Kegg Pathway: Bile acid biosynthesis

Cell Signal. 2008 Jun 27;
Nguyen A, Bouscarel B

Bile acids are mainly recognized for their role in dietary lipid absorption and cholesterol homeostasis. However, recent progress in Bile acid research suggests that Bile acids are important signaling molecules that play a role in glucose homeostasis. Among the various supporting evidence, several reports have demonstrated an improvement of the glycemic index of type 2 diabetic patients treated with diverse Bile acid binding resins. Herein, we review the diverse interactions of Bile acids with various signaling/response pathways, including calcium mobilization and protein kinase activation, membrane receptor-mediated responses, and nuclear receptor responses. Some of the effects of the Bile acids are direct through the activation of specific receptors, i.e., TGR5, CAR, VDR, and FXR, while others imply modulation of the hormonal, growth factor and/or neuromediator responses, i.e., glucagon, EGF, and acetylcholine. We also discuss recent evidence implicating the interaction of Bile acids with glucose homeostasis mechanisms, with the integration of our understanding of how the signaling mechanisms modulated by Bile acid could regulate glucose metabolism.

Environ Health Perspect. 2008 Jul; 116(7): 880-5
Milnes MR, Garcia A, Grossman E, Grün F, Shiotsugu J, Tabb MM, Kawashima Y, Katsu Y, Watanabe H, Iguchi T, Blumberg B

BACKGROUND: Nuclear receptor subfamily 1, group I, member 2 (NR1I2), commonly known as steroid and xenobiotic receptor (SXR) in humans, is a key ligand-dependent transcription factor responsible for the regulation of xenobiotic, steroid, and Bile acid metabolism. The ligand-binding domain is principally responsible for species-specific activation of NR1I2 in response to xenobiotic exposure. OBJECTIVES: Our objective in this study was to create a common framework for screening NR1I2 orthologs from a variety of model species against environmentally relevant xenobiotics and to evaluate the results in light of using these species as predictors of xenobiotic disposition and for assessment of environmental health risk. METHODS: Sixteen chimeric fusion plasmid vectors expressing the Gal4 DNA-binding domain and species-specific NR1I2 ligand-binding domain were screened for activation against a spectrum of 27 xenobiotic compounds using a standardized cotransfection receptor activation assay. RESULTS: NR1I2 orthologs were activated by various ligands in a dose-dependent manner. Closely related species show broadly similar patterns of activation; however, considerable variation to individual compounds exists, even among species varying in only a few amino acid residues. CONCLUSIONS: Interspecies variation in NR1I2 activation by various ligands can be screened through the use of in vitro NR1I2 activation assays and should be taken into account when choosing appropriate animal models for assessing environmental health risk.

Genes Dev. 2008 Jul 15; 22(14): 1871-6
Duggavathi R, Volle DH, Mataki C, Antal MC, Messaddeq N, Auwerx J, Murphy BD, Schoonjans K

Female fertility requires normal ovarian follicular growth and ovulation. The nuclear receptor liver receptor homolog 1 has been implicated in processes as diverse as Bile acid metabolism, steroidogenesis, and cell proliferation. In the ovary, Lrh1 is expressed exclusively in granulosa and luteal cells. Using somatic targeted mutagenesis, we show that mice lacking Lrh1 in granulosa cells are sterile, due to anovulation. The preovulatory stimulus fails to elicit cumulus expansion, luteinization, and follicular rupture in these mice. Multiple defects, including severely reduced transactivation of the Lrh1 target gene, nitric oxide synthase 3, leads to increased intrafollicular estradiol levels in the absence of Lrh1. This further causes dysfunction of prostaglandin and hyaluronic acid cascades and interrupts cumulus expansion. Lack of Lrh1 also interferes with progesterone synthesis because of failure of normal expression of the Lrh1 targets, steroidogenic acute regulatory protein and cytochrome P450 side-chain cleavage. In addition, expression of extracellular matrix proteases essential for ovulation is compromised. These results demonstrate that Lrh1 is a regulator of multiple mechanisms essential for maturation of ovarian follicles and for ovulation. Lrh1 is therefore a key modulator of female fertility and a potential target for contraception.

Int J Toxicol. 2007; 26 Suppl 2: 79-112

Glycyrrhetinic acid and its salts and esters and Glycyrrhizic acid and its salts and esters are cosmetic ingredients that function as flavoring agents or skin-conditioning agents - miscellaneous or both. These chemicals may be isolated from licorice plants. Glycyrrhetinc acid is described as at least 98% pure, with 0.6% 24-OH-Glycyrrhetinic acid, not more than 20 mu g/g of heavy metals and not more than 2 mu g/g of arsenic. Ammonium Glycyrrhizate has been found to be at least 98% pure and Dipotassium Glycyrrhizate has been found to be at least 95% pure. Glycyrrhetinic acid is used in cosmetics at concentrations of up to 2%; Stearyl Glycyrrhetinate, up to 1%; Glycyrrhizic acid, up to 0.1%; Ammonium Glycyrrhizate, up to 5%; Dipotassium Glycyrrhizate, up to 1%; and Potassium Glycyrretinate, up to 1%. Although Glycyrrhizic acid is poorly absorbed by the intestinal tract, it may be hydrolyzed to Glycyrrhetinic acid by a beta -glucuronidase produced by intestinal bacteria. Glycyrrhetinic acid and Glycyrrhizic acid bind to rat and human albumin, but do not absorb well into tissues. Glycyrrhetinic acid and Glycyrrhizic acid and metabolites are mostly excreted in the Bile, with very little excreted in urine. Dipotassium Glycyrrhizate was undetectable in the receptor chamber when tested for transepidermal permeation through pig skin. Glycyrrhizic acid increased the dermal penetration of diclofenac sodium in rat skin. Dipotassium Glycyrrhizate increased the intestinal absorption of calcitonin in rats. In humans, Glycyrrhetinic acid potentiated the effects of hydrocortisone in the skin. Moderate chronic or high acute exposure to Glycyrrhizic acid, Ammonium Glycyrrhizate, and their metabolites have been demonstrated to cause transient systemic alterations, including increased potassium excretion, sodium and water retention, body weight gain, alkalosis, suppression of the renin-angiotensis-aldosterone system, hypertension, and muscular paralysis; possibly through inhibition of 11beta -hydroxysteroid dehydrogenase-2 (11beta -OHSD2) in the kidney. Glycyrrhetinic acid and its derivatives block gap junction intracellular communication in a dose-dependent manner in animal and human cells, including epithelial cells, fibroblasts, osteoblasts, hepatocytes, and astrocytes; at high concentrations, it is cytotoxic. Glycyrrhetinic acid and Glycyrrhizic acid protect liver tissue from carbon tetrachloride. Glycyrrhizic acid has been used to treat chronic hepatitis, inhibiting the penetration of the hepatitis A virus into hepatocytes. Glycyrrhetinic acid and Glycyrrhizic acid have anti-inflammatory effects in rats and mice. The acute intraperitoneal LD(50) for Glycyrrhetinic acid in mice was 308 mg/kg and the oral LD(50) was > 610 mg/kg. The oral LD(50) in rats was reported to be 610 mg/kg. Higher LD(50) values were generally reported for salts. Little short-term, subchronic, or chronic toxicity was seen in rats given ammonium, dipotassium, or disodium salts of Glycyrrhizic acid. Glycyrrhetinic acid was not irritating to shaved rabbit skin, but was considered slightly irritating in an in vitro test. Glycyrrhetinic acid inhibited the mutagenic activity of benzo[a]pyrene and inhibited tumor initiation and promotion by other agents in mice. Glycyrrhizic acid inhibited tumor initiation by another agent, but did not prevent tumor promotion in mice. Glycyrrhizic acid delayed mortality in mice injected with Erlich ascites tumor cells, but did not reduce the mortality rate. Ammonium Glycyrrhizate was not genotoxic in in vivo and in vitro cytogenetics assays, the dominant lethal assay, an Ames assay, and heritable translocation tests, except for possible increase in dominant lethal mutations in rats given 2000 mg/kg day(-1) in their diet. Disodium Glycyrrhizate was not carcinogenic in mice in a drinking water study at exposure levels up to 12.2 mg/kg day(-1) for 96 weeks. Glycyrrhizate salts produced no reproductive or developmental toxicity in rats, mice, golden hamsters, or Dutch-belted rabbits, except for a dose-dependent increase (at 238.8 and 679.9 mg/kg day(-1)) in sternebral variants in a study using rats. Sedation, hypnosis, hypothermia, and respiratory depression were seen in mice given 1250 mg/kg Glycyrrhetinic acid intraperitoneally. Rats fed a powdered diet containing up to 4% Ammonium Glycyrrhizate had no treatment related effects in motor function tests, but active avoidance was facilitated at 4%, unaffected at 3%, and depressed at 2%. In a study of 39 healthy volunteers, a no effect level of 2 mg/kg/day was determined for Glycyrrhizic acid given orally for 8 weeks. Clinical tests in seven normal individuals given oral Ammonium Glycyrrhizate at 6 g/day for 3 days revealed reduced renal and thermal sweat excretion of Na+ and K+, but carbohydrate and protein metabolism were not affected. Glycyrrhetinic acid at concentrations up to 6% was not a skin irritant or a sensitizer in clinical tests. Neither Glycyrrhizic acid, Ammonium Glycyrrhizate, nor Dipotassium Glycyrrhizate at 5% were phototoxic agents or photosensitizers. Birth weight and maternal blood pressure were unrelated to the level of consumption of Glycyrrhizic acid in 1049 Finnish women with infants, but babies whose mother consumed > 500 mg/wk were more likely to be born before 38 weeks. The Cosmetic Ingredient Review (CIR) Expert Panel noted that the ingredients in this safety assessment are not plant extracts, powders, or juices, but rather are specific chemical species that may be isolated from the licorice plant. Because these chemicals may be isolated from plant sources, however, steps should be taken to assure that pesticide and toxic metal residues are below acceptable levels. The Panel advised the industry that total polychlorobiphenyl (PCB)/pesticide contamination should be limited to not more than 40 ppm, with not more than 10 ppm for any specific residue, and that toxic metal levels must not contain more than 3 mg/kg of arsenic (as As), not more than 0.002% heavy metals, and not more than 1 mg/kg of lead (as Pb). Although the Panel noted that Glycyrrhizic acid is cytotoxic at high doses and ingestion can have physiological effects, there is little acute, short-term, subchronic, or chronic toxicity and it is expected that these ingredients would be poorly absorbed through the skin. These ingredients are not considered to be irritants, sensitizers, phototoxic agents, or photosensitizers at the current maximum concentration of use. Accordingly, the CIR Expert Panel concluded that these ingredients are safe in the current practices of use and concentration. The Panel recognizes that certain ingredients in this group are reportedly used in a given product category, but the concentration of use is not available. For other ingredients in this group, information regarding use concentration for specific product categories is provided, but the number of such products is not known. In still other cases, an ingredient is not in current use, but may be used in the future. Although there are gaps in knowledge about product use, the overall information available on the types of products in which these ingredients are used and at what concentration indicate a pattern of use. Within this overall pattern of use, the Expert Panel considers all ingredients in this group to be safe.

J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Jun 18;
Zhang ZC, Xu M, Sun SF, Qiao X, Wang BR, Han J, Guo DA

A liquid chromatography-diode array detection-electrospray ionization ion trap mass spectrometry (LC-DAD-ESI-MS(n)) method was established for the analysis of danshensu, caffeic acid, ferulic acid and isoferulic acid in rat plasma, Bile, urine and feces after oral administration or intravenous injection. Liquid-liquid extraction was employed for the preparation of biosamples, and the chromatographic separation was carried out using an Agilent Zorbax Extend C(18) reversed phase column and acetonitrile-0.1% formic acid as the moBile phase. Totally nineteen metabolites were detected and identified as prototype, methylated, hydroxylated, sulfated and glucuronized conjugates. The metabolism of the individual phenolic acids in biosamples was investigated, and the metabolic pathway was proposed. By comparing the metabolism of different compounds which shared similar structures, we were able to find that methylation was the main pathway of danshensu metabolism, and the double bond on the side chain was critical for the drug excretion via Bile and the formation of glucuronized conjugates. The results proved that the established method was simple, sensitive and reliable, which could be used to detect and identify the structures of metabolites and to better understand their in vivo metabolism.

Eur J Pharmacol. 2008 Jun 19;
Hasanein P, Shahidi S, Komaki A, Mirazi N

Cholestasis is associated with increased activity of the endogenous opioid system that results in analgesia. Endocannabinoid system can reduce pain sensitivity. The use of inhibitors of endocannabinoid metabolism is a novel means of pharmacologically increasing endocannabinoid levels. Considering the interaction that has been shown between the endogenous opioid and endocannabinoid systems in nociception processing, we studied the effects of URB597, a selective inhibitor of FAAH (fatty acid amide hydrolase), on modulation of nociception in a model of elevated endogenous opioid tone, cholestasis. Cholestasis was induced by ligation of the main Bile duct using two ligatures and then transection of the duct at the midpoint between them. Seven days after surgery, tail-flick latencies were measured at 60 min after drug administration. A significant increase (P<0.001) in nociception threshold was observed in cholestatic rats compared to unoperated and sham groups. Administration of URB597 (0.3 mg/kg, i.p.) in cholestatic animals significantly (P<0.001) increased tail-flick latency compared to the vehicle treated cholestatic group. URB597 injection to unoperated and sham groups caused a significant (P<0.05, P<0.05) increase in tail-flick latency compared to their respective vehicle treated groups. The antinociceptive effect of URB597 was blocked by coadministration of a cannabinoid CB(1) receptor antagonist, AM251 (1 mg/kg, i.p.) but not by a cannabinoid CB(2) receptor antagonist, SR144528 (1 mg/kg, i.p.) with URB597. These data showed that URB597 as a FAAH inhibitor potentiates antinociception induced by cholestasis in tail-flick test and that the inhibitory effects of URB597 in this model are mediated by cannabinoid CB(1) and not CB(2) receptors.

Talanta. 2008 May 30; 75(4): 1002-7
Cui L, Chan W, Wu JL, Jiang ZH, Chan K, Cai Z

Metabolism and pharmacokinetic studies on rat were conducted for lithospermic acid B, one of the components from Radix Salviae Miltiorrhizae (danshen) that shows many bioactivities. Liquid chromatography-electrospray ionization mass spectrometry method was applied for the determination of lithospermic acid B and its metabolites in samples from in vitro and in vivo metabolism studies. Rat plasma samples collected after intravenous administration were analyzed for obtaining pharmacokinetic data of lithospermic acid B. Four O-methylated metabolites, namely one monomethyl-, two dimethyl- and one trimethyl-lithospermic acid B, were detected when lithospermic acid B was incubated in rat hepatic cytosol. These four metabolites were also detected in rat Bile, plasma and feces samples after intravenous administration of lithospermic acid B. The in vitro and in vivo results indicate that the methylation is the main metabolic pathway of lithospermic acid B. The danshen component and its methylated metabolites were excreted to rat Bile and feces.

Proc Natl Acad Sci U S A. 2008 Jun 3; 105(22): 7893
Schekman R

Drug Metab Pharmacokinet. 2008; 23(3): 175-80
Jing J, Ren W, Chen X, Wang Y, Yu Q, Wang G, Davey AK, Wang J, Jing N

To study the metabolites of glycyrrhetic acid (GA) in rat Bile, an analytical method was developed to identify GA and its metabolites by liquid chromatography mass spectrometry (LC-MS). Rat Bile was collected after i.v. injection of GA. Three major GA-related peaks were detectable in rat Bile by high-performance liquid chromatography (HPLC) analysis at 254 nm. LC-MS spectra showed their protonated molecular ions at m/z 727, 647, and 551. Furthermore, the three metabolites were also confirmed to exist in rat Bile on LC-MS total ion chromatogram (TIC). Taken together with the susceptible nature to beta-glucuronidase digestion and alkaline conditions, they were identified to be a novel sulfate-glucuronide diconjugate and the known monoglucuronide and sulfate conjugate, respectively.

Gastroenterology. 2008 May 15;
Duez H, Veen JV, Duhem C, Pourcet B, Touvier T, Fontaine C, Derudas B, Baugé E, Havinga R, Bloks VW, Wolters H, van der Sluijs FH, Vennström B, Kuipers F, Staels B

BACKGROUND & AIMS: Conversion into Bile acids represents an important route to remove excess cholesterol from the body. Rev-erbalpha is a nuclear receptor that participates as one of the clock genes in the control of circadian rhythmicity and plays a regulatory role in lipid metabolism and adipogenesis. Here, we investigate a potential role for Rev-erbalpha in the control of Bile acid metabolism via the regulation of the neutral Bile acid synthesis pathway. METHODS: Rev-erbalpha-deficient mice display a lower synthesis rate and an impaired excretion of Bile acids into the Bile and feces. Expression of CYP7A1, the rate-limiting enzyme of the neutral pathway, is decreased in livers of Rev-erbalpha-deficient mice, whereas adenovirus-mediated hepatic Rev-erbalpha overexpression induces its expression. Moreover, Bile acid feeding resulted in a more pronounced suppression of hepatic CYP7A1 expression in Rev-erbalpha-deficient mice. Hepatic expression of E4BP4 and the orphan nuclear receptor small heterodimer partner (SHP), both negative regulators of CYP7A1 expression, is increased in Rev-erbalpha-deficient mice. RESULTS: Promoter analysis and chromatin immunoprecipitation experiments demonstrated that SHP and E4BP4 are direct Rev-erbalpha target genes. Finally, the circadian rhythms of liver CYP7A1, SHP, and E4BP4 messenger RNA levels were perturbed in Rev-erbalpha-deficient mice. CONCLUSIONS: These data identify a role for Rev-erbalpha in the regulatory loop of Bile acid synthesis, likely acting by regulating both hepatic SHP and E4BP4 expression.

Transplantation. 2008 Jun 15; 85(11): 1625-31
Yska MJ, Buis CI, Monbaliu D, Schuurs TA, Gouw AS, Kahmann ON, Visser DS, Pirenne J, Porte RJ

BACKGROUND: Intrahepatic Bile duct strictures are a serious complication after non-heart-beating (NHB) liver transplantation. Bile salt toxicity has been identified as an important factor in the pathogenesis of Bile duct injury and cholangiopathies. The role of Bile salt toxicity in the development of biliary strictures after NHB liver transplantation is unclear. METHODS: In a porcine model of NHB liver transplantation, we studied the effect of different periods of warm ischemia in the donor on Bile composition and subsequent Bile duct injury after transplantation. After induction of cardiac arrest in the donor, liver procurement was delayed for 0 min (group A), 15 min (group B), or more or equal to 30 min (group C). Livers were subsequently transplanted after 4 hr of cold preservation. In the recipients, Bile flow was measured, and Bile samples were collected daily to determine the Bile salt-to-phospholipid ratio. Severity of Bile duct injury was semiquantified by using a histologic grading scale. RESULTS: Posttransplantation survival was directly related to the duration of warm ischemia in the donor. The Bile salt-to-phospholipid ratio in Bile produced early after transplantation was significantly higher in group C, compared with group A and B. Histopathologic condition showed the highest degree of Bile duct injury in group C. CONCLUSION: Prolonged warm ischemia in NHB donors is associated with the formation of toxic Bile after transplantation, with a high biliary Bile salt-to-phospholipid ratio. These data suggest that Bile salt toxicity contributes to the pathogenesis of Bile duct injury after NHB liver transplantation.

Eur J Drug Metab Pharmacokinet. 2008 Jan-Mar; 33(1): 17-22
Rasković A, Mikov M, Skrbić R, Jakovljević V, Vasović V, Posa M, Kuhajda K, Kevresan S, Tomic Z, Siladji D

This study investigated the effect of a commercial preparation of stevioside and a synthetic compound, sodium salt of monketocholic acid (MKC), administered per os (p.o.) and also adminstered via an osmotic pump, on glycemia in normoglycemic and diabetic Wistar rats. Diabetes was induced with alloxan, 100 mg/kg, i.p. Normoglycemic and diabetic rats were treated p.o. for five days either with physiological solution (1 ml/kg, controls), stevioside (20 mg/kg), MKC (4 mg/kg) and a combination of stevioside (20 mg/kg) and MKC (4 mg/kg). Apart from p.o. adminstration, stevioside and MKC were also administered via a subcutaneously (s.c.) implanted osmotic pump. During treatment and upon termination of the latter, glycemia was measured and the rats that were treated p.o. were subjected to the oral glucose tolerance test (OGTTT) at a dose of 1 g/kg. Following this animals were anesthetized with urethane (0.75 g/kg, i.p.) and killed by cardiopunction to determine C-peptide levels in the serum. In all three groups of normoglycemic rats highest decrease in glucose levels was observed on the fourth day of the experiment. The stevioside + MKC combination showed a stronger hypoglycemic effect compared to individual treatments with stevioside and MKC (3.73:4.80:4.73 mmol/L). In the group of diabetic rats that received both substances via the osmotic pump, the hypoglycemic action was also stronger compared to the individual treatments with stevioside and MKC (16.15:18.89:18.75 mmol/L). The treatment of healthy rats with both substances p.o. caused no statistically significant difference in glycemia, whereas in diabetic rats the combination of stevioside + MKC showed a statistically significant decrease in glycemia compared to control values. In both groups of rats, treatment with stevioside and MKC and their combination prevented an increase in glucose concentrations in the OGTT. Only the administration of stevioside by osmotic pump yielded a statistically significant increase in the concentrations of C-peptide in the serum of healthy rats. Compared to controls, the concentrations of C-peptide in diabetic rats were significantly higher after treatment with either stevioside or its combination with MKC, irrespective of the mode of administration.

Life Sci. 2008 Jul 4; 83(1-2): 19-28
Sugiyama E, Ishikawa Y, Li Y, Kagai T, Nobayashi M, Tanaka N, Kamijo Y, Yokoyama S, Hara A, Aoyama T

Eicosapentaenoic acid (EPA) is known to lower plasma cholesterol level and triglycerides, but its precise molecular mechanisms have not been reported. The objective of this study was to determine the mechanism of action of EPA in lowering plasma cholesterol and triglyceride levels. In this study, we found that long-term, highly purified EPA administration effectively reduced plasma and hepatic cholesterol levels in wild-type mice but not in peroxisome proliferator-activated receptor alpha (PPARalpha)-null mice. The significant down-regulation was detected at the transcriptional level on genes involved in cholesterol biosynthesis and cholesterol efflux in the liver only in wild-type mice. Limited changes were found in molecules involved in lipoprotein assembly and uptake, intracellular cholesterol transport, Bile acid biosynthesis, and Bile secretion. Transcription factors regulating cholesterol homeostasis were insignificantly modulated by the EPA treatment, except for sterol response element-binding protein-2 (SREBP-2). Based on these findings, EPA potentially lowers the plasma cholesterol levels by suppressing gene expression of cholesterol biosynthesis enzymes and a cholesterol efflux protein from the liver. In mature SREBP-2, processing ability appears to play an important role in the presence of PPARalpha. Our study provides novel evidence of an additional rationale for the use of EPA in the prevention and treatment of hypercholesterolemia.

Prog Lipid Res. 2008 May 15;
Hunt MC, Alexson SE

Peroxisomes are single membrane bound organelles present in almost all eukaryotic cells, and to date have been shown to contain approximately 60 identified enzymes involved in various metabolic pathways, including the oxidation of a variety of lipids. These lipids include very long-chain fatty acids, methyl branched fatty acids, prostaglandins, Bile-acid precursors and xenobiotics that are either beta-oxidized or alpha-oxidized in peroxisomes. The recent identification of several acyl-CoA thioesterases and acyltransferases in peroxisomes has revealed their various functions in acting as auxiliary enzymes in alpha- and beta-oxidation in this organelle. To date, 9 functional acyl-CoA thioesterases and acyltransferases have been identified in mouse and 4 functional acyl-CoA thioesterases and acyltransferases in human, thus these enzymes make up a substantial portion of peroxisomal proteins. This review will therefore focus on new and emerging roles for these enzymes in assisting with the oxidation of various lipids, amidation of lipids for excretion from peroxisomes, and in controlling coenzyme A levels in peroxisomes.

Anticancer Agents Med Chem. 2008 Jun; 8(5): 540-63
Zimber A, Gespach C

Bile acids, their physiology and metabolism, their role in carcinogenesis and other major human diseases are recently undergoing significant progress. Starting in 1999 when the orphan nuclear receptor FXR was shown to be specifically activated by Bile acids, these compounds became part of the arsenal of ligands of the steroid hormone superfamily of nuclear receptors, including receptors of Vitamin D3, retinoids (RAR, RXR), and thyroid hormone. Another decisive discovery pointed later that the pregnane X-receptor (PXR) is activated by the endogenous toxic lithocholic acid, as well as several xenobiotics and drugs. Bile acids have recently emerged as key regulators of their own metabolism, and of lipid and carbohydrate metabolism. They have important role as promoters of esophageal and colon cancers, cholangiocarcinoma, as well as new implications in breast cancer development and metastasis. This Review will emphasize novel aspects of Bile acids, FXR and PXR as regulators of interfaces at cell proliferation and differentiation, cell death, survival, invasion, and metastasis during normal development and cancer progression. Signaling pathways controlled by Bile acids will be presented and discussed in relation to their impact on gene expression. The biological and pharmacological significance of Bile acids and their recently developed synthetic derivatives and conjugates, as well as new development in the design of FXR agonists and antagonists for clinical applications in cancer prevention and therapy, will be evaluated. This part includes advances in the utilization of Bile acid transporters in drug resistance, therapeutic targeting and delivery of anticancer drugs, as well as therapeutic combinations using new Bile acid derivatives, sequestrating agents and reabsorption inhibitors, and their limitations.

Expert Opin Emerg Drugs. 2008 Jun; 13(2): 363-81
Pollex RL, Joy TR, Hegele RA

BACKGROUND: Many patients at high risk for coronary heart disease (CHD) fail to reach target lipid levels with currently available medications, and a small but clinically relevant proportion of patients experience adverse effects. Thus, additional pharmaceutical strategies are required to fill these gaps in efficacy and tolerability. OBJECTIVE: To provide an overview of both current and emerging antidyslipidemic drugs. METHODS: For the current antidyslipidemic drugs, we focus primarily on statins, Bile acid sequestrants, fibrates, ezetimibe, and niacin. Emerging antidyslipidemic drugs herein discussed were identified by searching the Pharmaprojects database for 'hypercholesterolemia drugs' (Phase II or Phase III), 'HDL-based therapies', and 'PCSK9 inhibition'. RESULTS/CONCLUSIONS: Combinations of currently existing medications are most easily applicable. Meanwhile, strategies to raise HDL-C rely on a deep understanding of the complexity of HDL metabolism. Furthermore, novel approaches to further reduce LDL-C warrant careful evaluation of benefit-risk ratio. Finally, the medical community will have to rely on late-phase CHD outcome studies as the final arbiter of clinical application for any new antidyslipidemia treatment.

J Anim Physiol Anim Nutr (Berl). 2008 Jun 3;
Spielmann J, Kluge H, Stangl GI, Eder K

This study was performed to assess the effects of potato protein and fish protein on concentrations of lipids in plasma and lipoproteins and the expression of genes involved in lipid metabolism in pigs used as an animal model. Therefore, 27 young male pigs with an average body weight of 22 kg were fed diets supplemented with protein extracted from potatoes (containing 849 g protein/kg dry matter), Alaska Pollack fillet as a source of fish protein (containing 926 g crude protein/kg dry matter) or casein which was used as control, for 3 weeks. Diets were formulated to supply identical amounts of each protein to the pigs by the three protein sources, namely 116 g/day in first week and 150 g/day in the second and third week. Pigs fed potato protein had lower concentrations of cholesterol in plasma and LDL than pigs fed casein (p < 0.05); no effect was observed on concentrations of HDL cholesterol and triglycerides. Pigs fed fish protein had lower cholesterol concentrations in plasma, LDL and HDL, and lower triglyceride concentrations in triglyceride-rich lipoproteins than pigs fed casein (p < 0.05). mRNA concentrations of genes involved in Bile acid synthesis and cholesterol uptake were higher in pigs fed fish protein than in pigs fed casein (p < 0.05); no effect on these genes was observed in pigs fed potato protein. Expression of genes involved in lipogenesis and fatty acid oxidation was not altered by fish protein. In conclusion, this study shows that fish protein and potato protein lower plasma cholesterol concentrations in pigs. The hypocholesterolaemic effect of fish protein might be in part caused by a stimulation of Bile acid synthesis; the reason for the hypocholesterolaemic effect of potato protein requires further elucidation.

Drug Metab Dispos. 2008 May 30;
Prakash C, Johnson K, Schroeder C, Potchoiba M

Disposition of lasofoxifene (LAS) was investigated in rats and monkeys after oral administration of a single oral dose of [14C]LAS. Total mean recoveries of the radiocarbon were 96.7 and 94.3% from rats and monkeys, respectively. The major route of excretion in both species was the feces and based on a separate study in the Bile duct-cannulated rat, this likely reflects excretion in Bile rather than incomplete absorption. Whole-body autoradioluminography suggested that [14C]LAS radioequivalents distributed rapidly in the rat with most tissues achieving maximal concentrations at 1 h. Half-life of radioactivity was longest in the uvea (124 h) and shortest in the spleen (~ 3 h). LAS was extensively metabolized in both rats and monkeys since no unchanged drug was detected in urine and/or Bile. Based on AUC(0-24) values, >78% of the circulating radioactivity was due to the metabolites. A total of 22 metabolites were tentatively identified by LC-MS/MS. Based on the structures of the metabolites, six metabolic pathways of LAS were identified: hydroxylation at the tetraline ring, hydroxylation at the aromatic ring attached to tetraline, methylation of the catechol intermediates by catechol-O-methyl transferase, oxidation at the pyrrolidine ring and direct conjugation with glucuronic acid and sulfuric acid. LAS and its glucuronide conjugate (M7) were the major circulating drug related moieties in both rats and monkeys. However, there were notable species-related qualitative and quantitative differences in the metabolic profiles. The catechol (M21) and its sulfate conjugate (M10) were observed only in monkeys while the glucuronide conjugate of the methylated catechol (M8), and hydroxy-LAS (M9) were detected only in rats.

Zhonghua Gan Zang Bing Za Zhi. 2008 May; 16(5): 383-6
Zou SL, Liu J, Lan Y, Cheng H, Gan XL

OBJECTIVE: To investigate the effects and mechanism of farnesoid X receptor (FXR) and its ligands on the metabolism of Bile acids in rats with estrogen-induced intrahepatic cholestasis of pregnancy (ICP). METHODS: An ICP rat model was established with estradiol benzoate (EB) injections. Then FXR ligand chenodeoxycholic acid (CDCA) was administrated (100 mg/kg daily) to ICP rats for 5 days. The serum TBA and expression of FXR and Bile salt export pump (BSEP) in the rat livers were examined by immunohistochemistry and reverse transcription PCR. RESULTS: The levels of TBA in the CDCA group rats were significantly lower than the untreated rats [(17.2+/-4.1)mumol/L vs (29.3+/-6.4)mumol/L], and the expressions of mRNA and protein of FXR were significantly higher [(0.76+/-0.09 vs 0.53+/-0.06, P less than 0.05 and 2.35+/-0.06 vs 1.83+/-0.05, P less than 0.017, respectively)], and the expressions of BSEP were also higher [(0.99+/-0.21 vs 0.76+/-0.07, P less than 0.017 and 1.88+/-0.03 vs 1.46+/-0.06, P less than 0.017, respectively)]. CONCLUSIONS: FXR plays an important role in modulating the metabolism of Bile acids. CDCA can lower the levels of serum TBA by upregulating the expression of FXR and BSEP and then increasing the transport of the Bile acids. These facts might present a new idea and target for the treatment of ICP. [Chinese FullText URL http://zhgz.chinajournal.net.cn].

Am J Gastroenterol. 2008 Jun; 103(6): 1510-6
Capello A, Moons LM, Van de Winkel A, Siersema PD, van Dekken H, Kuipers EJ, Kusters JG

OBJECTIVES: Barrett's esophagus (BE) is a premalignant condition of the esophagus. It is a consequence of mucosal injury from chronic gastroesophageal reflux in which Bile acids are an important toxic component. The farnesoid X receptor (FXR) is a nuclear receptor involved in the regulation of Bile acid synthesis, transport, and absorption. FXR activation is also involved in the induction of the innate immune response. This suggests that FXR is involved in the pathogenesis and the inflammation seen in BE. METHODS: mRNA levels of FXR and the FXR-regulated genes, ileal Bile acid-binding protein (IBABP), small heterodimer partner (SHP), and chemokines interleukin (IL)-8 and macrophage inflammatory protein 3 alpha (MIP3 alpha), were determined by real time-polymerase chain reaction (RT-PCR). Protein expression was determined by immunohistochemistry. RESULTS: FXR was not expressed in squamous epithelium of healthy subjects (N = 7), but was present in both squamous and columnar epithelium of BE patients. Compared to the squamous epithelium of BE patients, their columnar epithelium displayed a 2.3-fold (P= 0.02) increase in FXR mRNA. Also, IBABP (2.2-fold; P= 0.0029), SHP (2.7-fold; P= 0.007), IL-8 (1.5-fold; P= 0.04), and MIP3 alpha (1.7-fold; P= 0.019) transcription levels were increased. Exposure of esophageal cell line TE7 to deoxycholic acid (DCA) resulted in a similar induction. The induction was abolished by the FXR antagonist guggulsterone. CONCLUSIONS: Expression levels of the Bile acid receptor FXR, the Bile acid metabolism genes IBABP and SHP, and the chemokines IL-8 and MIP3 alpha are increased in Barrett's epithelium. The in vitro induction of FXR by DCA suggests that Bile acids can actively induce the inflammatory response in BE by recruiting immune cells.