (0.5%) or administration of a synthetic liver X receptor (LXR) agonist strongly upregulated CYP7A1 expression in CYP8B1−/− mice, compared to CYP8B1+/+ mice. Cholesterol-fed CYP8B1−/− mice also showed a significant rise in HDL cholesterol and increased levels of liver ABCA1 mRNA. A combined CA (0.25%)/cholesterol (0.5%) diet enhanced absorption of intestinal cholesterol in both groups of mice, increased their liver cholesterol content, and reduced their expression of CYP7A1 mRNA. The ABCG5/G8 liver mRNA was increased in both groups of mice, but cholesterol crystals were only observed in bile from the CYP8B1+/+ mice. The results demonstrate the cholesterol-sparing effects of CA: enhanced absorption and reduced conversion into bile acids. Farnesoid X receptor (FXR)-mediated suppression of CYP7A1 in mice seems to be a predominant mechanism for regulation of bile acid synthesis under normal conditions and, as confirmed, able to override LXR-mediated mechanisms. Interaction between FXR- and LXR-mediated stimuli might also regulate expression of liver ABCG5/G8. As previously reported by us, mice with targeted disruption of the CYP8B1 gene (CYP8B1−/−) fail to produce cholic acid (CA), upregulate their bile acid synthesis, reduce the absorption of dietary cholesterol and, after cholesterol feeding, accumulate less liver cholesterol than wild-type (CYP8B1+/+) mice. In the present study, cholesterol-enriched diet (0.5%) or administration of a synthetic liver X receptor (LXR) agonist strongly upregulated CYP7A1 expression in CYP8B1−/− mice, compared to CYP8B1+/+ mice. Cholesterol-fed CYP8B1−/− mice also showed a significant rise in HDL cholesterol and increased levels of liver ABCA1 mRNA. A combined CA (0.25%)/cholesterol (0.5%) diet enhanced absorption of intestinal cholesterol in both groups of mice, increased their liver cholesterol content, and reduced their expression of CYP7A1 mRNA. The ABCG5/G8 liver mRNA was increased in both groups of mice, but cholesterol crystals were only observed in bile from the CYP8B1+/+ mice. The results demonstrate the cholesterol-sparing effects of CA: enhanced absorption and reduced conversion into bile acids. Farnesoid X receptor (FXR)-mediated suppression of CYP7A1 in mice seems to be a predominant mechanism for regulation of bile acid synthesis under normal conditions and, as confirmed, able to override LXR-mediated mechanisms. Interaction between FXR- and LXR-mediated stimuli might also regulate expression of liver ABCG5/G8. The relationship between cholesterol and atherosclerosis is now well established, but complete understanding of the pathological processes will demand increased knowledge of the overall cholesterol homeostasis as a whole. In humans, a delicate metabolic balance exists between dietary uptake, endogenous synthesis, and biliary excretion. In fact, excess cholesterol is removed via the bile, either after conversion into bile acids or as intact molecules kept in solution by bile acids and phospholipids. Recent progress demonstrates the complexity of this process, which involves multiple transporters, enzyme systems, and nuclear receptors (1Russell D.W. The enzymes, regulation, and genetics of bile acid synthesis.Annu. Rev. Biochem. 2003; 72: 137-174Google Scholar). The major bile acids in mammals are cholic acid (CA), chenodeoxycholic acid (CDCA), and muricholic acids. The latter are more hydrophilic, and are most abundant in rodents. In humans, CA and CDCA are the dominating bile acids, together with the secondary bile acids deoxycholic acid (DCA) and lithocholic acid, which originate in microbiological actions in the large intestine (2Li-Hawkins J.L. Gåfvels M. Olin M. Lund E.G. Andersson U. Schuster G. Björkhem I. Russell D. Eggertsen G. Cholic acid mediates negative feedback regulation of bile acid synthesis.J. Clin. Invest. 2002; 110: 1191-1200Google Scholar). CA is a tricarboxylic acid, mainly produced via the neutral pathway. The enzyme sterol 12α-hydroxylase (CYP8B1) is necessary for its synthesis; otherwise CDCA is produced. In the intestine, CA is a key factor, together with phospholipids, in the formation of micelles to achieve an efficient absorption of cholesterol. In the mouse, it functions as a specific ligand for the nuclear receptor farnesoid X receptor (FXR), which mediates the downregulation of CYP7A1 and CYP8B1 (2Li-Hawkins J.L. Gåfvels M. Olin M. Lund E.G. Andersson U. Schuster G. Björkhem I. Russell D. Eggertsen G. Cholic acid mediates negative feedback regulation of bile acid synthesis.J. Clin. Invest. 2002; 110: 1191-1200Google Scholar). Activated FXR is also reported to modify the expression of bile acid transporters in the liver, which are sodium-taurocholate cotransport polypeptide for bile acid uptake, bile salts export pump (BSEP) for bile acid secretion, and intestine ileal bile acid binding protein (3Moore J.T. Goodwin B. Willson T.M. Kliewer S.A. Nuclear receptor regulation of genes involved in bile acid metabolism.Crit. Rev. Eukaryot. Gene Expr. 2002; 12: 119-135Google Scholar). Over the last few years, research efforts in the field of cholesterol and bile acid metabolism have utilized an increasing number of genetically modified mice. A general approach in many studies is to feed high-fat, high-cholesterol diets to such experimental mouse models. Generally, normal mice do not develop atherosclerosis when put on such atherogenic diets, even if their plasma cholesterol levels could vary depending on the strain (4Svenson K. Bogue M. Peters L.L. Identifying new mouse models of cardiovascular disease: a review of high-throughput screens of mutagenized and inbred strains.J. Appl. Physiol. 2003; 94: 1650-1659Google Scholar). However, genetically modified strains, for example, LDL receptor-deficient mice, develop advanced arteriosclerotic lesions when fed diets containing cholesterol and CA (5Breslow J.L. Mouse models of atherosclerosis.Science. 1996; 272: 685-688Google Scholar). Such a combined diet has also been utilized to induce formation of gallstones in susceptible mouse strains. Even if CA is a key element in these pathologic processes, its exact mode of action is not well defined. To better understand the biological roles for sterol 12α-hydroxylase/CA, we created an experimental mouse model genetically deficient for CYP8B1; these mice do not synthesize CA (2Li-Hawkins J.L. Gåfvels M. Olin M. Lund E.G. Andersson U. Schuster G. Björkhem I. Russell D. Eggertsen G. Cholic acid mediates negative feedback regulation of bile acid synthesis.J. Clin. Invest. 2002; 110: 1191-1200Google Scholar). They have an increased expression of CYP7A1, which causes elevated bile acid synthesis and also biochemical changes, suggesting that the FXR effector system is downregulated. In addition, the animals show a reduced absorption of dietary cholesterol and do not increase their storage of liver cholesterol when fed cholesterol, compared with normal mice (6Murphy C. Parini P. Wang J. Bjorkhem I. Eggertsen G. Gafvels M. Cholic acid as key regulator of cholesterol synthesis, intestinal absorption and hepatic storage in mice.Biochim. Biophys. Acta. 2005; 1735: 167-175Google Scholar). The present study characterizes the effects of the administration of cholesterol-enriched and cholesterol-plus-CA diets to CYP8B1−/− mice, with a focus on the cholesterol and bile acid metabolism. Our results indicate that CA per se is an important factor in the regulation of the endogenous cholesterol balance, affecting both degradation and synthesis of cholesterol, as well as its excretion and absorption. Sodium cholate (≥99%), cholesterol (>99%), and the liver X receptor (LXR) agonist TO-901317 were purchased from Sigma-Aldrich Corp., St. Louis, MO. The FXR agonist GW4064 was kindly supplied by F. Hoffman-La Roche Ltd, Basel, Switzerland. Mice deficient for the sterol 12α-hydroxylase by targeted disruption of the gene have previously been characterized (2Li-Hawkins J.L. Gåfvels M. Olin M. Lund E.G. Andersson U. Schuster G. Björkhem I. Russell D. Eggertsen G. Cholic acid mediates negative feedback regulation of bile acid synthesis.J. Clin. Invest. 2002; 110: 1191-1200Google Scholar). The corresponding wild-type animals were obtained by crossbreeding of heterozygous individuals. Generally, males aged 2–6 months were used. Mice of both genotypes were housed at 22–24°C at a light cycle of 8 AM to 8 PM in groups of four to six animals and kept on the following diets for 7 days: i) standard chow (0.025% cholesterol, w/w); ii) 0.5% cholesterol (w/w); iii) 0.5% cholesterol plus 0.25% sodium cholate. Controls were kept on standard chow. All diets contained 10% peanut oil (w/w). Both the LXR agonist TO-901317 and the FXR agonist GW4064 were given in gavage for 5 days in doses of 10 mg/kg/day and 50 mg/kg/day, respectively, to groups of CYP8B1+/+ and −/− mice. To control animals, 1% methylcellulose was given in the same way. The last dose was delivered 2 h before the animals were euthanized. Water was available ad libitum. Animals were euthanized by cervical dislocation following CO2 anesthesia, and the liver and gallbladder were quickly washed in physiological saline and immediately frozen in liquid nitrogen. Blood was collected by heart puncture. Animals used for sampling gallbladder bile were fasted for 12 h, and light microscopy was performed on 5 μl aliquots of bile. Serum total cholesterol was determined by the standard enzymatic procedure. Lipoprotein cholesterol profiles were obtained by fast-protein liquid chromatography. Liver total and free cholesterol were determined by the method described by Bjorkhem (7Bjorkhem I. Serum cholesterol determination by mass fragmentography.Clin. Chim. Acta. 1974; 54: 185-193Google Scholar). To obtain a relative index of hepatic de novo cholesterol synthesis, the concentration of lathosterol was assayed by isotope dilution-mass spectrometry as reported (8Lund E. Sisfontes L. Reihner E. Bjorkhem I. Determination of serum levels of unesterified lathosterol by isotope dilution-mass spectrometry.Scand. J. Clin. Lab. Invest. 1989; 49: 165-171Google Scholar), and the ratio of lathosterol to total cholesterol was calculated. Cholesterol absorption was assayed, after feeding the specified diets for 6 days, by the fecal dual-isotope method, essentially as reported by Schwarz et al. (9Schwarz M. Russell D.W. Dietschy J.M. Turley S.D. Marked reduction in bile acid synthesis in cholesterol 7a-hydroxylase-deficient mice does not lead to diminished tissue cholesterol turnover or to hypercholesterolemia.J. Lipid Res. 1998; 39: 1833-1843Google Scholar), except that feces were collected for 24 h after administering the radioactive gavage. Percent cholesterol reabsorbed was estimated by the standard equation. [5,6-3H]β-sitostanol was obtained from American Radiolabel Chemicals, Inc., St. Louis, MO and [4-12C]cholesterol from Amersham Biosciences, Uppsala, Sweden. Total RNA was isolated from 75–100 mg of liver tissue using the Quick Prep Total RNA Extraction Kit (Amersham Biosciences). Oligo-dT-primed cDNA synthesis was carried out on 3 μg of liver total RNA using Superscript III reverse transcriptase (Invitrogen Life Technologies; Carlsbad, CA). Real-time PCR was carried out on an ABI Prism 7000 Sequence Detection System (Applied Biosystems; Foster City, CA) using either TaqMan probes (labeled with the fluorochromes FAM or VIC and dark quencher or TAMRA) or SYBR Green. The following genes were analyzed: mouse HMG-CoA reductase, CYP7A1, CYP8B1, CYP27, SHP, ABCA1, ABCG5, ABCG8, BSEP, MDR2, apoA-1, LDLR, SREBP1C, and SREBP2. As an internal standard, mouse hypoxanthine phosphoribosyl transferase was utilized. Control of the PCR efficiency was done by plotting standard curves using different dilutions of cDNA. The PCR products were sequenced to confirm that they represented the correct fragments. Fecal samples were collected from mice kept in individual cages for 24 h. Analysis of neutral sterols and bile acids by gas-liquid chromatography was performed essentially as reported by Miettinen, Ahrens, and Grundy (10Miettinen T.A. Ahrens E.H. Grundy S.M. Quantitative isolation and gas-liquid chromatographic analysis of total dietary and fecal neutral steroids.J. Lipid Res. 1965; 6: 411-424Google Scholar), Miettinen (11Miettinen T.A. Gas-liquid chromatographic determination of fecal neutral sterols using a capillary column.Clin. Chim. Acta. 1982; 124: 245-248Google Scholar), and Grundy, Ahrens, and Miettinen (12Grundy S.M. Ahrens E.H. Miettinen T.A. Quantitative isolation and gas-liquid chromatographic analysis of total fecal bile acids.J. Lipid Res. 1965; 6: 397-410Google Scholar). Gallbladder bile samples were examined on slides for cholesterol crystals by polarizing light microscopy. The composition of bile acids in gallbladder bile was analyzed by gas-liquid chromatography, as reported (13Hunt M. Yang Y-Z. Eggertsen G. Gåfvels M. Einarsson C. Alexson S. The peroxisome proliferator-activated receptor alpha (PPARα) regulates bile acid biosynthesis.J. Biol. Chem. 2000; 275: 28947-28953Google Scholar). Total bile acid concentration was determined by an enzymatic method (14Fausa O. Skålhegg B.A. Quantitative determination of bile acids and their conjugates using thin-layer chromatography and a purified 3alpha-hydroxysteroid dehydrogenase.Scand. J. Gastroenterol. 1974; 9: 249-254Google Scholar), as was cholesterol (15Roda A. Festi D. Sama C. Mazzella G. Alini R. Roda E. Barbara L. Enzymatic determination of cholesterol in bile.Clin. Chim. Acta. 1975; 64: 337-341Google Scholar). Phospholipids were assayed by the method described by Rouser, Fleischer, and Yamamoto (16Rouser G. Fleischer S. Yamamoto A. Two dimensional thin-layer chromatographic separation of polar lipids and determination of phospholipids by phosphorous analysis of spots.Lipids. 1970; 5: 494-496Google Scholar). The relative concentrations of biliary lipids were expressed as molar percentages of the total biliary lipids. The cholesterol saturation was calculated according to Carey (17Carey M.C. Critical tables for calculating the cholesterol saturation of native bile.J. Lipid Res. 1978; 19: 945-955Google Scholar). Data are presented as means ± SEM. Statistical analysis was performed with STATISTICA software. The significance of differences was tested by two-way ANOVA, followed by planned comparisons. To stabilize the variances, data were logarithmically transformed when a correlation was found (18Parini P. Angelin B. Stavreus-Evers A. Freyschuss B. Eriksson H. Rudling M. Biphasic effects of the natural estrogen 17beta-estradiol on hepatic cholesterol metabolism in intact female rats.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1817-1823Google Scholar). Feeding CYP8B1+/+ mice a cholesterol diet resulted in a distinct increase in total liver cholesterol content, from a mean level of 2.3 μg/mg liver tissue to 7.4 μg/mg (Fig. 1A). The fraction of cholesteryl esters (CEs) rose from approximately 34% to 74%. CYP8B1−/− animals on chow had lower cholesterol values (1.7 μg/mg) than did the CYP8B1+/+ mice, demonstrating only a weak rise to 2.3 μg/mg on the cholesterol diet and no increase in CEs. Hepatic cholesterol synthesis, as evaluated by the ratio of lathosterol to cholesterol, was higher in the CYP8B1−/− mice than in the CYP8B1+/+ animals (Fig. 1B). Cholesterol diet induced a reduction in both groups, but the rate of cholesterol synthesis was still more pronounced in the CYP8B1-null mice. The mRNA levels for HMG-CoA reductase and SREBP2 showed a similar pattern, although the CYP8B1-null mice had much higher levels of HMG-CoA reductase mRNA than the CYP8B1+/+ animals (Fig. 1C, D).Fig. 1.Alterations of the metabolism of cholesterol in the livers of the CYP8B1+/+ (+/+) and CYP8B1−/− (−/−) mice fed normal chow (N.), chow with 0.5% cholesterol (Ch.) or chow with 0.5% cholesterol/0.25% cholic acid (Ch.+CA). A: Hepatic total cholesterol concentration. Upper dotted areas represent free cholesterol and lower esterified cholesterol concentrations. B: Lathosterol-to-cholesterol ratio was used as an indication of the relative level of de novo hepatic cholesterol synthesis. C: Quantitation of the mRNA levels for HMG-CoA reductase, using mouse hypoxanthine phosphoribosyl transferase (HPRT) as an internal control. The value found for the CYP8B1+/+ animals on normal chow was set to 1.0. D: Quantitation of the mRNA levels for SREBP2, using HPRT as an internal standard. For both C and D, data are given as fold differences of the value for the CYP8B1+/+ mice on normal chow, set to 1.0. *, Significant differences between CYP8B1+/+ and CYP8B1−/− mice with the same diet or the same treatment; ¤, significant differences between the diet-treated groups and the chow groups, or two agonist groups, compared with vehicle group having the same genotype; #, significant differences between the cholesterol-enriched diet groups and the cholesterol-plus-CA diet groups with the same genotype. Values are expressed as means ± SEM of four to six observations. P < 0.05 was considered to be significant.View Large Image Figure ViewerDownload (PPT)Fig. 1.Alterations of the metabolism of cholesterol in the livers of the CYP8B1+/+ (+/+) and CYP8B1−/− (−/−) mice fed normal chow (N.), chow with 0.5% cholesterol (Ch.) or chow with 0.5% cholesterol/0.25% cholic acid (Ch.+CA). A: Hepatic total cholesterol concentration. Upper dotted areas represent free cholesterol and lower esterified cholesterol concentrations. B: Lathosterol-to-cholesterol ratio was used as an indication of the relative level of de novo hepatic cholesterol synthesis. C: Quantitation of the mRNA levels for HMG-CoA reductase, using mouse hypoxanthine phosphoribosyl transferase (HPRT) as an internal control. The value found for the CYP8B1+/+ animals on normal chow was set to 1.0. D: Quantitation of the mRNA levels for SREBP2, using HPRT as an internal standard. For both C and D, data are given as fold differences of the value for the CYP8B1+/+ mice on normal chow, set to 1.0. *, Significant differences between CYP8B1+/+ and CYP8B1−/− mice with the same diet or the same treatment; ¤, significant differences between the diet-treated groups and the chow groups, or two agonist groups, compared with vehicle group having the same genotype; #, significant differences between the cholesterol-enriched diet groups and the cholesterol-plus-CA diet groups with the same genotype. Values are expressed as means ± SEM of four to six observations. P < 0.05 was considered to be significant.View Large Image Figure ViewerDownload (PPT)Fig. 1.Alterations of the metabolism of cholesterol in the livers of the CYP8B1+/+ (+/+) and CYP8B1−/− (−/−) mice fed normal chow (N.), chow with 0.5% cholesterol (Ch.) or chow with 0.5% cholesterol/0.25% cholic acid (Ch.+CA). A: Hepatic total cholesterol concentration. Upper dotted areas represent free cholesterol and lower esterified cholesterol concentrations. B: Lathosterol-to-cholesterol ratio was used as an indication of the relative level of de novo hepatic cholesterol synthesis. C: Quantitation of the mRNA levels for HMG-CoA reductase, using mouse hypoxanthine phosphoribosyl transferase (HPRT) as an internal control. The value found for the CYP8B1+/+ animals on normal chow was set to 1.0. D: Quantitation of the mRNA levels for SREBP2, using HPRT as an internal standard. For both C and D, data are given as fold differences of the value for the CYP8B1+/+ mice on normal chow, set to 1.0. *, Significant differences between CYP8B1+/+ and CYP8B1−/− mice with the same diet or the same treatment; ¤, significant differences between the diet-treated groups and the chow groups, or two agonist groups, compared with vehicle group having the same genotype; #, significant differences between the cholesterol-enriched diet groups and the cholesterol-plus-CA diet groups with the same genotype. Values are expressed as means ± SEM of four to six observations. P < 0.05 was considered to be significant.View Large Image Figure ViewerDownload (PPT) In both CYP8B1+/+ and CYP8B1−/− mice, the cholesterol diet induced a rise in bile acid production, as evaluated by the fecal excretion of bile acids (Fig. 2A). In the latter group, it was nearly twice as high as in the CYP8B1+/+ animals, both when fed normal chow and cholesterol-enriched diet. This is well in agreement with the much higher levels of CYP7A1 mRNA found in the CYP8B1−/− mice, especially after the cholesterol feeding, when the levels were more than 4-fold higher, compared with the CYP8B1+/+ animals (Fig. 2B). The levels of CYP27 mRNA did not differ significantly between the different groups of mice. The expression of SHP mRNA, a ubiquitous effector molecule for FXR, was, as expected, approximately 50% lower in the chow-fed CYP8B1−/− mice, compared with the CYP8B1+/+ mice. No significant changes were precipitated by the cholesterol diet in the former group, whereas the SHP levels in the CYP8B1+/+ mice tended to decrease (data not shown). We also determined the mRNA levels for the bile salt export pump (BSEP, ABCB11) and the multidrug resistance gene 2 (MDR2, ABCB4), the proteins thought to transport bile acids and phospholipids, respectively, from the hepatocytes into the bile canaliculi. No significant differences were observed between CYP8B1+/+ and CYP8B1−/− animals, either on normal or on cholesterol-enriched diet (data not shown).Fig. 2.A: Excretion of fecal bile acids. Feces were collected from individual CYP8B1+/+ or CYP8B1−/− animals for 24 h after 6 days of feeding normal chow, chow with 0.5% cholesterol, or chow with 0.5% cholesterol/0.25% CA. B: Quantitation of the hepatic mRNA levels for CYP7A1. C: Quantitation of the hepatic mRNA levels for ABCG5. D: Quantitation of the hepatic mRNA levels for ABCG8. The mRNA quantitations were performed with HPRT as an internal standard. *, Significant differences between CYP8B1+/+ and CYP8B1−/− mice with the same diet or the same treatment; ¤, significant differences between the diet-treated groups and the chow groups, or two agonist groups, compared with vehicle group having the same genotype. #, significant differences between the cholesterol-enriched diet groups and the cholesterol-plus-CA diet groups with the same genotype. Values are expressed as average amount of bile acids excreted per mouse for 24 h. Levels are expressed as means ± SEM of four to six observations. P < 0.05 was considered to be significant.View Large Image Figure ViewerDownload (PPT)Fig. 2.A: Excretion of fecal bile acids. Feces were collected from individual CYP8B1+/+ or CYP8B1−/− animals for 24 h after 6 days of feeding normal chow, chow with 0.5% cholesterol, or chow with 0.5% cholesterol/0.25% CA. B: Quantitation of the hepatic mRNA levels for CYP7A1. C: Quantitation of the hepatic mRNA levels for ABCG5. D: Quantitation of the hepatic mRNA levels for ABCG8. The mRNA quantitations were performed with HPRT as an internal standard. *, Significant differences between CYP8B1+/+ and CYP8B1−/− mice with the same diet or the same treatment; ¤, significant differences between the diet-treated groups and the chow groups, or two agonist groups, compared with vehicle group having the same genotype. #, significant differences between the cholesterol-enriched diet groups and the cholesterol-plus-CA diet groups with the same genotype. Values are expressed as average amount of bile acids excreted per mouse for 24 h. Levels are expressed as means ± SEM of four to six observations. P < 0.05 was considered to be significant.View Large Image Figure ViewerDownload (PPT)Fig. 2.A: Excretion of fecal bile acids. Feces were collected from individual CYP8B1+/+ or CYP8B1−/− animals for 24 h after 6 days of feeding normal chow, chow with 0.5% cholesterol, or chow with 0.5% cholesterol/0.25% CA. B: Quantitation of the hepatic mRNA levels for CYP7A1. C: Quantitation of the hepatic mRNA levels for ABCG5. D: Quantitation of the hepatic mRNA levels for ABCG8. The mRNA quantitations were performed with HPRT as an internal standard. *, Significant differences between CYP8B1+/+ and CYP8B1−/− mice with the same diet or the same treatment; ¤, significant differences between the diet-treated groups and the chow groups, or two agonist groups, compared with vehicle group having the same genotype. #, significant differences between the cholesterol-enriched diet groups and the cholesterol-plus-CA diet groups with the same genotype. Values are expressed as average amount of bile acids excreted per mouse for 24 h. Levels are expressed as means ± SEM of four to six observations. P < 0.05 was considered to be significant.View Large Image Figure ViewerDownload (PPT) The gallbladder bile in the CYP8B1−/− mice consisted mainly of muricholic acids with minor quantities of ursodeoxycholic acid (UDCA) and DCA (Table 1.). After cholesterol feeding, no major changes occurred in their bile acid proportions, except that in the CYP8B1+/+ animals, CA decreased slightly and β-muricholic acid increased. Biliary cholesterol and cholesterol saturation index (CSI %) were higher in the control CYP8B1+/+ animals than in the CYP8B1−/− animals, whereas no differences were observed in the phospholipid concentration (Table 2). Feeding cholesterol to the CYP8B1+/+ mice resulted in an increase of biliary cholesterol and of the CSI %, whereas only modest effects were observed in the CYP8B1−/− mice. Only minor changes were observed in the phospholipid content.TABLE 1.The bile acid composition in mouse gallbladder bileCYP8B1 GenotypeDietary TreatmentCholic Acidβ-Muricholic Acidα-Muricholic Acid + CDCADCAUDCA+/+N.59.0 ± 2.930.9 ± 3.86.2 ± 2.02.2 ± 1.01.7 ± 1.1−/−N.2.2 ± 2.2aP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/− mice fed normal chow, chow with 0.5% cholesterol, and chow with 0.5% cholesterol/0.25% CA, respectively.50.7 ± 2.9aP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/− mice fed normal chow, chow with 0.5% cholesterol, and chow with 0.5% cholesterol/0.25% CA, respectively.36.8 ± 1.5aP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/− mice fed normal chow, chow with 0.5% cholesterol, and chow with 0.5% cholesterol/0.25% CA, respectively.Trace8.6 ± 0.8aP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/− mice fed normal chow, chow with 0.5% cholesterol, and chow with 0.5% cholesterol/0.25% CA, respectively.+/+Ch.45.0 ± 2.2bP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/−mice fed chow with 0.5% cholesterol and chow with 0.5% cholesterol/0.25% CA and those who were fed normal chow.38.5 ± 3.511.1 ± 1.52.8 ± 0.92.7 ± 0.8−/−Ch.2.1 ± 2.6aP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/− mice fed normal chow, chow with 0.5% cholesterol, and chow with 0.5% cholesterol/0.25% CA, respectively.52.0 ± 3.435.8 ± 1.8aP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/− mice fed normal chow, chow with 0.5% cholesterol, and chow with 0.5% cholesterol/0.25% CA, respectively.Trace10.8 ± 0.9aP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/− mice fed normal chow, chow with 0.5% cholesterol, and chow with 0.5% cholesterol/0.25% CA, respectively.+/+Ch.+CA84.6 ± 2.9bP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/−mice fed chow with 0.5% cholesterol and chow with 0.5% cholesterol/0.25% CA and those who were fed normal chow.,cP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/− mice fed chow with 0.5% cholesterol/0.25% CA and those fed chow with 0.5% cholesterol.5.2 ± 3.8bP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/−mice fed chow with 0.5% cholesterol and chow with 0.5% cholesterol/0.25% CA and those who were fed normal chow.,cP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/− mice fed chow with 0.5% cholesterol/0.25% CA and those fed chow with 0.5% cholesterol.1.6 ± 2.0cP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/− mice fed chow with 0.5% cholesterol/0.25% CA and those fed chow with 0.5% cholesterol.8.4 ± 1.0bP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/−mice fed chow with 0.5% cholesterol and chow with 0.5% cholesterol/0.25% CA and those who were fed normal chow.,cP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/− mice fed chow with 0.5% cholesterol/0.25% CA and those fed chow with 0.5% cholesterol.0.3 ± 1.1−/−Ch.+CA75.7 ± 2.6bP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/−mice fed chow with 0.5% cholesterol and chow with 0.5% cholesterol/0.25% CA and those who were fed normal chow.,cP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/− mice fed chow with 0.5% cholesterol/0.25% CA and those fed chow with 0.5% cholesterol.13.1 ± 3.4aP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/− mice fed normal chow, chow with 0.5% cholesterol, and chow with 0.5% cholesterol/0.25% CA, respectively.,bP < 0.05. Significant difference between CYP8B1+/+ and CYP8B1−/−mice fed chow with 0.5% cholesterol and chow with 0.5% cholesterol/0.25% CA and those who were fed normal chow.,cP < 0.05. Significant difference between C" @default.
W2077885768 created "2016-06-24" @default.
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W2077885768 date "2006-02-01" @default.
W2077885768 modified "2023-10-01" @default.
W2077885768 title "Studies on LXR- and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice" @default.
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