1. Bile Acids and Bile Salts

2. Bile consists of a watery mixture of organic and inorganic compounds
Bile consists of a watery mixture of organic and inorganic compounds. Phosphatidylcholine and bile salts (conjugated bile acids) are quantitatively the most important organic components of bile.
Bile can either pass directly from the liver where it is synthesized into the duodenum through the common bile duct, or be stored in the gallbladder when not immediately needed for digestion.

3. Structure of the bile acids
The bile acids contain 24 carbons, with two or three hydroxyl groups and a side chain that terminates in a carboxyl group.
The carboxyl group has a pKa of about six and, therefore, is not fully ionized at physiologic pH—hence, the term “bile acid.”
The bile acids are amphipathic.
Therefore, the molecules have both a polar and a nonpolar face, and can act as emulsifying agents in the intestine, helping prepare dietary triacylglycerol and other complex lipids for degradation by pancreatic digestive enzymes

4. Synthesis of bile acids
Bile acids are synthesized in the liver by a multistep, multiorganelle pathway in which hydroxyl groups are inserted at specific positions on the steroid structure, the double bond of the cholesterol B ring is reduced, and the hydrocarbon chain is shortened by three carbons, introducing a carboxyl group at the end of the chain.
The most common resulting compounds, cholic acid (a triol) and chenodeoxycholic acid (a diol, are called “primary” bile acids.

5. Regulation of bile acid synthesis
The rate-limiting step in bile acid synthesis is the introduction of a hydroxyl group at carbon 7 of the steroid nucleus by cholesterol-7-α-hydroxylase, an ER-associated cytochrome P450 (CYP) enzyme found only in liver.
The enzyme is down-regulated by cholic acid and up-regulated by cholesterol.

6. Synthesis of bile salts
Before the bile acids leave the liver, they are conjugated to a molecule of either glycine or taurine (an endproduct of cysteine metabolism) by an amide bond between the carboxyl group of the bile acid and the amino group of the added compound.
These new structures are called bile salts and include glycocholic and glycochenodeoxycholic acids, and taurocholic and taurochenodeoxycholic acids

7. The ratio of glycine to taurine forms in the bile is approximately 3:1.
Addition of glycine or taurine results in the presence of a carboxyl group with a lower pKa(from glycine) or a sulfonate group (from taurine), both of which are fully ionized (negatively charged) at physiologic pH.
Bile salts are more effective detergents than bile acids because of their enhanced amphipathic nature.
Bile salts provide the only significant mechanism for cholesterol excretion, both as a metabolic product of cholesterol and as a solubilizer of cholesterol in bile.

8. Action of intestinal flora on bile salts
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.

9. Enterohepatic circulation
Bile salts secreted into the intestine are efficiently reabsorbed (greater than 95%) and reused.
The mixture of primary and secondary bile acids and bile salts is absorbed primarily in the ileum.
They are actively transported from the intestinal mucosal cells into the portal blood, and are efficiently removed by the liver parenchymal cells.

10. Enterohepatic circulation
Bile acids are hydrophobic and require a carrier in the portal blood.
Albumin carries them in a noncovalent complex, just as it transports fatty acids in blood .
The liver converts both primary and secondary bile acids into bile salts by conjugation with glycine or taurine, and secretes them into the bile.
The continuous process of secretion of bile salts into the bile, their passage through the duodenum where some are converted to bile acids, and their subsequent return to the liver as a mixture of bile acids and salts is termed the enterohepatic circulation .

11. Bile salt deficiency: cholelithiasis
The movement of cholesterol from the liver into the bile must be accompanied by the simultaneous secretion of phospholipid and bile salts.
If this dual process is disrupted and more cholesterol enters the bile than can be solubilized by the bile salts and lecithin present, the cholesterol may precipitate in the gallbladder, initiating the occurrence of cholesterol gallstone disease—cholelithiasis .

12. Causes of cholelithiasis
Gross malabsorption of bile acids from the intestine, as seen in patients with severe ileal disease
Obstruction of the biliary tract, interrupting the enterohepatic circulation
Severe hepatic dysfunction, leading to decreased synthesis of bile salts, or other abnormalities in bile production
Excessive feedback suppression of bile acid synthesis as a result of an accelerated rate of recycling of bile acids.
Cholelithiasis also may result from increased biliary cholesterol excretion, as seen with the use of fibrates. [Fibrates, such as gemfibrozil,3 are used to reduce triacylglycerol levels in blood].