|
Updated: 03/13/08 12:05 PM |
|
 |
| HOME | HEAL | EDUCATE | RESEARCH | DIRECTORY | OUTREACH |
Authors: D.R. Saunders, C.E. Rubin, and J.D. Ostrow
Download Chapter ♦ Download Lecture Slides & Notes
Download Chapter ♦ Download Lecture Slides & Notes
|
I. Normal Bile Salt Absorption
|
||
| Bile salts may circulate 2-3 times during a meal. |
Bile salts are synthesized in the liver from cholesterol and are its catabolic end product. Bile salts are conjugated with taurine or glycine before excretion in the bile. A conjugated bile salt is a flat molecule, one side of which is water soluble and the other nonpolar or hydrophobic; they tend to accumulate at oil-water interfaces and stabilize them. Conjugated bile salts are detergents which are critical in maintaining the efficiency of fat absorption to >95%..
|
|
| Micelle = a multimolecular aggregate |
Above a critical concentration, bile salts form micelles, which are associations of amphipaths (water-loving and lipid-loving domains), whose aggregate size (<100 Ao) in water yields a solution which is optically clear. A micelle is not a fixed structure; molecules exchange rapidly in and out of the aggregate from and to the surrounding aqueous phase.
|
|
|
CCK release causes emptying of bile from gallbladder into duodenum.
Ileal Na+- bile salt transporter Entero-hepatic circulation of bile salts |
Between meals, bile salts flow in the bile mostly from the liver to the gallbladder where they are stored and concentrated by removal of water and sodium chloride. In response to food the duodenal mucosa releases the hormone CCK which contracts the gallbladder, opens the Sphincter of Oddi, and thus delivers the conjugated bile salts via the common duct to the intestinal lumen. There, mixed micelles are formed, consisting of conjugated bile salts, monoglycerides and fatty acids. After the fatty acids and monoglycerides have been absorbed, the bile salts are absorbed along the whole length of the small bowel, but mainly in the ileum. There, over 75% are absorbed actively by the ATP-dependent ileal bile acid transporter (IBAT).
Approximately 5% of the circulating bile salts are normally excreted in the feces. The bile salts absorbed from the intestine recycle through the portal vein to the liver and back again into the small bowel lumen. This recycling of bile salts through the enterohepatic circulation may occur several times during the digestion and absorption of a large fat meal. Under normal conditions, the amount of new bile salts synthesized from cholesterol in the liver daily just equals fecal losses. The body's bile salt pool is so small (approximately 3g, 6 mmoles) that the integrity of the enterohepatic circulation is essential to maintain an adequate concentration of conjugated bile salts within the intestinal lumen to assure micelle formation. A normal ileum is essential for maintenance of an adequate enterohepatic circulation. |
|
Figure 8 Hepatic Metabolism and Entero-Hepatic Cycling of Bile Salts The hepatocyte is the only cell in which bile salts are synthesized by several multistep pathways, involving ring hydroxylation and sidechain oxidation of cholesterol. After conjugation, the bile salts are actively secreted into bile by the canalicular 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 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, so that 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 hepatocytes allows 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. |
||
| Lithocholate is poorly absorbed |
The bile salts that are unabsorbed in the small intestine pass into the colon where anaerobic bacteria deconjugate and 7-a-dehydroxylate conjugated cholic acid to deoxycholate, and conjugated chenodeoxycholate to lithocholate. Deoxycholate is absorbed readily from the colon and is re-excreted by the liver after being conjugated.
|
|
|
Colonic bacteria form secondary bile salts |
Therefore, there are two primary (synthesized by the liver) bile acids, and one secondary (synthesized by bacteria) bile acid which are conjugated in the liver with either of two amino acids: taurine or glycine to yield six conjugated bile acids in the proximal duodenum. These salts are absorbed by three mechanisms: passive ionic diffusion, passive nonionic diffusion, and active absorption. Passive ionic diffusion is the slowest; whereas, passive nonionic diffusion and active transport are five times as fast. Normally, only taurine and glycine bile salt conjugates are present in the proximal small bowel and their pKa values are low enough (1.5 and 3.5) that these substances are almost completely ionized and therefore absorbed slowly and inefficiently. In the ileum deconjugation by luminal bacteria yields some bile salts of a pKa near the luminal pH and thus unconjugated bile salts are present in both ionic and nonionic forms. In the ileum, bile salts are absorbed by the two passive mechanisms as well as by IBAT which absorbs conjugated and deconjugated bile salts with equal facility.
|
|
Figure 9 Unconjugated and conjugated bile salts and their pKa values |
||
|
Next Section (J): Bile Salt Malabsorption » |
||