A simple, precise and sensitive method for separation and determination of total bile acid sulfates in human urine is described. The sulfate fraction of urinary bile acids was separated with lipophilic anion exchange gel, piperidinohydroxypropyl Sephadex LH-20 after sample clean-up with Sep-Pak C18 cartridge. The obtained sulfate fraction was submitted to solvolysis with a small volume of dimethoxypropane-HCl solution and subjected to enzymatic-fluorimetrical assay using 3 alpha-hydroxysteroid dehydrogenase and resazurin. In this method, no influence of existing salts in the reaction mixture on fluorescence intensity was observed and solvolysis reaction was almost complete. Overall recoveries of glycine- and taurine-conjugated bile acid 3-sulfates from normal urine ranged from 90.5 to 93.7% and those of unconjugates from 48.7 to 78.0%. The sensitivity of the described method enabled to estimate total bile acid sulfates with 0.5 ml of normal urine and precision tests showed the satisfactory accuracy. The
Since the last International Bile Acid Meeting in Freiburg in 1996, considerable progress has been made in several areas of bile acid research. The different pathways of bile acid synthesis and their regulation have been further characterized. The molecular mechanisms for biliary secretion of bile acids have been elucidated and genetic defects of bile acid transport have been defined. Injurious as well as protective effects of different bile acids on the liver have been further studied. Finally, the beneficial effects of ursodeoxycholic acid in cholestatic liver diseases have been substantiated and the potential mechanisms of action have been explored. This book, the proceedings of the Falk Symposium No. 108 (XV International Bile Acid Meeting), held in Titisee, Germany, October 12-13, 1998, is dedicated to both basic and clinical aspects of bile acid research with a focus on bile acids and cholestasis.Bile Acids and Cholestasis - XV International Bile Acid Meeting, 1 was published 1999 under ...
Dec 22, 2005. SAN DIEGO, CA - Dec 22, 2005 - Diazyme Laboratories, a company that applies its proprietary enzyme technologies to develop low cost and high quality diagnostic products for clinical and research uses, announced today that the U.S. Food and Drug Administration (FDA) has granted Diazyme 510(K) clearance to market its Enzymatic Total Bile Acids (TBA) Assay Kit for the quantitative determination of total bile acids in human blood samples.. Total bile acids is a well known bio-marker for diagnosis of liver diseases. Serum total bile acids are elevated in patients with acute hepatitis, chronic hepatitis, liver sclerosis, and liver cancer. Total bile acids levels are found to be the most sensitive indicator for monitoring the effectiveness of interferon treatment of chronic hepatitis C patients. Moreover, total bile acids tests are also widely used to screen pregnant women for the condition of obstetric cholestasis, a disease that is caused by elevated total bile acids in the bloodstream ...
Bile acids are C24 steroids that are derived in the liver from cholesterol and secreted into the intestinal lumen to aid in emulsification of dietary lipids and lipid-soluble vitamins. The indigenous intestinal microflora modify bile acids, producing up to 20 unique bile acid metabolites. The 7α-dehydroxylation of the bile acids is the most physiologically important bile acid biotransformation. All known intestinal bacteria capable of bile acid 7α-dehydroxylation are anaerobic, gram-positive rods of the genera Clostridium and Eubcicterium. Bile acid 7α-dehydroxylating bacteria often contain bile salt hydrolase, which hydrolyzes the peptide bond in taurine-conjugated bile acids to yield a free bile acid and taurine. Taurine is an organosulfonate containing a sulfite moiety. There have been no published reports indicating whether 7α-dehydroxylating bacteria can utilize taurine. Given that taurine and taurine-conjugated bile acids are found at great concentrations in the intestine, the ability to
Faecal bile acid excretion and intestinal transit time were studied in 18 children with inflammatory bowel disease in clinical remission and with normal stools: 16 with ulcerative colitis, two with Crohns colitis, mean age 14 years (range 10-17 years). Five healthy children, mean age 12.4 years (range 10-17 years), were studied as control subjects. Most patients were taking sulphasalazine, but none were taking steroids. Transit time was determined by carmine and did not differ between groups. Faeces were collected for 72 hours, and faecal water was prepared by centrifugation of faeces at 15,000 x g for two hours. Bile acids in total faeces and faecal water were studied using capillary gas-liquid chromatography-mass spectrometry. Faecal excretion of total bile acids, unconjugated bile acids, and glycine and taurine conjugates were significantly increased in patients as was faecal water excretion of total bile acids, particularly the taurine conjugates and cholic and chenodeoxycholic acids. Total ...
The multifactorial mechanisms promoting weight loss and improved metabolism following Roux-en-Y gastric bypass (GB) surgery remain incompletely understood. Recent rodent studies suggest that bile acids can mediate energy homeostasis by activating the G-protein coupled receptor TGR5 and the type 2 thyroid hormone deiodinase. Altered gastrointestinal anatomy following GB could affect enterohepatic recirculation of bile acids. We assessed whether circulating bile acid concentrations differ in patients who previously underwent GB, which might then contribute to improved metabolic homeostasis. We performed cross-sectional analysis of fasting serum bile acid composition and both fasting and post-meal metabolic variables, in three subject groups: (i) post-GB surgery (n = 9), (ii) without GB matched to preoperative BMI of the index cohort (n = 5), and (iii) without GB matched to current BMI of the index cohort (n = 10). Total serum bile acid concentrations were higher in GB (8.90 +/- 4.84 micromol/l) than in
To study the effect of steroid hormones on bile acid synthesis by cultured rat hepatocytes, cells were incubated with various amounts of these compounds during 72 h and conversion of [4-14C]cholesterol into bile acids was measured. Bile acid synthesis was stimulated in a dose-dependent way by glucocorticoids, but not by sex steroid hormones, pregnenolone or the mineralocorticoid aldosterone in concentrations up to 10 microM. Dexamethasone proved to be the most efficacious inducer, giving 3-fold and 7-fold increases in bile acid synthesis during the second and third 24 h incubation periods respectively, at a concentration of 50 nM. Mass production of bile acids as measured by g.l.c. during the second day of culture (28-52 h) was 2.2-fold enhanced by 1 microM-dexamethasone. No change in the ratio of bile acids produced was observed during this period in the presence of dexamethasone. Conversion of [4-14C]7 alpha-hydroxycholesterol, an intermediate of the bile acid pathway, to bile acids was not ...
Bile acids are usually found conjugated to glycine or taurine, a derivative of cysteine. Cells require the presence of an active bile acid transporter for uptake of these conjugated derivatives (10). To test whether conjugated bile acids would also activate FXR, we coexpressed the human ileal bile acid transporter (IBAT) with FXR in CV-1 cells (11). FXR was strongly activated by 3 μM of the taurine or glycine conjugates of CDCA, LCA, and DCA (Fig. 2G). Weaker activation was seen with the conjugated forms of CA, and tauro-MCA was inactive (Fig. 2G). These data indicate that FXR can be activated by conjugated bile acids in tissues that express bile acid transporters such as the terminal ileum, liver, and kidney. The relation between the chemical structure of bile acids and their activation of FXR is in close agreement with the reported effects of bile acids on induction of I-BABP expression in Caco-2 cells and inhibition of Cyp7a expression in hepatocytes (3, 12). Coactivator proteins interact ...
Chenodeoxycholoyl-CoA is bile acid Coenzyme A ester. In humans, bile acids conjugated with glycine and taurine are the major solutes in bile, and unconjugated bile acids are almost nondetectable in normal bile. Conjugated bile acids are less toxic and are more efficient promoters of intestinal absorption of dietary lipid than unconjugated bile acids. The synthesis of bile acid and amino acid conjugates in human liver is the result of two independent enzymatic reactions with a bile acid coenzyme A thioester intermediate formation of bile acid-CoA esters, considered the rate-limiting step in bile acid amidation and catalyzed by an ATP-dependent microsomal enzyme, bile acid-CoA synthetase (EC 6.2.1.7). In the second reaction, the thioester bond is cleaved, and an amide bond is formed between the bile acid and the amino acids glycine or taurine. The bile acid-CoA:amino acid N-acyltransferase (EC 2.3.1.65) catalyzes this reaction in the cytosol prior to secretion into bile. In human liver the ...
1. The biliary excretion of total bilirubin and bile acids, and the fate of tracer doses of radioactive sulphated and non-sulphated bile acids, were studied in patients with percutaneous transhepatic bile drainage.. 2. Non-sulphated bile acids were excreted in bile early after biliary decompression, and the serum total 3α-hydroxy bile acid concentrations fell rapidly to normal. Biliary bilirubin excretion was both less than and delayed compared with that of bile acids, and the serum bilirubin concentration fell more slowly.. 3. The serum disappearance of [3H]chenodeoxycholate-3-sulphate was slower than that of [14C]glycocholate in all patients with bile drainage, the difference being more marked in the jaundiced patients.. 4. The radioactive sulphated bile acids were recovered predominantly in the urine of the jaundiced patients. In contrast [14C]glycocholate was excreted almost exclusively in bile. In an anicteric patient, radioactive sulphated bile acid disappeared from the serum more ...
In addition to their well-known function as dietary lipid detergents, bile acids have emerged as important signalling molecules that regulate energy homeostasis. Recent studies have highlighted that disrupted bile acid metabolism is associated with metabolism disorders such as dyslipidaemia, intestinal chronic inflammatory diseases and obesity. In particular, type 2 diabetes (T2D) is associated with quantitative and qualitative modifications in bile acid metabolism. Bile acids bind and modulate the activity of transmembrane and nuclear receptors (NR). Among these receptors, the G-protein-coupled bile acid receptor 1 (TGR5) and the NR farnesoid X receptor (FXR) are implicated in the regulation of bile acid, lipid, glucose and energy homeostasis. The role of these receptors in the intestine... in energy metabolism regulation has been recently highlighted. More precisely, recent studies have shown that FXR is important for glucose homeostasis in particular in metabolic disorders such as T2D and ...
The secondary bile acids are derived from the primary bile acids by the enzymatic action of intestinal bacteria through the process of deconjugation and dehydroxylation. The secondary bile acids in humans include deoxycholic acid and lithocholic acid, formed from the 7alpha-dehydroxylation of cholic acid and chenodeoxycholic acid, respectively ...
Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with ...
Bile acids have been suggested to play an important role in the etiology of colon and gastric cancer after gastrectomy, but the molecular biology of these effects is poorly understood. We evaluated the effect of different bile acids on human gastric and colon carcinoma cells and identified genes by RNA arbitrarily primed PCR for differential display that are modulated following treatment with hydrophobic bile acids. Thioredoxin reductase (TR) mRNA was upregulated after treatment with taurochenodeoxycholic acid (TCDCA) in St 23132 cells. This raised the question whether deoxycholic acid (DCA) would have regulative effects on TR in HT-29 cells. After an incubation time of 6 h with DCA, TR mRNA expression was increased up to threefold. Ursodeoxycholic acid had no influence on TR mRNA expression. The upregulation of TR after DCA incubation was almost identical to incubation with 12-O-tetradecanoylphorbol-13-acetate. This implies that hydrophobic bile acids mediate oxidative stress in ...
The serum concentration of TBA in healthy neonates significantly exceeds that in children over 1 year of age, a condition called physiological cholestasis.9 The urinary TBA:creatinine ratio was raised in the first week after birth, then decreased gradually. The high concentration of TBA in urine may be attributable to either an enhanced stimulation of the enterohepatic circulation of bile acids or an impaired hepatic clearance or excretion.10The highest value for TBA in meconium was in neonates. This value is greatly influenced by events or conditions during pregnancy, such as the presence of biliary bile in the fetal duodenum or the ingestion of amniotic fluid by the fetus.10 11 Ketonic bile acids are usually considered to result from the bacterial oxidation of primary bile acids.12 In this study we detected ketonic bile acids early in life. The intestine may be colonised by bacterial flora during the first week.13 A high concentration of 3-oxo Δ4 bile acids in serum or urine has been ...
Hyocholic acid is a bile acid. Bile acids are steroid acids found predominantly in the bile of mammals. The distinction between different bile acids is minute, depending only on the presence or absence of hydroxyl groups on positions 3, 7, and 12. Bile acids are physiological detergents that facilitate excretion, absorption, and transport of fats and sterols in the intestine and liver. Bile acids are also steroidal amphipathic molecules derived from the catabolism of cholesterol. They modulate bile flow and lipid secretion, are essential for the absorption of dietary fats and vitamins, and have been implicated in the regulation of all the key enzymes involved in cholesterol homeostasis. Bile acids recirculate through the liver, bile ducts, small intestine and portal vein to form an enterohepatic circuit. They exist as anions at physiological pH and, consequently, require a carrier for transport across the membranes of the enterohepatic tissues. The unique detergent properties of bile acids are ...
1] Islam KB, et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology. 2011 Nov;141(5):1773-81.. [2] Hellström PM, et al. Role of bile in regulation of gut motility. J Intern Med. 1995 Apr;237(4):395-402.. [3] Trauner M, et al. Bile acids as regulators of hepatic lipid and glucose metabolism. Dig Dis. 2010;28(1):220-4.. [4] Watanabe M, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006 Jan 26;439(7075):484-9.. [5] Zhou H, Hylemon PB. Bile acids are nutrient signaling hormones. Steroids. 2014 Aug;86:62-8.. [6] McMillin M, DeMorrow S. Effects of bile acids on neurological function and disease. FASEB J. 2016 Nov;30(11):3658-68.. [7] Fiorucci S, Distrutti E. Bile acid-activated receptors,iIntestinal microbiota, and the treatment of metabolic disorders. Trends Mol Med. 2015 Nov;21(11):702-14.. [8] de Aguiar Vallim TQ, et al. Pleiotropic roles of bile acids in metabolism. Cell Metab. ...
Bile acids are steroidal amphipathic molecules derived from the catabolism of cholesterol. They modulate bile flow and lipid secretion, are essential for the absorption of dietary fats and vitamins, and have been implicated in the regulation of all the key enzymes involved in cholesterol homeostasis. Bile acids recirculate through the liver, bile ducts, small intestine and portal vein to form an enterohepatic circuit. They exist as anions at physiological pH and, consequently, require a carrier for transport across the membranes of the enterohepatic tissues. Individual bile acid carriers have now been cloned from several species. Na(+)-dependent transporters that mediate uptake into hepatocytes and reabsorption from the intestine and biliary epithelium and an ATP-dependent transporter that pumps bile acids into bile comprise the classes of transporter that are specific for bile acids. In addition, at least four human and five rat genes that code for Na(+)-independent organic anion carriers with ...
We investigated the effect of increasing dietary cholesterol on bile acid pool sizes and the regulation of the two bile acid synthetic pathways (classic, via cholesterol 7α-hydroxylase, and alternative, via sterol 27-hydroxylase) in New Zealand white rabbits fed 3 g cholesterol/per day for up to 15 days. Feeding cholesterol for one day increased hepatic cholesterol 75% and cholesterol 7α-hydroxylase activity 1.6 times without significant change of bile acid pool size or sterol 27-hydroxylase activity. After three days of cholesterol feeding, the bile acid pool size increased 83% (P < 0.01), and further feeding produced 10%-20% increments, whereas cholesterol 7α-hydroxylase activity declined progressively to 60% below baseline. In contrast, sterol 27-hydroxylase activity rose 58% after three days of cholesterol feeding and remained elevated with continued intake. Bile drainage depleted the bile acid pool and stimulated downregulated cholesterol 7α-hydroxylase activity but did not affect ...
The enterohepatic circulation of bile acids is one of the most efficient recycling routes in the human body. It is a complex process involving numerous transport proteins, which serve to transport bile acids from the small intestine into portal circulation, from the portal circulation into the hepatocyte, from the hepatocyte into the bile, and from the gall bladder to the small intestine. The tremendous transport capacity and organ specificity of enterohepatic circulation combined with versatile derivatization possibilities, rigid steroidal backbone, enantiomeric purity, availability, and low cost have made bile acids attractive tools in designing pharmacological hybrid molecules and prodrugs with the view of improving intestinal absorption, increasing the metabolic stability of pharmaceuticals, specifically targeting drugs to organs involved in enterohepatic circulation, as well as sustaining therapeutically reasonable systemic concentrations of active agents. This article briefly describes bile acid
The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size, and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as ...
The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size, and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as ...
We have demonstrated in vitro the efficacy of the taurine-conjugated dihydroxy bile salts deoxycholate and chenodeoxycholate in solubilizing both cholesterol and phospholipid from hamster liver bile-canalicular and contiguous membranes and from human erythrocyte membrane. On the other hand, the dihydroxy bile salt ursodeoxycholate and the trihydroxy bile salt cholate solubilize much less lipid. The lipid solubilization by the four bile salts correlated well with their hydrophobicity: glycochenodeoxycolate, which is more hydrophobic than the tauro derivative, also solubilized more lipid. All the dihydroxy bile salts have a threshold concentration above which lipid solubilization increases rapidly; this correlates approximately with the critical micellar concentration. The non-micelle-forming bile salt dehydrocholate solubilized no lipid at all up to 32 mM. All the dihydroxy bile acids are much more efficient at solubilizing phospholipid than cholesterol. Cholate does not show such a pronounced ...
Dietary nutrients interact with gene networks to orchestrate adaptive responses during metabolic stress. Here, we identify Baf60a as a diet-sensitive subunit of the SWI/SNF chromatin-remodeling complexes in the mouse liver that links the consumption of fat- and cholesterol-rich diet to elevated plasma cholesterol levels. Baf60a expression was elevated in the liver following feeding with a western diet. Hepatocyte-specific inactivation of Baf60a reduced bile acid production and cholesterol absorption, and attenuated diet-induced hypercholesterolemia and atherosclerosis in mice. Baf60a stimulates expression of genes involved in bile acid synthesis, modification, and transport through a CAR/Baf60a feedforward regulatory loop. Baf60a is required for the recruitment of the SWI/SNF chromatin-remodeling complexes to facilitate an activating epigenetic switch on target genes. These studies elucidate a regulatory pathway that mediates the hyperlipidemic and atherogenic effects of western diet ...
Phospholipids and bile acids, by virtue of their amphiphilic properties, can interact in nonpolar media forming "inverted" structures (micelles) which presumably have an hydrophilic core and might act as diffusional carriers (ionophores) of electrolytes across low dielectric constant media or lipid membranes.. The Na+ ionophoretic capability of various purified phospholipids and the modulating effects of bile acids and phospatidylcholine was examined by: (a) measurement of 22Na+ partition into the organic phase (chloroform) of a two-phase system and (b) direct measurement of the translocation of 22Na+ across a bulk chloroform phase separating two aqueous phases in a Pressman cell. All phospholipids tested, except for phosphatidylcholine, showed ionophoretic capability for Na+ at micromolar concentrations. Cardiolipin and phosphatidylserine were the most efficient Na+ carriers, comparable with monensin, an established Na+ ionophore. In contrast, cholic acid as well as other bile acids ...
FXR is expressed at high levels in the liver and intestine. Chenodeoxycholic acid and other bile acids are natural ligands for FXR. Similar to other nuclear receptors, when activated, FXR translocates to the cell nucleus, forms a dimer (in this case a heterodimer with RXR) and binds to hormone response elements on DNA, which up- or down-regulates the expression of certain genes.[6] One of the primary functions of FXR activation is the suppression of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis from cholesterol. FXR does not directly bind to the CYP7A1 promoter. Rather, FXR induces expression of small heterodimer partner (SHP), which then functions to inhibit transcription of the CYP7A1 gene. In this way, a negative feedback pathway is established in which synthesis of bile acids is inhibited when cellular levels are already high. FXR has also been found to be important in regulation of hepatic triglyceride levels.[7] Studies have also shown the FXR to ...
Andriamiarina, R.; Laraki, L.; Pelletier, X.; Debry, G., 1989: Effects of stigmasterol-supplemented diets on fecal neutral sterols and bile acid excretion in rats
x] J Biol Chem. 2011 Aug 12;286(32):28382-95. Nutritional regulation of bile acid metabolism is associated with improved pathological characteristics of the metabolic syndrome. Liaset B, Hao Q, Jørgensen H, Hallenborg P, Du ZY, Ma T, Marschall HU, Kruhøffer M, Li R, Li Q, Yde CC, Criales G, Bertram HC, Mellgren G, Ofjord ES, Lock EJ, Espe M, Frøyland L, Madsen L, Kristiansen K. "Bile acids (BAs)3 are synthesized in the liver from cholesterol. After their synthesis, they are conjugated to the amino acids taurine or glycine in a species-dependent manner (1). Conjugation of bile acids increases their solubility and facilitates their secretion into bile (2). [...] the dietary levels of these amino acids might be crucial for BA conjugation and secretion [...] In conclusion, we provide compelling evidence that plasma bile acid levels can be modulated by the dietary protein source in high fat-treated rats. Increased levels of plasma BAs were associated with a significant reduction in diet-induced ...
x] J Biol Chem. 2011 Aug 12;286(32):28382-95. Nutritional regulation of bile acid metabolism is associated with improved pathological characteristics of the metabolic syndrome. Liaset B, Hao Q, Jørgensen H, Hallenborg P, Du ZY, Ma T, Marschall HU, Kruhøffer M, Li R, Li Q, Yde CC, Criales G, Bertram HC, Mellgren G, Ofjord ES, Lock EJ, Espe M, Frøyland L, Madsen L, Kristiansen K. "Bile acids (BAs)3 are synthesized in the liver from cholesterol. After their synthesis, they are conjugated to the amino acids taurine or glycine in a species-dependent manner (1). Conjugation of bile acids increases their solubility and facilitates their secretion into bile (2). [...] the dietary levels of these amino acids might be crucial for BA conjugation and secretion [...] In conclusion, we provide compelling evidence that plasma bile acid levels can be modulated by the dietary protein source in high fat-treated rats. Increased levels of plasma BAs were associated with a significant reduction in diet-induced ...
This gene encodes a member of the G protein-coupled receptor (GPCR) superfamily. This protein functions as a cell surface receptor for bile acids. Treatment of cells expressing this GPCR with bile acids induces the production of intracellular cAMP, activation of a MAP kinase signaling pathway, and internalization of the receptor. The receptor is implicated in the suppression of macrophage functions and regulation of energy homeostasis by bile acids.[2] One effect of this receptor is to activate deiodinases which convert the prohormone thyroxine (T4) to the active hormone triiodothyronine (T3). T3 in turn activates the thyroid hormone receptor which increases metabolic rate.[3][4] ...
The primary bile acids (BAs) are synthetized from colesterol in the liver, conjugated to glycine or taurine to increase their solubility, secreted into bile, concentrated in the gallbladder during fasting, and expelled in the intestine in response to dietary fat, as well as bio-transformed in the colon to the secondary BAs by the gut microbiota, reabsorbed in the ileum and colon back to the liver, and minimally lost in the feces. BAs in the intestine not only regulate the digestion and absorption of cholesterol, triglycerides, and fat-soluble vitamins, but also play a key role as signaling molecules in modulating epithelial cell proliferation, gene expression, and lipid and glucose metabolism by activating farnesoid X receptor (FXR) and G-protein-coupled bile acid receptor-1 (GPBAR-1, also known as TGR5) in the liver, intestine, muscle and brown adipose tissue ...
Alterations in glucocorticoid (GC) biosynthesis and metabolism are associated with a variety of pathophysiological disorders including cholestasis, diabetes and other metabolic disorders. Bile acids (BA) are also important modulators of metabolic functions and regulate cholesterol, triglyceride and glucose homeostasis as well as being critical for dietary fat digestion, enterohepatic function, and postprandial thermogenesis. In intact cells and in vivo, the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme converts inactive GC precursors (cortisone in humans, and 11-dehydrocorticosterone in mice and rats) into their active forms (cortisol and corticosterone, respectively) thereby amplifying local intracellular GC levels. Interconversion by 11β-HSD1 of other sterols has also been described. These include conversions of 7keto-cholesterol to 7β-hydroxycholesterol, 7-oxodehydroepiandrosterone (7-oxo-DHEA) to 7α-hydroxy- and 7β-hydroxy DHEA, 7- oxo-lithocholic acid (LCA, a bile acid; ...
Receptor for bile acid. Bile acid-binding induces its internalization, activation of extracellular signal-regulated kinase and intracellular cAMP production. May be involved in the suppression of macrophage functions by bile acids.
The invention relates to tetrazole derivatives of bile acids, processes for their preparation, and use of these compounds as medicaments and cholesterol lowering agents. The tetrazole-bile acid derivatives are of the formula G1--X--G2, where G1 is H, a bile acid radical, or a bile acid radical which is modified on the hydroxyl functions and/or on the carboxyl group, X is a single bond or a bridge group between G1 and G2, and G2 is of the formula: ##STR1##
Acyl-CoA synthetase involved in bile acid metabolism. Proposed to catalyze the first step in the conjugation of C24 bile acids (choloneates) to glycine and taurine before excretion into bile canaliculi by activating them to their CoA thioesters. Seems to activate secondary bile acids entering the liver from the enterohepatic circulation. In vitro, also activates 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholestanate (THCA), the C27 precursor of cholic acid deriving from the de novo synthesis from cholesterol.
Obeticholic acid (abbreviated to OCA, trade name Ocaliva), is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It is used as a drug to treat primary biliary cholangitis, and is undergoing development for several other liver diseases and related disorders. Intercept Pharmaceuticals Inc. hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma. The natural bile acid, chenodeoxycholic acid, was identified in 1999 as the most active physiological ligand for the farnesoid X receptor (FXR), which is involved in many physiological and pathological processes. A series of alkylated bile acid analogues were designed, studied and patented by Roberto Pellicciari and colleagues at the University of Perugia, with 6α-ethyl-chenodeoxycholic acid emerging as the most highly potent FXR agonist. FXR-dependent processes in liver and intestine were proposed as therapeutic targets in human diseases. ...
Organic anion transporting polypeptides (OATPs) are uptake transporters for a broad range of endogenous compounds and xenobiotics. To investigate the physiologic and pharmacologic roles of OATPs of the 1A and 1B subfamilies, we generated mice lacking all established and predicted mouse Oatp 1a/1b transporters (referred to as Slco1a/1b(-/-) mice, as SLCO genes encode OATPs). Slco1a/1b(-/-) mice were viable and fertile but exhibited markedly increased plasma levels of bilirubin conjugated to glucuronide and increased plasma levels of unconjugated bile acids. The unexpected conjugated hyperbilirubinemia indicates that Oatp1a/1b transporters normally mediate extensive hepatic reuptake of glucuronidated bilirubin. We therefore hypothesized that substantial sinusoidal secretion and subsequent Oatp1a/1b-mediated reuptake of glucuronidated compounds can occur in hepatocytes under physiologic conditions. This alters our perspective on normal liver functioning. Slco1a/1b(-/-) mice also showed drastically ...
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The synthesis and excretion of bile acids comprise the major pathway of cholesterol catabolism in mammals. Synthesis provides a direct means of converting cholesterol, which is both hydrophobic and insoluble, into a water-soluble and readily excreted molecule, the bile acid. The biosynthetic steps t …
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Farnesoid X receptor (FXR, NR1H4) is a ligand activated transcription factor belonging to the nuclear receptor (NR) superfamily, and is highly expressed in the liver, intestine, and kidney, in both humans and rodents. Bile acids (BAs) are the endogenous ligands of FXR. FXR mainly functions as the BA sensor by regulating genes that are critically involved in BA homeostasis. FXR has also been shown to play important roles in lipid, cholesterol and glucose metabolism, as well as inflammation, tumorigenesis, and liver regeneration. FXR deficiency is implicated in numerous liver diseases and mice with modulation of FXR have been used as animal models to study liver physiology and pathology. Genome-wide studies in mouse livers and intestines suggest FXRs diverse and broadly tissue specific functions. In the first aim, we studied the genome-wide FXR binding and transcriptome profiles upon FXR activation in primary human hepatocytes (PHHs) and HepG2 cells. Chromatin immunoprecipitation followed by ...
Bile Acid Factors™ consists of a mixture of highly concentrated bile acids (also called bile salts), mostly in the conjugated form, from U.S. and/or New Zealan
The effect of exercise training on upregulation of molecular markers of bile acid metabolism in the liver of ovariectomized rats fed a cholesterol-rich diet
The IUPHAR/BPS Guide to Pharmacology. GPBA receptor - Bile acid receptor. Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance of drug targets.
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The fetal thyroid gland is active and secretes thyroid hormones from the 12th week. It is independent of maternal control, although maternal thyroid hormones do cross the placenta. Hypothyroidism This may present with fatigue, hair loss, dry skin, abnormal weight gain, poor appetite, cold intolerance, bradycardia and delayed tendon reflexes. If untreated, there is double the rate of spontaneous miscarriages and stillbirths compared to the normal population, as well as a risk of fetal neurological impairment. There is a positive family history in up to 50% of cases. Transaminases are increased (less than threefold), and alkaline phosphatase levels are raised (above normal pregnancy values). Bilirubin is usually < 100mamol/l,and there may be pale stools and dark urine. Serum total bile acid concentration is increased early in the disease and may be the optimum marker. There are no serious long-term maternal risks but there is a risk of preterm labour, fetal distress and intrauterine fetal death. ...
Glucuronidation is considered an important detoxification pathway of bile acids especially in cholestatic conditions. Glucuronides are less toxic than the parent free forms and are more easily excreted in urine.
In this work, we show that in nondiabetic subjects, plasma 12α-hydroxylated BAs are disproportionately increased in association with IR. This finding provides evidence that BA composition is altered within the normal range of insulin sensitivity, and is consistent with insulin-dependent regulation of the 12α-hydroxylase CYP8B1. Our prior work has shown that Cyp8b1 is a target gene of transcription factor FoxO1, whose ability to promote Cyp8b1 transcription is inhibited by insulin via Akt-dependent phosphorylation and nuclear exclusion of FoxO1 (12). These findings dovetail with earlier studies of BA composition, as increased 12α-hydroxylated BAs have been observed in mice lacking hepatic insulin receptors and rodent models of diabetes (13-17). Because FoxO is expected to be more active in IR, owing to decreased Akt-mediated nuclear exclusion, the finding that FoxO1 activates Cyp8b1 reveals a plausible mechanism for upregulation of 12α-hydroxylated BA synthesis in these models.. Surprisingly, ...
A chronic voluntary exercise paradigm, which mimics the exercise pattern of many humans, influences the hepatic clearance of several organic anions and a bile acid, whereas a neutral organic compound is seemingly unaffected. To extend these observations, the present work has evaluated in female Sprague-Dawley rats the effect of 6 weeks of voluntary running on the hepatobiliary elimination of endogenous bile acids and glutathione and exogenously injected rose bengal, digoxin, and acetaminophen. Inactive rats had mobility limited to their cages, whereas exercised rats had free access to a 44-in running wheel. In comparison to weight-matched sedentary rats, the exercised rats ran 4.3 +/- 0.3 miles/day, consumed 45% more food daily, had slightly greater liver/body weight ratios, and slightly elevated basal bile flow rates. Biliary excretion of endogenous bile acids was increased significantly, and excretion of reduced and oxidized glutathione was increased in exercised rats by 190% and 173% of ...
Bile acids, a structurally related group of molecules derived from cholesterol, have a long history as therapeutic agents in medicine, from treatment for primarily ocular diseases in ancient Chinese medicine to modern day use as approved drugs for certain liver diseases. Despite evidence supporting a neuroprotective role in a diverse spectrum of age-related neurodegenerative disorders, including several small pilot clinical trials, little is known about their molecular mechanisms or their physiological roles in the nervous system. We review the data reported for their use as treatments for neurodegenerative diseases and their underlying molecular basis. While data from cellular and animal models and clinical trials support potential efficacy to treat a variety of neurodegenerative disorders, the relevant bile acids, their origin, and the precise molecular mechanism(s) by which they confer neuroprotection are not known delaying translation to the clinical setting.