Bile acids, secondary lithocholic acid

Although products of fat digestion, including cholesterol, are absorbed in the first 100 cm of small intestine, the primary and secondary bile acids are absorbed almost exclusively in the ileum, and 98—99% are returned to the liver via the portal circulation. This is known as the enterohepatic circulation (Figure 26—6). However, lithocholic acid, because of its insolubility, is not reabsorbed to any significant extent. Only a small fraction of the bile salts escapes absorption and is therefore eliminated in the feces. Nonetheless, this represents a major pathway for the elimination of cholesterol. Each day the small pool of bile acids (about 3-5 g) is cycled through the intestine six to ten times and an amount of bile acid equivalent to that lost in the feces is synthesized from cholesterol, so that a pool of bile acids of constant size is maintained. This is accomplished by a system of feedback controls. 

Bile acids within the enterohepatic circulation that undergo absorption in the terminal ileum encounter a relatively low number of species and population of bacteria and return to the liver in portal blood relatively unchanged. However, the approximately 5% of the bile-acid pool that enters the colon provides substrate for the extensive microbial population that deconjugate and oxidise hydroxyl groups leading to formation of the secondary bile acids deoxycholic and lithocholic acids that are the major bile acids in faeces. 

Figure 5.2 Therapeutic interventions for decreasing colorectal mucosal bile acid exposure as a CRC chemoprevention strategy. 1) Lifestyle modifications including reduction in dietary animal fat and increased fibre intake may, at least partly, be explained by reduction in luminal primary (cholic acid [CA] and chenodeoxycholic acid [CDCA]) and secondary (deoxycholic acid [DCA] and lithocholic acid [LCA]) bile acids. 2) Reduction of secondary bile acids, which are believed to have pro-carcinogenic activity could be obtained by decreased bacterial conversion from primary bile acids. 3) Alternatively, bile acids could be sequestered by chemical binding agents, e.g. aluminium hydroxide (Al(OH)3) or probiotic bacteria. 4) Exogenous ursodeoxycholic acid (UDCA) can reduce the luminal proportion of secondary bile acids and also has direct anti-neoplastic activity on colonocytes in vitro.

P. K. Baijal, D. W. Fitzpatrick and R. P. Bird, Comparative effects of secondary bile acids, deoxycholic and lithocholic acids, on aberrant crypt foci growth in the postinitiation phases of colon carcinogenesis, Nutr. Cancer, 1998, 31, 81. 

A and B are in cis position relative to each other (see p. 54). One to three hydroxyl groups (in a position) are found in the steroid core at positions 3, 7, and 12. Bile acids keep bile cholesterol in a soluble state as micelles and promote the digestion of lipids in the intestine (see p.270). Cholic add and cheno-deoxychoMc acid are primary bile acids that are formed by the liver. Their dehydroxylation at C-7 by microorganisms from the intestinal flora gives rise to the secondary bile acids lithocholic acid and deoxycholic acid. 

Bacteria in the intestine can remove glycine and taurine from bile salts, regenerating bile acids. They can also convert some of the primary bile acids into "secondary" bile acids by removing a hydroxyl group, producing deoxycholic acid from cholic acid and lithocholic acid from chenodeoxycholic acid (Figure 18.11). 

Some dietary factors can also change the bile acid species and, by doing so, alter cholesterol absorption. The liver synthesizes the primary bile acids, cholic and chenodeoxycholic acid. Bacteria in the intestine can convert some of the primary bile acids into secondary bile acids, producing deoxycholic from cholic acid and lithocholic from chenodeoxycholic acid. When certain dietary components alter the intestinal microflora, the rate of secondary bile... 

Bile acids are steroids, characterised by a carbon skeleton with four fused rings, generally arranged in a 6-6-6-S fashion. Primary bile acids are cholic acid and chenodeoxycholic acid (Figure 6.2). Within the intestines, bacteria convert primary bile acids to secondary bile acids, for example deoxycholate (from cholate) and lithocholate (from chenodeoxycholate). Both primary and secondary bile acids are re-absorbed by the intestines and delivered back to the liver via the portal circulation. 

The secondary bile acids result from the activity of anaerobic intestinal microorganisms in the ileum, caecum and colon, (s. fig. 3.3) Deconjugation, with the subsequent release of free bile acids, is a prerequisite for these reactions. This is followed by 7a-dehydroxylation of cholic acid and chenodeoxycholic acid to yield deoxy-cholic acid and lithocholic acid, respectively. 7a-de-hydrogenation and oxidation of chenodeoxycholic acid also yield ketolithocholic acid ... 

There are four major bile acids (see Figures 47-5 to 47-7). Cholic acid and chenodeoxycholic acid, the primary bile acids, are synthesized in the liver. Bacteria metabolize these primary bile acids to the secondary bile acids—deoxy-cholic acid and lithocholic acid, respectively. Bile acids are conjugated in the liver with the amino acids glycine or taurine. This decreases passive absorption in the biliary tree and proximal small intestine, but permits conservation through active transport in the terminal ileum. This combi-... 

The bile acid pool normally consists of about 2-4 g of conjugated and unconjugated primary and secondary bile acids. Daily loss of bile acids in feces, mostly as lithocholate, is about 0.2-0.4 g. Hepatic synthesis of bile acids equals this amount, so that the size of the bile acid pool is maintained at a constant level. 

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). 

Expression of IBABP and ASBT is regulated by the famesoid X receptor (FXR), a nuclear orphan receptor (246, 247). A specific binding site for F3 was found on the promotor region of the IBABP gene, named bile acid response element (BARE) (248). The response was greatest in the presence of chenodeoxy-cholic acid (CDCA), whereas cholic acid was much less effective and the secondary bile acids deoxycholic and lithocholic acid had variable responses. 

Quantitatively, the most important bile acid microbial transformation of cholic and chenodeoxycholic acid is the 7a-dehydroxylation yielding the secondary bile acids deoxycholic acid and lithocholic acid, respectively. The 7 -dehydroxylation alters markedly the physical properties and physiological effects of the bile acid molecule. There is a decrease in the solubility of secondary bile acids in aqueous solutions and an alteration of the critical micellar concentration (Chapter 13). 

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). 

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