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Updated: 03/13/08 01:44 PM |
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| HOME | HEAL | EDUCATE | RESEARCH | DIRECTORY | OUTREACH |
Authors: W. Volwiler, R.A. Willson, A.M. Larson, and J.D. Ostrow
Download Chapter ♦ Download Lecture Slides & Notes
Download Chapter ♦ Download Lecture Slides & Notes
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H. Bile Salt Metabolism and Turnover (Figure 12)
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| The hepatocyte synthesizes and secretes primary bile salt conjugates that are reabsorbed in the ileum and returned to the liver (EHC) |
The two primary bile salts, cholic acid and chenodeoxycholic acid, are synthesized in the hepatocyte from cholesterol. They are conjugated with the amino acids glycine or taurine prior to their secretion into bile. Primary bile salt conjugates are poorly reabsorbed in the small intestine proximal to the distal ileum, but are actively reabsorbed by the ileal bile salt transporter (IBAT) and recirculated to the liver via the portal venous system (enterohepatic circulation [EHC]).
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Anerobic ileocolonic bacteria deconjugate and dehydroxylate primary bile salts to form toxic secondary bile salts
Lithocholate poorly absorbed from colon |
The bile salts that are not absorbed pass to the distal ileum and colon, where anerobic bacteria enzymatically deconjugate and then remove the 7α-hydroxy group from the primary bile salts, yielding two more hydrophobic and toxic secondary bile salts, which also undergo EHC. One of these (deoxycholate, formed from cholate) is readily absorbed from the colon and re-excreted in a conjugated form by the liver. The other secondary bile salt (lithocholate, formed from chenodeoxycholate) is poorly absorbed; the small fraction absorbed is efficiently conjugated and sulphated by the human liver and then excreted in bile and lost from the body in the feces.
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Figure 12 Hepatic Metabolism and Entero-Hepatic Cycling of Bile Salts The hapatocyte is the only cell in which bile salts are synthesized. Two multistep pathways mediate ring hydroxylation and sidechain oxidation of cholesterol. After conjugation, the bile salts are actively secreted into bile by the cnalicular bile salt export pump (BSEP). In the small bowel, some passive absorption of bile salts occurs but 85-90% are removed by active absorption in the distal ileum, mediated by the ABC protein, IBAT (Intestinal Bile Acid Transporter). The remaining 10-15% of bile salts that reach the colon is in large part deconjugated and dehydroxylated by anerobic colonic bacteria; the resulting unconjugated bile acids can be passively absorbed. These processes result in absorption into the portal circulation of 95% of the bile salts secreted into the bile, sothat only 5% appear in the stool. In the steady state, this fecal excretion (0.4-1.2 mmol/day) balances hepatic synthesis of bile salts, but the vast majority of the bile salts fluxing through the liver and back into the bile (24-60 mmol/day) come from the intestine (entero-hepatic circulation, EHC). This EHC occurs principally during the 1-4 cycles that occur two hours after each meal, following emptying into the duodenum of the average 6 mmol pool of bile salts stored in the gallbladder between meals. The highly efficient (>95%) uptake of the recycled bile salts by the haptocytes allwos only a small fraction to enter the systemic circulation, where it is mostly bound to plasma proteins. Thus, the bile salt concentrations in systemic plasma are normally less than 10 μM and less than 0.001 mmol/day appears in the urine. Modified from Undergraduate Teaching Project ©American Gastroenterological Assn., Unit 27, slide 54, produced by Milner-Fenwick, Timonium, MD. Reproduced with Permission. |
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95% of secreted bile salts undergo enterohepatic circulation (EHC)
Hepatic synthesis = fecal loss |
Normally, more than 90% of the secreted bile salts are reabsorbed by the small intestine. Most of this intestinal reabsorption occurs in the distal ileum, mediated by the ATP-dependent intestinal bile acid transporter (IBAT) in the apical membrane of the ileal enterocytes. This permits an efficient enterohepatic recirculation of bile salts that are recycled (especially following meals) about 6 to 10 times daily. The normal total body pool of bile salts (approximately 6 millimoles, mainly in the EHC), is maintained because the rate of hepatic synthesis balances the daily fecal loss of 0.4-1.2 millimoles.
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| Regulation of bile salt synthesis |
Regulation of the hepatic synthesis of bile salts is determined by a) health of the hepatocytes, b) supply of precursor cholesterol, c) amount of the enterohepatic return of bile salts (feedback inhibition by dihydroxy bile salts), and d) genetic factors poorly understood.
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| Hepatic synthesis of bile salts can increase only 4-5X |
The hepatic capacity to synthesize bile salts is limited. If the EHC of bile salts decreases, hepatic synthesis can increase only to 4-5X above its normal synthetic rate (from 3-5% to 20-25% of total secreted bile salts). Therefore, if interruption of the EHC increases the fecal loss of bile salts more than 4-5X, the hepatic secretion of bile salts and the enterohepatic pool of bile salts must fall. With lesser interruption of the EHC, the increased synthesis compensates for the increased loss, and the bile salt pool is maintained.
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Next Section (I): Bilirubin Metabolism and Jaundice » |
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