scholarly journals The Role of the Enterohepatic Circulation of Bile Salts and Nuclear Hormone Receptors in the Regulation of Cholesterol Homeostasis: Bile Salts as Ligands for Nuclear Hormone Receptors

2003 ◽  
Vol 17 (4) ◽  
pp. 265-271 ◽  
Author(s):  
Richard N Redinger
Keyword(s):  
Bile Acid ◽  
Bile Salt ◽  
Bile Acids ◽  
Bile Salts ◽  
Hormone Receptors ◽  
Enterohepatic Circulation ◽  
Retinoid X Receptor ◽  
Cholesterol Homeostasis ◽  
Nuclear Hormone Receptors ◽  
Salt Toxicity

The coordinated effect of lipid activated nuclear hormone receptors; liver X receptor (LXR), bound by oxysterol ligands and farnesoid X receptor (FXR), bound by bile acid ligands, act as genetic transcription factors to cause feed-forward cholesterol catabolism to bile acids and feedback repression of bile acid synthesis, respectively. It is the coordinated action of LXR and FXR, each dimerized to retinoid X receptor, that signal nuclear DNA response elements to encode proteins that prevent excessive cholesterol accumulation and bile salt toxicity, respectively. LXR helps prevent hypercholesterolemia by enhancing transporters for cholesterol efflux that enhance reverse cholesterol transport, while FXR enhances intestinal reabsorption and preservation of bile salts by increasing the ileal bile acid binding protein. FXR also targets sodium taurocholate cotransport peptide and bile salt export pump (protein) genes to limit bile salt uptake and enhance export, respectively, which prevents bile salt toxicity. Other nuclear hormone receptors such as pregnan X receptor, which share the obligate partner, retinoid X receptor, and vitamin D receptor also function as bile acid sensors to signal detoxification by hydroxylation of toxic bile acids. Pharmacologically targeted receptor agonists (or antagonists) may be developed that alter cholesterol and bile salt concentrations by modulating nuclear hormone receptors and/or their coactivators or corepressors to positively affect cholesterol homeostasis and bile salt metabolism. It is the coordinated transcription factor action of LXR, which responds to ligand binding of circulating oxysterols in both liver and peripheral tissues, and FXR responding to bile salts within the enterohepatic circulation that make possible the regulation of cholesterol and bile acid homeostasis.

scholarly journals Overview of Bile Acids Signaling and Perspective on the Signal of Ursodeoxycholic Acid, the Most Hydrophilic Bile Acid, in the Heart

Biomolecules ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 159 ◽  
Author(s):  
Noorul Izzati Hanafi ◽  
Anis Syamimi Mohamed ◽  
Siti Hamimah Sheikh Abdul Kadir ◽  
Mohd Hafiz Dzarfan Othman
Keyword(s):  
Heart Failure ◽  
Bile Acid ◽  
Chronic Heart Failure ◽  
Ursodeoxycholic Acid ◽  
Bile Acids ◽  
G Protein ◽  
Hormone Receptors ◽  
Nuclear Hormone Receptors ◽  
Heart Failure Patients ◽  
G Protein Coupled

Bile acids (BA) are classically known as an important agent in lipid absorption and cholesterol metabolism. Nowadays, their role in glucose regulation and energy homeostasis are widely reported. BAs are involved in various cellular signaling pathways, such as protein kinase cascades, cyclic AMP (cAMP) synthesis, and calcium mobilization. They are ligands for several nuclear hormone receptors, including farnesoid X-receptor (FXR). Recently, BAs have been shown to bind to muscarinic receptor and Takeda G-protein-coupled receptor 5 (TGR5), both G-protein-coupled receptor (GPCR), independent of the nuclear hormone receptors. Moreover, BA signals have also been elucidated in other nonclassical BA pathways, such as sphingosine-1-posphate and BK (large conductance calcium- and voltage activated potassium) channels. Hydrophobic BAs have been proven to affect heart rate and its contraction. Elevated BAs are associated with arrhythmias in adults and fetal heart, and altered ratios of primary and secondary bile acid are reported in chronic heart failure patients. Meanwhile, in patients with liver cirrhosis, cardiac dysfunction has been strongly linked to the increase in serum bile acid concentrations. In contrast, the most hydrophilic BA, known as ursodeoxycholic acid (UDCA), has been found to be beneficial in improving peripheral blood flow in chronic heart failure patients and in protecting the heart against reperfusion injury. This review provides an overview of BA signaling, with the main emphasis on past and present perspectives on UDCA signals in the heart.

scholarly journals Bile salts of the green turtle Chelonia mydas (L.)

1978 ◽  
Vol 171 (2) ◽  
pp. 409-412 ◽  
Author(s):  
G A D Haslewood ◽  
S Ikawa ◽  
L Tökés ◽  
D Wong
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cholic Acid ◽  
Green Turtle ◽  
Bile Salts ◽  
Deoxycholic Acid ◽  
Enterohepatic Circulation ◽  
Chelonia Mydas ◽  
Independent Evolution ◽  
Alpha 7

1. Bile salts of the green turtle Chelonia mydas (L.) were analysed as completely as possible. 2. They consist of taurine conjugates of 3 alpha, 7 alpha, 12 alpha, 22 xi-tetrahydroxy-5 beta-cholestan-26-oic acid (tetrahydroxysterocholanic acid) and 3 alpha 12 alpha, 22 xi-trihydroxy-5 beta-cholestan-26-oic acid, with minor amounts of 3 alpha, 7 alpha, 12 alpha-trihydroxy-5beta-cholan-24-oic acid (cholic acid), 3alpha, 12 alpha-dihydroxy-5beta-cholan-24-oic acid (deoxycholic acid) and possibly other bile acids. 3. Cholic acid and deoxycholic acid represent the first known examples of bile acids common to chelonians and other animal forms: they may indicate independent evolution in chelonians to C24 bile acids. 4. The discovery of a 7-deoxy C27 bile acid is the first evidence that C27 bile acids or their conjugates have an enterohepatic circulation.

scholarly journals Bile Acid Signaling and Cardioprotection

2018 ◽  
Author(s):  
Noorul Izzati Hanafi ◽  
Anis Syamimi Mohamed ◽  
Siti Hamimah Sheikh Abdul Kadir
Keyword(s):  
Heart Failure ◽  
Bile Acid ◽  
Chronic Heart Failure ◽  
Bile Acids ◽  
Hormone Receptors ◽  
Lipid Absorption ◽  
Nuclear Hormone Receptors ◽  
Serum Bile Acid ◽  
Secondary Bile Acid ◽  
Heart Failure Patients

Bile acids (BA) are classically known as an agent important in lipid absorption and cholesterol metabolism. Nowadays, BAs have been found to be involved in various cellular signaling pathways such as protein kinase cascades, cyclic AMP (cAMP) synthesis and calcium mobilization. In addition, they have also been shown to regulate glucose and energy homeostasis. Bile acids are ligands for several nuclear hormone receptors, including FXR. Recently, muscarinic receptor and TGR5, G-protein-coupled receptor (GPCR), have been suggested to play a role in bile acid activity which is independent of nuclear hormone receptors. Moreover, BAs have also been studied in other GPCR associated pathways, namely sphingosine-1-posphate and glucagon receptor. Hydrophobic bile acids have been proven to affect heart rate and its contraction. Elevated bile acids are associated with arrhythmias in adults and fetal heart. Altered ratios of primary and secondary bile acid are reported in chronic heart failure patients. Meanwhile in patients with liver cirrhosis, cardiac dysfunction has been strongly linked to the increase of serum bile acid concentrations. In contrast, the most hydrophilic BA known as ursodeoxycholic acid has been found beneficial in improving peripheral blood flow in chronic heart failure patients and protecting heart against reperfusion injury.

Abstract 282: Murine Abcb1 Functions as an Efflux Transporter for Bile Salts After Chronic Administration of a Western Diet

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Stephen D Lee ◽  
Sheila J Thornton ◽  
Kishor M Wasan
Keyword(s):  
Bile Acid ◽  
Bile Salt ◽  
Bile Acids ◽  
Knockout Mice ◽  
Health Research ◽  
Bile Salts ◽  
Molar Ratio ◽  
Wild Type ◽  
Transport Pathway ◽  
Efflux Mechanism

Rationale: Removal of bile salts from the liver is the final step of the reverse cholesterol transport pathway. We studied the contribution of Abcb1 (P-glycoprotein), in bile acid efflux. Although a number of endogenous substrates have been postulated for Abcb1 based on in vitro evidence, studies using animal models have not supported these claims. Recent studies in mice demonstrated that in the absence of the Bile Salt Efflux Pump (Bsep), Abcb1 is required for removal of bile salts, especially when challenged with a cholic acid containing diet. To date, no study using atherogenic diets has demonstrated the role of Abcb1 in the removal of bile salts in the presence of functional Bsep. Methods: We fed male mice lacking both isoforms of Abcb1 (Abcb1a -/- /1b -/- ) and wild-type controls a diet providing either 25% or 45% of the kcal from fat, supplemented with either normal chow or high levels of cholesterol (0.02% w/w or 0.2% w/w respectively) for nine weeks; n=5 per group. On the tenth week, we assessed the efflux of cholesterol, phospholipid and bile acids to the gallbladder. Enzymatic assays were used to measure cholesterol and phospholipid, the pool of bile acids was quantified by HPLC to determine the concentrations of the six most prevalent murine bile acids. Results: Abcb1 knockout mice have a >30% reduction in the moles of bile salt normalized to phospholipid relative to wild type mice after administration of diets containing either elevated fat or cholesterol (p<0.05). Neither the efflux of phospholipid, nor the molar composition of the six bile acids was affected by deletion of Abcb1. Conclusions: We conclude that Abcb1 is a secondary efflux mechanism required for the removal of bile acids after consumption of diets rich in fat and/or cholesterol. Although Abcb1 knockout mice have reduced total bile acids in the gallbladder, the molar ratio of the specific bile acids is the same as in the wild type mice. These data suggest that Abcb1 effluxes the six bile acids in a non-specific manner, unlike Bsep which preferentially effluxes hydrophobic bile acids. The lack of specificity demonstrated by Abcb1 is desirable for a low- affinity secondary efflux mechanism, which supplements Bsep activity in bile acid output. Acknowledgments: Canadian Institutes of Health Research, Michael Smith Foundation for Health Research

Bile Flow and Composition During Bile Acid Depletion and Administration

1974 ◽  
Vol 52 (2) ◽  
pp. 334-348 ◽  
Author(s):  
Curtis D. Klaassen
Keyword(s):  
Bile Acid ◽  
Bile Salt ◽  
Bile Acids ◽  
Bile Flow ◽  
Enterohepatic Circulation ◽  
Acid Excretion ◽  
Bile Formation ◽  
Bile Acid Excretion ◽  
Rat Bile ◽  
Acid Administration

Relatively similar concentrations of the inorganic ions were detected in rat, rabbit, and dog bile; however, dog bile had a higher concentration of protein, cholesterol, phospholipid phosphorous, and percentage solids than rat bile, and rabbit bile had the lowest concentration. The biliary excretion of bile acids was altered in each species by: (1) interruption of the enterohepatic circulation; (2) rapid administration of an exogenous load of bile acids; and (3) constant infusion of an exogenous load of bile acids. Bile acid and phospholipid phosphorous concentration and percentage solids increased after bile acid administration in all three species; however, species differences in bilirubin concentration were observed and a marked decrease was detected in rabbit and dog bile but it markedly increased in rat bile. When the enterohepatic circulation was interrupted in the dog and rat, the bile acid concentration markedly decreased with only minor changes in bile flow. This not only supports the theory that there is a bile salt independent fraction of bile formation, but also demonstrates that canalicular bile formation can be maintained at relatively normal rates with almost no excretion of bile acids. Marked discrepancy between bile acid excretion and bile flow was observed in the rat after bile acid administration, in that a marked increase in bile acid excretion was observed but little or no increase in flow. When bile flow was plotted against bile acid excretion for the three species, the slope of the line was less during bile acid administration than during depletion, indicating that the bile acids are accompanied by less water during bile acid administration than during depletion. Variation in the bile flow intercept with zero bile acid excretion (thought to represent the bile salt-independent fraction) was relatively large, which is probably due in part to alteration in the production of the bile salt independent fraction when bile acid secretion is altered. It appears that both the choleretic property of bile acids varies during various rates of bile acid excretion and the bile salt-independent fraction is not constant. Therefore, calculation of the bile salt independent fraction as previously performed should be interpreted with extreme caution. Thus, it appears difficult to determine the quantitative importance of bile acid excretion in bile formation.

Cholestyramine Protection against Ochratoxin A Toxicity: Role of Ochratoxin A Sorption by the Resin and Bile Acid Enterohepatic Circulation

1999 ◽  
Vol 62 (12) ◽  
pp. 1461-1465 ◽  
Author(s):  
ABDELHAMID KERKADI ◽  
CLAUDE BARRIAULT ◽  
RONALD R. MARQUARDT ◽  
ANDRZEJ A. FROHLICH ◽  
IBRAHIM M. YOUSEF ◽  
...  
Keyword(s):  
Bile Salt ◽  
Bile Acids ◽  
Ochratoxin A ◽  
Mechanism Of Action ◽  
Plasma Levels ◽  
Bile Salts ◽  
Enterohepatic Circulation ◽  
Fixed Amount

We have shown that the addition of cholestyramine (CHA, a resin known to bind bile salts in the gastrointestinal tract) to ochratoxin A (OTA)-contaminated rat diets reduced plasma levels of the toxin and prevented OTA-induced nephrotoxicity. To elucidate the mechanism of action of CHA, we carried out in vitro experiments to determine whether the resin may bind the toxin. For comparative purposes, binding of bile salts to the resin was also examined. Results showed that CHA binds both OTA and bile salts (taurodeoxycholate [TDC] and taurocholate [TCA]). Also, CHA showed greater affinity for OTA and TDC than for TCA. At 1 mM concentration, 96% of OTA and 80% of TDC were bound to the resin, while for TCA binding was only 50%. However, saturation of the resin was reached at higher levels with bile acids compared to OTA (3.67 mmol/g resin for TCA and 3.71 mmol/g resin for TDC versus 2.85 mmol/g resin for OTA). To characterize the nature of the binding of the toxin to CHA, NaCl (0 to 200 mM) was added to a fixed amount of OTA or bile acids. As expected, TCA absorption was decreased by the addition of NaCl (&lt;50 mM), indicating electrostatic binding. However, OTA and TDC sorption was decreased only at high concentrations of NaCl (&gt;150 mM), suggesting a stronger binding to the resin than that shown with TCA. Sequential competitive studies demonstrated that CHA binds more OTA than TCA. The results of the in vivo study show the role of bile salts in OTA absorption. The toxin's plasma levels at 1 and 3 h after a single oral dose of OTA were significantly decreased in bile salt–depleted rats compared to the control. Thus, the alteration of the bile salt biliary pool and OTA enterohepatic circulation may be an additional mechanism of action of the resin against mycotoxin toxicity.

scholarly journals Regulation of Bile Acid and Cholesterol Metabolism by PPARs

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-15 ◽  
Author(s):  
Tiangang Li ◽  
John Y. L. Chiang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cholesterol Metabolism ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Major Pathway ◽  
Therapeutic Implications

Bile acids are amphipathic molecules synthesized from cholesterol in the liver. Bile acid synthesis is a major pathway for hepatic cholesterol catabolism. Bile acid synthesis generates bile flow which is important for biliary secretion of free cholesterol, endogenous metabolites, and xenobiotics. Bile acids are biological detergents that facilitate intestinal absorption of lipids and fat-soluble vitamins. Recent studies suggest that bile acids are important metabolic regulators of lipid, glucose, and energy homeostasis. Agonists of peroxisome proliferator-activated receptors (PPARα, PPARγ, PPARδ) regulate lipoprotein metabolism, fatty acid oxidation, glucose homeostasis and inflammation, and therefore are used as anti-diabetic drugs for treatment of dyslipidemia and insulin insistence. Recent studies have shown that activation of PPARαalters bile acid synthesis, conjugation, and transport, and also cholesterol synthesis, absorption and reverse cholesterol transport. This review will focus on the roles of PPARs in the regulation of pathways in bile acid and cholesterol homeostasis, and the therapeutic implications of using PPAR agonists for the treatment of metabolic syndrome.

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