Bile acids chenodeoxycholic acid

Bile acids are also natural ligands for the farnesoid X receptor (FXR), a receptor that belongs to the nuclear hormone receptor superfamily. The hydrophobic bile acid chenodeoxycholic acid (CDCA) is the most potent... 

FXR RXR Bile acids, chenodeoxycholic acid Represses CYP7A, CYP8B, CYP27A... 

Dried bile from the Himalayan bear (Yutan) has been used for centuries in China to treat liver disease. UDCA (ursodiol, Actigall) is a hydrophilic, dehydroxylated bile acid that is formed by epimerization of the bile acid, chenodeoxycholic acid (CDCA Chenodiol), in the gut by intestinal bacteria. It comprises approximately 1 to 3% of the total bile acid pool in human beings but is present at much higher concentrations in bears. When administered orally, litholytic bile acids, such as chenodiol and ursodiol, can alter relative concentrations of bile acids, decrease biliary lipid secretion, and reduce the cholesterol content of the bile so that it is less lithogenic. Ursodiol also may have cytoprotective effects on hepatocytes and effects on the immune system that account for some of its beneficial effects in cholestatic liver diseases. 

The formation of the other major primary bile acid, chenodeoxycholic acid, from cholesterol is similar to that of cholic acid, except that no 12-hydroxylation takes place. 

Contrasting with rodents, BAT is found in small amounts in adult humans. It has been proposed that skeletal muscle rather than BAT may play a pivotal role in energy homeostasis in adult humans. The authors also demonstrated that cultured human skeletal muscle myoblasts express D2 and high levels of TGR5, and a number of common bile acids (cholic acid, taurocholic acid, deoxycholic acid, chenodeoxycholic acid) were able to increase cAMP levels concomitant with increased D2 activity (Figure 7.4). Taurocholic acid was also able to... 

Hydroxylation, shortening of the hydrocarbon chain, and addition of a carboxyl group convert cholesterol in a complex series of reactions to the bile acids, cholic acid, and chenodeoxycholic acid. 

Plasma and urine samples from atherosclerotic and control rats were comparatively analyzed by ultrafast liquid chromatography coupled with ion trap-time-of-flight (IT-TOF) MS (UFLC-IT/TOF-MS) (16). They identified 12 metabolites in rat plasma and 8 metabolites in rat urine as potential biomarkers. Concentrations of leucine, phenylalanine, tryptophan, acetylcar-nitine, butyrylcamitine, propionylcamitine, and spermine in plasma and 3-0-methyl-dopa, ethyl /V2-acety I -1. -argininate, leucylproline, glucuronate, A(6)-(A-threonylcarbonyl)-adenosine, and methyl-hippuric acid in urine were decreased in atherosclerosis rats ursodeoxycholic acid, chenodeoxycholic acid, LPC (06 0), LPC (08 0), and LPC (08 1) in plasma and hippuric acid in urine were increased in atherosclerosis rats. The altered metabolites demonstrated abnormal metabolism of phenylalanine, tryptophan, bile acids, and amino acids. Lysophosphatidylcholine (LPC) plays an important role in inflammation and cell proliferation, which shows a relationship between LPC in the progress of atherosclerosis and other inflammatory diseases. 

Scalia and Games developed a packed column SFC method for the analysis of free bile acids cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) [32]. The baseline separation of all five bile acids was achieved on a packed phenyl column with a methanol-modified carbon dioxide in less than 4 min. The elution order showed a normal-phase mechanism because the solutes eluted in the order of increasing polarity following the number of hydroxyl groups on the steroid nucleus. The method was also applied to the assay of UDCA and CDCA in capsule and tablet formulations. The method was found to be linear in the range 1.5-7.5 ng/ml (r > 0.99, n = 6). The average recoveries (n= 10) for UDCA and CDCA were 100.2% with a RSD of 1.7% and 101.5% with a RSD of 2.2%, respectively. The reproducibility of the method was less than 1.5% (n = 10) for both UDCA and CDCA. 

Bile Salts Enable the Digestion of Lipids Cholesterol is the precursor of both steroids and bile salts and is an integral component of cell membranes. It is eliminated from the body via conversion to bile salts and direct secretion into the bile. In fact, the word cholesterol (from the Greek chole (bile) and stereos (solid)) was used originally to describe the material of which gallstones are made. In the process of degradation, it is converted to the primary bile acids cholic acid and chenodeoxycholic acid in approximately equal amounts. The salts of these acids are excreted in bile. They perform two important functions in the digestive tract ... 

The bile acids cholic acid and chenodeoxycholic acid are synthesized from cholesterol in the liver (Dl, S3). Several structural modifications are necessary to convert cholesterol, with its 27 carbon atoms, C-5,6 double bond and 3p-hydroxyl group, to a 24-carbon atom, saturated, 3,7 and 12a-hydroxyl-ated bile acid. The major reactions in this transformation are shown in Figs. 3 and 4. The reactions are catalyzed by mitochondrial, microsomal, soluble, and possibly peroxisomal enzymes. 

The two bile acids, cholic acid and chenodeoxycholic acid, which are synthesized from cholesterol in the liver, are termed primary bile acids. Each day, around one-third to one-quarter of the primary bile acid pool is lost or converted to secondary bile acids by anaerobic bacteria in the intestine. This is achieved by 7a-dehydroxylation, a process which converts cholic acid to deoxycholic acid (3a,12a-dihydroxy-5p-cholan-24-oic acid) and chenodeoxycholic acid into lithocholic acid (3a-hydroxy-5 -cholan-24-oic acid). 

Huijghebaert et al. [23] isolated a bile salt sulfatase-producing strain designated, Clostridium S, from rat feces. This bacterium hydrolyzed the 3-sulfates of lithocholic acid, chenodeoxycholic acid, deoxycholic acid and cholic acid but not the 7-or 12-monosulfates. Sulfatase activity required the 3-sulfate group to be in the equatorial position. A free C-24 or C-26 carboxyl group was also required for sulfatase activity in whole cells of this bacterium. The 3-sulfate of cholesterol, Cj,-and Cji-steroids were not hydrolyzed by Clostridium S, [24]. Nevertheless, C,9- and C2]-steroid sulfates are hydrolyzed in the gut by microbial activity suggesting that the intestinal microflora may contain bacteria with steroid sulfatases possessing different substrate specificities. However, it should be noted that enzyme substrate specificity studies carried out in whole cells may reflect both cell wall permeability and enzyme specificity. 

Lithocholic acid, formed through the reactions described by Mitro-poulos and Myant (c/. Fig. 5 and Section III), is by definition a primary bile acid. Lithocholic acid is predominantly a secondary bile acid formed from chenodeoxycholic acid (Chapter 11 in this volume). Lithocholic acid is transformed by rat liver into 3a,6/S-dihydroxy-5/3-cholanoic acid, chenodeoxycholic acid, and a- and /S-muricholic acids (Chapter 11 in this volume). 

Fig. 2. Possible pathways for primary bile salt synthesis in man compiled from various sources (see text). V, Cholesterol VI, cholest-5-ene-3i3,7a-diol VII, 7a-hydroxycholest-4-en-3-one VIII, 7a-hydroxy-5/S-cholestan-3-one IX, 5/3-cholestane-3a,7a-diol X, 3a,7a-dihydroxy-5/3-cholestanoic acid XI, 3a,7a-dihydroxy-5/5-cholanoic acid (chenodeoxycholic acid) XII, 7a,12a-dihydroxy-cholest-4-en-3-one XIII, 7a,12a-dihydroxy-5/3-cholestan-3-one XIV, 5 -cholestane-3a,7a,12a-triol XV, 3a,7a,12a-trihydroxy-5/5-cholestanoic acid XV, 3a,7a,12a-trihydroxy-5/3-cholanoic acid XVI, 3a,7a,12a-trihydroxy-5/3-cholanoic acid (cholic acid).

It seems to be a general observation that the proportion of chenodeoxy-cholic acid is increased in liver cirrhosis. Thus the ratio cholic acid/cheno-deoxycholic acid has been found to be decreased in the bile (23), serum (52,134,193,195-198), and urine (88,199) of cirrhotic subjects. Since the ratios of cholic acid, chenodeoxycholic acid, and deoxycholic acid appear to be approximately the same in bile and serum (200,201), and perhaps also in urine, it seems quite obvious that the bile acid pattern in any of these three sources is similar to that produced by the liver. Simultaneous determinations of bile acids from bile, serum, and urine have not been made, however. The relative increase of chenodeoxycholic acid has been interpreted to indicate a hindrance of 12a-hydroxylation in liver injury when the formation of cholic acid is decreased in favor of chenodeoxycholic acid (202). This, on the other hand, changes the pattern of secondary bile acids so that relatively more lithocholic acid is formed in the colon (191,200,202), the amount of deoxycholic acid being reduced (23,52,134,193,195-198), particularly because quantitatively only a small portion of the bile acids escapes daily from the ileum to the colon (23). 

Goncalves P, Catarino T, Gregorio 1, Martel F. Inhibition of butyrate uptake by the primary bile salt chenodeoxycholic acid in intestinal epithelial cells. / Cell Biochem. 2012 113(9) 2937—2947. 

The primary bile acids are synthesized in the liver from cholesterol. These are cholic acid (found in the largest amount) and chenodeoxycholic acid (Figure 26-7). 

FXR is activated by endogenous bile acids such as chenodeoxycholic add. Other known agonists include farnesol, GW4064 with an EC50 of 70 nM, or AGN-31 (Chart 14.5) [12]. 

The broad-spectrum antibiotic chlorotetracycline and the aminoglycoside antibiotic kanamycin are observed to lower the cholesterol levels by forming salts with bile acids (e.g.. cholic acid, deoxycholic acid and chenodeoxycholic acid) in the intestinal canal,... 

Figure 4.14 Structures of cholic and chenodeoxycholic acids which are the acids that form the bile salt The asterisk indicates the position at which an ester bond is formed with taurine or glycine so that bile salts are taurocholate, chenodeoxytaurocholate, gly-cocholate, and glycochenodeoxycholate are formed. The structure of taurine is H2NCH2CH2SO3 and glycine is H2NCH2COOH.

Figure 1.1 illustrates a condensed version of the classical pathway of bile-acid synthesis, a series of 12 enzymatic reactions that convert cholesterol, which is insoluble, into BAs, which are water soluble. The cholesterol is first converted to 7 alpha-hydroxy cholesterol, followed by the series of enzymatic transformations, eventually producing cholic and chenodeoxycholic acids (not all steps shown). The rate-limiting enzyme in this pathway is cholesterol 7 alpha-hydroxylase (CYP 7A1), which originates from microsomal cytochrome P-450 enzymes, expressed only in the liver hepatocytes. 

Abbreviations used for bile acids in Tables 3.1-3.6 DOC (deoxycholate), LC (lithocholate), CDOC (chenodeoxycholate), C (cholate), GDOC (glycodeoxycholate), TDOC (taurodeoxy-cholate), GCDOC (glycochenodeoxycholate), TCDOC (taurochenodeoxycholate), GC (gly-cocholate), TC (taurocholate). 

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