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Biomedical subjects

Gerald Salen

Publications and source records attributed to Gerald Salen.

At least 19 recordsLinked to original sources
PubMed2006

The stimulatory effect of LXRalpha is blocked by SHP despite the presence of a LXRalpha binding site in the rabbit CYP7A1 promoter.

The transcription of the cholesterol 7alpha-hydroxylase gene (CYP7A1) is greatly decreased in cholesterol-fed rabbits. To determine whether the molecular structure of the promoter is responsible for this downregulation, we cloned the rabbit CYP7A1 promoter, identified the binding sites for alpha-fetoprotein transcription factor (FTF) and liver X receptor (LXRalpha), and studied the effects of FTF, LXRalpha, and SHP on its transcription. Adding LXRalpha/retinoid X receptor together with their ligands (L/R) to the promoter/reporter construct transfected into HepG2 cells greatly increased its activity. FTF did not increase promoter activity, nor did it enhance the stimulatory effect of L/R. Mutating the FTF binding site abolished the promoter baseline activity. Increasing amounts of SHP abolished the effect of L/R, and FTF enhanced the ability of SHP to decrease promoter activity below baseline levels. Thus, downregulation of CYP7A1 in cholesterol-fed rabbits is attributable secondarily to the activation of farnesoid X receptor, which increases SHP expression to override the positive effects of LXRalpha. Although FTF is a competent factor for maintaining baseline activity, it does not further enhance and may suppress CYP7A1 transcription.

Animals↗
PubMed2006

Hypercholesterolemia in rats with hepatomas: increased oxysterols accelerate efflux but do not inhibit biosynthesis of cholesterol.

Hypercholesterolemia is an important paraneoplastic syndrome in patients with hepatoma, but the nature of this defect has not yet been identified. We investigated the molecular mechanisms of hypercholesterolemia in a hepatoma-bearing rat model. Buffalo rats were implanted in both flanks with Morris hepatoma 7777 (McA-RH7777) cells. After 4 weeks, tumor weight was 5.5+/-1.7 g, and serum cholesterol level increased from 60+/-2 to 90+/-2 mg/dL. Protein and mRNA expression of the ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) was markedly higher in tumors than in livers. These increases were associated with activation of liver X receptor alpha (LXRalpha) as a result of the increased tissue oxysterol concentrations. The accumulation of oxysterols in the hepatomas appeared to be caused mainly by the upregulation of cholesterol biosynthesis, despite the increased tissue sterol concentrations. Overexpression of the sterol regulatory element-binding protein (SREBP) processing system relative to sterol concentration contributed to the resistance to sterols in this tumor. In addition, bile acid biosynthesis was inhibited despite the reduced expression of the small heterodimer partner (SHP) and activated LXRalpha, which also appeared to contribute to the accumulation of oxysterols followed by the acceleration of cholesterol efflux. In conclusion, hypercholesterolemia in McA-RH7777 hepatoma-bearing rats was caused by increased cholesterol efflux from tumors as a result of activation of LXRalpha. Overexpression of the SREBP processing system contributed to the activation of LXRalpha by maintaining high oxysterol levels in tissue.

ATP Binding Cassette Transporter 1↗
PubMed2006

Stigmasterol reduces plasma cholesterol levels and inhibits hepatic synthesis and intestinal absorption in the rat.

Plant sterols compete with cholesterol (cholest-5-en-3beta-ol) for intestinal absorption to limit absorption and lower plasma concentrations of cholesterol. Stigmasterol (24-ethyl-cholesta-5,22-dien-3beta-ol; Delta(22) derivative of sitosterol [24-ethyl-cholest-5-en-3beta-ol]), but not campesterol (24-methyl-cholest-5-en-3beta-ol) and sitosterol, is reported to inhibit cholesterol biosynthesis via inhibition of sterol Delta(24)-reductase in human Caco-2 and HL-60 cell lines. We studied the effect of feeding 0.5% stigmasterol on plasma and liver sterols and intestinal cholesterol and sitosterol absorption in 12 wild-type Kyoto (WKY) and 12 Wistar rats. After 3 weeks of feeding, cholesterol and sitosterol absorption was determined in 6 rats from each group by plasma dual-isotope ratio method. After 3 more weeks, plasma and hepatic sterols and hepatic enzyme activities were determined in all rats. After feeding stigmasterol, baseline plasma cholesterol was 1.3 times and plant sterols 3 times greater in WKY compared with Wistar rats. Stigmasterol feeding lowered plasma cholesterol by approximately 11%, whereas plasma campesterol and sitosterol levels were virtually unchanged in both rat strains, and stigmasterol constituted 3.2% of plasma sterols in WKY rats and 1% in Wistar rats. After 6 weeks of feeding, cholesterol and sitosterol absorption decreased 23% and 30%, respectively, in WKY, and 22% and 16%, respectively, in the Wistar rats as compared with untreated rats. The intestinal bacteria in both rat strains metabolized stigmasterol to mainly the 5beta-H stanol (>40%), with only small amounts of 5alpha-H derivative (approximately 1.5%), whereas the C-22 double bond was resistant to bacterial metabolism. Hepatic stigmasterol levels increased from 11 microg/g liver tissue to 104 mug/g in WKY rats and from 5 microg/g liver tissue to 21 microg/g in Wistar rats. 3-Hydroxy-3-methylglutaryl coenzyme A reductase activity was suppressed 4-fold in the WKY and almost 1.8-fold in Wistar rats, cholesterol 7alpha-hydroxylase activity was suppressed 1.6-fold in the WKY and 3.5-fold in Wistar rats, whereas cholesterol 27-hydroxylase activity was unchanged after feeding. In conclusion, stigmasterol, when fed, lowers plasma cholesterol levels, inhibits intestinal cholesterol and plant sterol absorption, and suppresses hepatic cholesterol and classic bile acid synthesis in Wistar as well as WKY rats. However, plasma and hepatic incorporation of stigmasterol is low.

Animals↗
PubMed2006

Intestinal cholesterol absorption inhibitor ezetimibe added to cholestyramine for sitosterolemia and xanthomatosis.

Sitosterolemia is a rare, recessively inherited disorder characterized by increased absorption and delayed removal of noncholesterol sterols, which is associated with accelerated atherosclerosis, premature coronary artery disease, hemolysis, and xanthomatosis. Treatments include low-sterol diet and bile salt-binding resins; however, these often do not reduce the xanthomatosis. We examined the effects of the intestinal cholesterol/phytosterol transporter inhibitor ezetimibe added to cholestyramine in a young female patient with sitosterolemia and associated xanthomatosis. The patient was an 11-year-old female with sitosterolemia presenting with prominent xanthomas in the subcutaneous tissue of both elbows who was receiving treatment with cholestyramine 2 g once daily. Bilateral carotid bruits were audible, and a grade II/VI systolic murmur was detected at the left upper sternal border. She also had a low platelet count of 111,000/microL. Ezetimibe 10 mg once daily was added to the patient's ongoing cholestyramine regimen, and she was evaluated for 1 year. The patient followed an unrestricted diet during the 1-year treatment period. After 1 year of treatment with ezetimibe added to ongoing cholestyramine therapy, the patient's plasma sitosterol and campesterol levels decreased by approximately 50%. Her carotid bruits completely resolved, her systolic murmur diminished, and her platelet count rose to 268,000/microL. More remarkably, the tuberous xanthomas on her elbows had completely regressed. Ezetimibe added to ongoing low-dose cholestyramine therapy led to a marked improvement in plasma sterol concentrations, complete regression of xanthomatosis, resolution of carotid bruits, and improvement in cardiac murmur in a young female patient with sitosterolemia.

Anticholesteremic Agents↗
PubMed2005

The missense mutation in Abcg5 gene in spontaneously hypertensive rats (SHR) segregates with phytosterolemia but not hypertension.

BACKGROUND: Sitosterolemia is a recessively inherited disorder in humans that is associated with premature atherosclerotic disease. Mutations in ABCG5 or ABCG8, comprising the sitosterolemia locus, STSL, are now known to cause this disease. Three in-bred strains of rats, WKY, SHR and SHRSP, are known to be sitosterolemic, hypertensive and they carry a missense 'mutation' in a conserved residue of Abcg5, Gly583Cys. Since these rat strains are also know to carry mutations at other genetic loci and the extent of phytosterolemia is only moderate, it is important to verify that the mutations in Abcg5 are causative for phytosterolemia and whether they contribute to hypertension. METHODS: To investigate whether the missense change in Abcg5 is responsible for the sitosterolemia we performed a segregation analysis in 103 F2 rats from a SHR x SD cross. Additionally, we measured tail-cuff blood pressure and measured intestinal lipid transport to identify possible mechanisms whereby this mutation causes sitosterolemia. RESULTS: Segregation analysis showed that the inheritance of the Gly583Cys mutation Abcg5 segregated with elevated plant sterols and this pattern was recessive, proving that this genetic change is responsible for the sitosterolemia in these rat strains. Tail-cuff monitoring of blood pressure in conscious animals showed no significant differences between wild-type, heterozygous and homozygous mutant F2 rats, suggesting that this alteration may not be a significant determinant of hypertension in these rats on a chow diet. CONCLUSION: This study shows that the previously identified Gly583Cys change in Abcg5 in three hypertension-susceptible rats is responsible for the sitosterolemia, but may not be a major determinant of blood pressure in these rats.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2005

Phase III trial of ursodeoxycholic acid to prevent colorectal adenoma recurrence.

BACKGROUND: Ursodeoxycholic acid (UDCA) treatment is associated with a reduced incidence of colonic neoplasia in preclinical models and in patients with conditions associated with an increased risk for colon cancer. We conducted a phase III, double-blind placebo-controlled trial of UDCA to evaluate its ability to prevent colorectal adenoma recurrence. METHODS: We randomly assigned 1285 individuals who had undergone removal of a colorectal adenoma within the past 6 months to daily treatment with UDCA (8-10 mg/kg of body weight; 661 participants) or with placebo (624 participants) for 3 years or until follow-up colonoscopy. Recurrence rates (number of recurrent adenomas per unit time) were compared by use of a Huber-White variance estimator. Proportions of participants with one or more recurrent adenomas were compared with a Pearson chi-square statistic; adjusted odds ratios (ORs) were obtained by logistic regression. All statistical tests were two-sided. RESULTS: We observed a non-statistically significant 12% reduction in the adenoma recurrence rate associated with UDCA treatment, compared with placebo treatment. However, UDCA treatment was associated with a statistically significant reduction (P = .03) in the recurrence of adenomas with high-grade dysplasia (adjusted OR = 0.61, 95% confidence interval = 0.39 to 0.96). We observed no statistically significant differences between UDCA and placebo groups in recurrence with regard to adenoma size, villous histology, or location. CONCLUSIONS: UDCA treatment was associated with a non-statistically significant reduction in total colorectal adenoma recurrence but with a statistically significant 39% reduction in recurrence of adenomas with high-grade dysplasia. Because severely dysplastic lesions have a high risk of progression to invasive colorectal carcinoma, this finding indicates that future chemoprevention trials of UDCA in individuals with such lesions should be considered.

Adenoma↗
PubMed2005

Effect of high plant sterol-enriched diet and cholesterol absorption inhibitor, SCH 58235, on plant sterol absorption and plasma concentrations in hypercholesterolemic wild-type Kyoto rats.

BACKGROUND AND AIMS: Plant sterols are widely distributed in human diet but are poorly absorbed so that their plasma levels are very low. However, when fed in large amounts, they lower plasma cholesterol levels by interfering with cholesterol absorption. We have studied the effect of 4 weeks of feeding a chow diet supplemented with 1% plant sterols [brassicasterol (6.3%), campesterol (28.5%), stigmasterol (15.6%) and sitosterol (49.6%)], with or without SCH 58235 (a derivative of ezetimibe), 30 mg/kg per day, known to suppress intestinal cholesterol absorption, on plasma, tissue, biliary, and fecal sterols in Wistar and wild-type Kyoto (WKY) rats, and their metabolism by intestinal bacteria. METHODS: After 2 weeks of feeding control or experimental diet, rats were given [3alpha-(3)H]sitosterol intravenously and [4-(14)C]sitosterol by mouth, and blood was collected after 1, 2, 3, and 5 days after labeling to determine sitosterol absorption. Feces were collected during the last 3 days and freeze dried. At the end of feeding, bile fistulas were created in 3 rats of each strain and bile was collected for 1 hour. All rats were then sacrificed and plasma and liver were collected for sterol measurements and activities of hepatic HMG-CoA reductase, cholesterol 7alpha-hydroxylase, and cholesterol 27-hydroxylase. RESULTS: Wild-type Kyoto rats were hypercholesterolemic compared to Wistar rats and had increased plant sterols in the plasma. Plasma cholesterol tended to be lower in WKY rats after feeding with plant sterol-enriched diet whereas plant sterol levels rose to approximately 31% of plasma sterols in WKY and 14% in Wistar rats. However, brassicasterol and stigmasterol, with a double bond at C-22, constituted less than 3.5% of total plasma plant sterols. After feeding, biliary plant sterols increased 2.25-fold in Wistar and 1.5-fold in WKY rats, suggesting less hepatic clearance in WKY rats. SCH 58235 feeding significantly increased plasma as well as biliary cholesterol levels in both the untreated and plant sterol-fed WKY rats, and the plasma plant sterols showed a tendency to increase but did not reach significant level. Intestinal bacteria in both rat strains metabolized all plant sterols to mainly the 5beta-H-stanols. However, the C-22 double bond was stable to bacterial degradation. Intestinal absorption of sitosterol and cholesterol was increased 1.5- and 1.3-fold, respectively, in the WKY rats as compared to the Wistar rats, and plant sterol feeding lowered absorption of these sterols in both strains. Absorption of both these sterols was also lowered in SCH 58235-treated rats in both strains and was further lowered when SCH 58235 and plant sterols were simultaneously fed. The activity of the rate-limiting enzyme, HMG-CoA reductase, was increased 1.57-fold in Wistar rats and 1.27-fold in WKY rats that were fed plant sterols as compared to untreated rats. CONCLUSIONS: (1) Plant sterol absorption was increased whereas hepatic elimination of all sterols was diminished in WKY rats accounting for elevated cholesterol and plant sterol levels. (2) The 1% plant sterol-enriched diet tended to lower plasma cholesterol levels whereas SCH 58235 feeding significantly increased plasma cholesterol levels in the WKY rats. (3) Intestinal absorption of sterols with C-22 double bond is diminished and the side-chain double bond is resistant to intestinal bacteria.

Animals↗
PubMed2005

FXR-activating ligands inhibit rabbit ASBT expression via FXR-SHP-FTF cascade.

The regulation of the rabbit apical sodium-dependent bile acid transporter (ASBT) was studied both in vivo and in vitro. New Zealand White rabbits were fed 0.5% deoxycholic acid (DCA) or SC-435, a competitive ASBT inhibitor, for 1 wk. In DCA-fed rabbits, ASBT expression was repressed, associated with activated FXR, and evidenced by increased ileal short heterodimer partner (SHP) mRNA. Feeding SC-435 to the rabbits blocked bile acid absorption, decreased SHP mRNA, and increased ASBT expression. A 1.9-kb rabbit ASBT 5'-flanking region (promoter) was cloned, and a cis-acting element for alpha-fetoprotein transcription factor (FTF) was identified (-1166/-1158). The effects of transcriptional factors and different bile acids on the rabbit ASBT promoter were studied in Caco-2 cells. FTF stimulated the rabbit ASBT promoter activity fourfold but not after the FTF binding site was deleted from the promoter. Increasing the SHP protein notably inhibited FTF-dependent trans-activation of rabbit ASBT. Adding hydrophobic bile acids deoxycholic acid, chenodeoxycholic acid, and cholic acid, activating ligands for FXR, inhibited rabbit ASBT promoter activity in Caco-2 cells, but this inhibitory effect was abolished after the FTF binding site was deleted. Ursodeoxycholic acid and ursocholic acid, nonactivating ligands for FXR, did not repress ASBT promoter activity. Thus the rabbit ASBT promoter is negative-feedback regulated by bile acids via a functional FTF binding site. Only FXR-activating ligands can downregulate rabbit ASBT expression through the regulatory cascade FXR-SHP-FTF.

Animals↗
PubMed2005

Comparison of changes in lipid profile after bilio-intestinal bypass and gastric banding in patients with morbid obesity.

BACKGROUND: The presence of hypercholesterolemia is currently not considered a selection criteria for performing gastric restrictive or diversionary bariatric surgery. METHODS: We prospectively investigated the effects of the bilio-intestinal bypass (BI-bypass) with a wide cholecysto-jejunal anastomosis and of adjustable gastric banding (AGB) on blood lipid concentrations in obese patients. To clarify the mechanism of the hypocholesterolemic effect of the BI-bypass, daily fecal sterol excretion was measured by gas-liquid chromatography (GLC). RESULTS: At 1 year after BI-bypass compared to baseline, the hypercholesterolemic (n=18) and the normocholesterolemic (n=19) patients significantly reduced total (-38% and -27%, respectively), LDL (-47% and -24%, respectively) and HDL (-11% and -13%, respectively) cholesterol and total / HDL cholesterol ratio (-25% and -13%, respectively). At 1 year after AGB, the total / HDL cholesterol ratio was significantly decreased (-11%) compared to baseline in hypercholesterolemic (n=12) but not in normocholesterolemic (n=6) patients, while total and LDL cholesterol were not affected in both groups. At 3 years after BI-bypass compared to baseline, the hypercholesterolemic (n=9) and the normocholesterolemic (n=11) patients significantly reduced total (-43% and -28%, respectively) and LDL (-53% and -29%, respectively) cholesterol and total / HDL cholesterol ratio (-38% and -21%, respectively). The BI-bypass induced a significant (P <0.005; n=7) 6-fold increase in mean fecal cholesterol output. CONCLUSIONS: The BI-bypass but not the AGB leads to a persistent and marked beneficial effect on blood LDL cholesterol associated with an increased cholesterol fecal output. BI-bypass but not AGB is indicated in morbidly obese patients with hypercholesterolemia.

Adult↗
PubMed2004

Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX), sterol 27-hydroxylase (CYP27A1) deficiency, is associated with markedly reduced chenodeoxycholic acid (CDCA), the most powerful activating ligand for farnesoid X receptor (FXR). We investigated the effects of reduced CDCA on FXR target genes in humans. Liver specimens from an untreated CTX patient and 10 control subjects were studied. In the patient, hepatic CDCA concentration was markedly reduced but the bile alcohol level exceeded CDCA levels in control subjects (73.5 vs. 37.8 +/- 6.2 nmol/g liver). Cholesterol 7alpha-hydroxylase (CYP7A1) and Na+/taurocholate-cotransporting polypeptide (NTCP) were upregulated 84- and 8-fold, respectively. However, small heterodimer partner (SHP) and bile salt export pump were normally expressed. Marked CYP7A1 induction with normal SHP expression was not explained by the regulation of liver X receptor alpha (LXRalpha) or pregnane X receptor. However, another nuclear receptor, hepatocyte nuclear factor 4alpha (HNF4alpha), was induced 2.9-fold in CTX, which was associated with enhanced mRNA levels of HNF4alpha target genes, CYP7A1, 7alpha-hydroxy-4-cholesten-3-one 12alpha-hydroxylase, CYP27A1, and NTCP. In conclusion, the coordinate regulation of FXR target genes was lost in CTX. The mechanism of the disruption may be explained by a normally stimulated FXR pathway attributable to markedly increased bile alcohols with activation of HNF4alpha caused by reduced bile acids in CTX liver.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Role of CYP27A in cholesterol and bile acid metabolism.

The CYP27A gene encodes a mitochondrial cytochrome P450 enzyme, sterol 27-hydroxylase, that is expressed in many different tissues and plays an important role in cholesterol and bile acid metabolism. In humans, CYP27A deficiency leads to cerebrotendinous xanthomatosis. To gain insight into the roles of CYP27A in the regulation of cholesterol and bile acid metabolism, cyp27A gene knockout heterozygous, homozygous, and wild-type littermate mice were studied. In contrast to homozygotes, heterozygotes had increased body weight and were mildly hypercholesterolemic, with increased numbers of lipoprotein particles in the low density lipoprotein size range. Cyp7A expression was not increased in heterozygotes but was in homozygotes, suggesting that parts of the homozygous phenotype are secondary to increased cyp7A expression and activity. Homozygotes exhibited pronounced hepatomegaly and dysregulation in hepatic cholesterol, bile acid, and fatty acid metabolism. Hepatic cholesterol synthesis and synthesis of bile acid intermediates were increased; however, side chain cleavage was impaired, leading to decreased bile salt concentrations in gallbladder bile. Expression of Na-taurocholate cotransporting polypeptide, the major sinusoidal bile salt transporter, was increased, and that of bile salt export pump, the major canalicular bile salt transporter, was decreased. Gender played a modifying role in the homozygous response to cyp27A deficiency, with females being generally more severely affected. Thus, both cyp27A genotype and gender affected the regulation of hepatic bile acid, cholesterol, and fatty acid metabolism.

Animals↗
PubMed2004

A mouse model of sitosterolemia: absence of Abcg8/sterolin-2 results in failure to secrete biliary cholesterol.

BACKGROUND: Mutations in either of two genes comprising the STSL locus, ATP-binding cassette (ABC)-transporters ABCG5 (encoding sterolin-1) and ABCG8 (encoding sterolin-2), result in sitosterolemia, a rare autosomal recessive disorder of sterol trafficking characterized by increased plasma plant sterol levels. Based upon the genetics of sitosterolemia, ABCG5/sterolin-1 and ABCG8/sterolin-2 are hypothesized to function as obligate heterodimers. No phenotypic difference has yet been described in humans with complete defects in either ABCG5 or ABCG8. These proteins, based upon the defects in humans, are responsible for regulating dietary sterol entry and biliary sterol secretion. METHODS: In order to mimic the human disease, we created, by a targeted disruption, a mouse model of sitosterolemia resulting in Abcg8/sterolin-2 deficiency alone. Homozygous knockout mice are viable and exhibit sitosterolemia. RESULTS: Mice deficient in Abcg8 have significantly increased plasma and tissue plant sterol levels (sitosterol and campesterol) consistent with sitosterolemia. Interestingly, Abcg5/sterolin-1 was expressed in both liver and intestine in Abcg8/sterolin-2 deficient mice and continued to show an apical expression. Remarkably, Abcg8 deficient mice had an impaired ability to secrete cholesterol into bile, but still maintained the ability to secrete sitosterol. We also report an intermediate phenotype in the heterozygous Abcg8+/- mice that are not sitosterolemic, but have a decreased level of biliary sterol secretion relative to wild-type mice. CONCLUSION: These data indicate that Abcg8/sterolin-2 is necessary for biliary sterol secretion and that loss of Abcg8/sterolin-2 has a more profound effect upon biliary cholesterol secretion than sitosterol. Since biliary sitosterol secretion is preserved, although not elevated in the sitosterolemic mice, this observation suggests that mechanisms other than by Abcg8/sterolin-2 may be responsible for its secretion into bile.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2004

Significance of plasma 7alpha-hydroxy-4-cholesten-3-one and 27-hydroxycholesterol concentrations as markers for hepatic bile acid synthesis in cholesterol-fed rabbits.

Plasma 7alpha-hydroxy-4-cholesten-3-one has been used as an index of hepatic bile acid synthesis. The aim of the current study was to ascertain whether the level of this oxysterol reflects hepatic cholesterol 7alpha-hydroxylase activity when plasma cholesterol concentrations are markedly changed. In addition, the relationship of hepatic sterol 27-hydroxylase activity with plasma concentrations of 27-hydroxycholesterol and 3beta-hydroxy-5-cholestenoic acid was studied. We used New Zealand white rabbits fed 2% cholesterol for 5 or 10 days and/or constructed bile fistula. Feeding cholesterol markedly increased and bile drainage reduced plasma cholesterol concentrations. Initially, in these models there was no correlation between plasma 7alpha-hydroxy-4-cholesten-3-one concentrations and hepatic cholesterol 7alpha-hydroxylase activities (r = -0.24, n = 10). Cholesterol feeding was associated with downregulated 7alpha-hydroxylase activities, while plasma 7alpha-hydroxy-4-cholesten-3-one concentrations were elevated in the presence of increased plasma cholesterol levels. However, this discrepancy was overcome and significant correlation was observed (r = 0.73, P <.05, n = 10) by expressing 7alpha-hydroxy-4-cholesten-3-one levels relative to cholesterol. In contrast, hepatic sterol 27-hydroxylase activities were not significantly correlated with plasma absolute (r = 0.23, difference not significant [NS], n = 10) nor cholesterol-related levels of 27-hydroxycholesterol (r = -0.13, NS, n = 10), or 3beta-hydroxy-5-cholestenoic acid concentrations (r = 0.30, NS, n = 10). In conclusion, plasma 7alpha-hydroxy-4-cholesten-3-one concentrations reflected hepatic cholesterol 7alpha-hydroxylase activities when the sterol levels were adjusted to plasma cholesterol concentrations in rabbits with hypercholesterolemia. The results suggest that plasma 7alpha-hydroxy-4-cholesten-3-one relative to cholesterol is a better marker for hepatic cholesterol 7alpha-hydroxylase activity than the absolute concentration when hypercholesterolemia is present. In contrast, 27-hydroxycholesterol and 3beta-hydroxy-5-cholestenoic acid levels in plasma did not reflect hepatic sterol 27-hydroxylase activities even if the levels were adjusted to plasma cholesterol concentrations.

Animals↗
PubMed2004

Hydrophilic 7 beta-hydroxy bile acids, lovastatin, and cholestyramine are ineffective in the treatment of cerebrotendinous xanthomatosis.

We compared the effect of treatments with hydrophilic bile acids (ursodeoxycholic and ursocholic acids), cholestyramine, and lovastatin versus chenodeoxycholic acid in 4 patients with cerebrotendinous xanthomatosis (CTX). Bile acids and bile alcohols in plasma, bile, and urine before and after treatment were quantitated by gas-liquid chromatography. Untreated, all patients showed abnormal biliary bile acid composition: cholic acid (72.7%) and chenodeoxycholic acid (6.2%), and polyhydroxylated C(27)-bile alcohols (10.0%), and elevated plasma cholestanol levels. Treatment with hydrophobic chenodeoxycholic acid inhibited abnormal bile acid synthesis (virtual disappearance of C(27)-bile alcohols from plasma, bile, and urine and marked reduction of plasma cholestanol levels). Hydrophilic ursodeoxycholic and ursocholic acids did not inhibit abnormal bile acid synthesis, while cholestyramine increased abnormal bile acid synthesis (continued increased formation of polyhydroxylated C(27)-bile alcohols and further elevation of plasma cholestanol levels). Lovastatin did not affect abnormal bile acid synthesis or reduce plasma cholestanol levels. The results demonstrate that impaired side-chain oxidation in bile acid synthesis due to mutations of Cyp27 results in increased formation of polyhydroxylated C(27)-bile alcohols and cholestanol in CTX. Hydrophobic chenodeoxycholic acid, but not cholestyramine, lovastatin, or hydrophilic 7beta-hydroxy acids, inhibited the abnormal synthetic pathway. The role of chenodeoxycholic acid in downregulating abnormal bile acid synthesis in CTX is emphasized.

Adult↗
PubMed2004

Inhibition of ileal bile acid transport lowers plasma cholesterol levels by inactivating hepatic farnesoid X receptor and stimulating cholesterol 7 alpha-hydroxylase.

We investigated the effect of SC-435, a competitive inhibitor of ileal apical sodium-dependent bile acid cotransporter (ASBT) on ileal bile acid absorption and the hepatic nuclear receptor FXR (farnesoid X receptor), which regulates cholesterol 7 alpha-hydroxylase (CYP7A1) activity and mRNA levels. Eighteen New Zealand White (NZW) rabbits were divided into 2 groups: controls (n = 10) and fed SC-435 125 mg/kg/d for 1 week (n = 8). In rabbits treated with SC-435, fecal bile acid outputs increased by more than 8 times, reflecting substantial bile acid malabsorption. Plasma cholesterol levels decreased 26%, while bile acid pool sizes and biliary bile acid outputs did not change after treatment. CYP7A1 activity increased 64% and mRNA rose by 4 times after treatment. The expression of FXR target genes in the liver, short heterodimer partner (SHP) and bile salt export pump (BSEP), decreased 11.6 and 2.6 times, respectively, after treatment, which indicates inactivation of hepatic FXR. However, the mRNA levels of ileal bile acid binding protein (IBABP) did not change significantly, while ileal ASBT mRNA expression increased by 2.4 times after treatment. Rabbits treated with SC-435 developed ileal bile acid malabsorption, which decreased the return of bile acids (FXR ligands) to the liver to inactivate hepatic FXR, which upregulated CYP7A1 and lowered plasma cholesterol levels. Although fecal bile acid malabsorption was substantial, increased bile acid production from hepatic cholesterol kept biliary bile acid outputs intact. Thus, a new balance was reached in the liver, where increased bile acid synthesis compensated for diminished ileal bile acid absorption to maintain the circulating enterohepatic bile acid pool.

Animals↗
PubMed2004

Results of a phase I multiple-dose clinical study of ursodeoxycholic Acid.

BACKGROUND: The hydrophilic bile acid, ursodeoxycholic acid (UDCA), may indirectly protect against colon carcinogenesis by decreasing the overall proportion of the more hydrophobic bile acids, such as deoxycholic acid (DCA), in aqueous phase stool. In the AOM rat model, treatment with UDCA resulted in a significant decrease in adenoma formation and colorectal cancer. It was hypothesized that there is a dose-response relationship between treatment with the more hydrophilic bile acid, UDCA, and a reduction in the proportion of the more hydrophobic bile acid, DCA, in the aqueous stool phase, suggesting the potential of UDCA as a chemopreventive agent. METHODS: Eighteen participants were randomized to 300, 600, or 900 mg/day UDCA for 21 days in this multiple-dose, double-blinded study. Seventy-two-hour stool samples were collected pretreatment and on days 18-20 of UDCA treatment for bile acid measurements. Pharmacokinetics were performed and blood bile acids were measured at days 1 and 21 of UDCA treatment. RESULTS: There were no serious adverse events associated with UDCA treatment. There was a dose-response increase in the posttreatment to baseline ratio of UDCA to DCA from the 300 mg/day to the 600 mg/day group, but not between the 600 and the 900 mg/day groups, in both aqueous and solid phase stool. This posttreatment increase was statistically significant in aqueous phase stool for the 300 and 600 mg/day treatment groups (P = 0.038 and P = 0.014, respectively), but was only marginally significant in the 900 mg/day treatment group (P = 0.057). Following the first dose administration, a dose-dependent increase in plasma ursodeoxycholic concentrations was observed in fasting subjects; however, when these levels were measured postprandially following 3 weeks of treatment, the areas under the plasma concentration-time profile (AUC) were not statistically different and remained relatively unchanged over time. CONCLUSIONS: UDCA treatment did not decrease the quantity of DCA in fecal water or solids; however, it did decrease the proportion of DCA in fecal water and solids in relation to UDCA. Thus, 3 weeks of UDCA treatment resulted in an overall increase in hydrophilicity of bile acids in the aqueous phase stool, with a peak effect observed with a daily dose of 600 mg/day. Much larger studies are needed to determine the effect of ursodeoxycholic administration on deoxycholic concentration, overall hydrophilicity of stool bile acids, and the long-term effects on intermediate biomarkers of cellular damage.

Administration, Oral↗
PubMed2003

Dietary cholesterol stimulates CYP7A1 in rats because farnesoid X receptor is not activated.

Cholesterol feeding upregulates CYP7A1 in rats but downregulates CYP7A1 in rabbits. To clarify the mechanism responsible for the upregulation of CYP7A1 in cholesterol-fed rats, the effects of dietary cholesterol (Ch) and cholic acid (CA) on the activation of the nuclear receptors, liver X-receptor (LXR-alpha) and farsenoid X-receptor (FXR), which positively and negatively regulate CYP7A1, were investigated in rats. Studies were carried out in four groups (n = 12/group) of male Sprague-Dawley rats fed regular chow (control), 2% Ch, 2% Ch + 1% CA, and 1% CA alone for 1 wk. Changes in mRNA expression of short heterodimer partner (SHP) and bile salt export pump (BSEP), target genes for FXR, were determined to indicate FXR activation, whereas the expression of ABCA1 and lipoprotein lipase (LPL), target genes for LXR-alpha, reflected activation. CYP7A1 mRNA and activity increased twofold and 70%, respectively, in rats fed Ch alone when the bile acid pool size was stable but decreased 43 and 49%, respectively, after CA was added to the Ch diet, which expanded the bile acid pool 3.4-fold. SHP and BSEP mRNA levels did not change after feeding Ch but increased 88 and 37% in rats fed Ch + CA. This indicated that FXR was activated by the expanded bile acid pool. When Ch or Ch + CA were fed, hepatic concentrations of oxysterols, ligands for LXR-alpha increased to activate LXR-alpha, as evidenced by increased mRNA levels of ABCA1 and LPL. Feeding CA alone enlarged the bile acid pool threefold and increased the expression of both SHP and BSEP. These results suggest that LXR-alpha was activated in rats fed both Ch or Ch + CA, whereas CYP7A1 mRNA and activity were induced only in Ch-fed rats where the bile acid pool was not enlarged such that FXR was not activated. In rats fed Ch + CA, the bile acid pool expanded, which activated FXR to offset the stimulatory effects of LXR-alpha on CYP7A1.

ATP Binding Cassette Transporter, Subfamily B, Mem↗