Bile Acids - Production and Distribution

Production and Distribution

In humans, bile acid synthesis begins when liver cells synthesize the two primary bile acids, cholic acid and chenodeoxycholic acid,:357-358 via the cytochrome P450-mediated oxidation of cholesterol. Approximately 600 mg of bile salts are synthesized daily to replace bile acids lost in the feces.:359 In humans, the rate-limiting step is the addition of a hydroxyl group on position 7 of the steroid nucleus by the enzyme cholesterol 7 alpha-hydroxylase. This enzyme is down-regulated by cholic acid and up-regulated by cholesterol.

When these two bile acids are secreted into the lumen of the intestine, intestinal bacteria dehydroxylate a portion of each of them to form the secondary bile acids, deoxycholic acid and lithocholic acid.:358 (Cholic acid becomes deoxycholic acid. Chenodeoxycholic acid becomes lithocholic acid.) All four of these bile acids can be taken back up into the blood stream, return to the liver, and be re-secreted in a process known as enterohepatic circulation.

Prior to secreting any of the four bile acids, the liver cells may also conjugate them with one of two amino acids, glycine or taurine, to form a total of 8 possible conjugated bile acids.:358 These conjugated bile acids are usually referred to as bile salts:358 because of their physiologically-important acid-base properties. The pKa of each of the unconjugated bile acids is 7, and the pH of the duodenum ranges between 3 and 5,:358 so when unconjugated bile acids are in the duodenum, they are almost always protonated (HA form), which makes them relatively insoluble in water. Conjugating bile acids with amino acids lowers the pKa of the bile-acid/amino-acid conjugate to between 1 and 4.:358 Thus conjugated bile acids are almost always in their deprotonated (A-) form in the duodenum, which makes them much more water soluble and much more able to fulfill their physiologic function of emulsifying fats.

One way this added solubility aids in bile salt function is by preventing passive re-absorption once secreted into the small intestine. As a result, the concentration of bile acids/salts in the small intestine can stay high enough to form micelles and solubilize lipids. "Critical micellar concentration" refers to both an intrinsic property of the bile acid itself and amount of bile acid necessary to function in the spontaneous and dynamic formation of micelles.

Bile acids also serve other functions, including eliminating cholesterol from the body, driving the flow of bile to eliminate catabolites from the liver, emulsifying lipids and fat-soluble vitamins in the intestine to form micelles that can be transported via the lacteal system, and aiding in the reduction of the bacteria flora found in the small intestine and biliary tract.

Synthesis of bile acids is a major route of cholesterol metabolism in most species other than humans. The body produces about 800 mg of cholesterol per day and about half of that is used for bile acid synthesis. In total about 20-30 grams of bile acids are secreted into the intestine daily. About 90% of excreted bile acids are reabsorbed by active transport in the ileum and recycled in what is referred to as the enterohepatic circulation, which moves the bile salts from the intestinal system back to the liver and the gallbladder. This allows a low rate of daily synthesis, but high secretion to the digestive system.