Notes of Chemistry BSC & MSC Bile Acids Synthesis and Utilization

Bile Acids Synthesis and Utilization

The end products of cholesterol utilization are the bile acids, synthesized in the liver. Synthesis of bile acids is one of the predominant mechanisms for the excretion of excess cholesterol. However, the excretion of cholesterol in the form of bile acids is insufficient to compensate for an excess dietary intake of cholesterol.

Synthesis of the 2 primary bile acids, cholic acid and chenodeoxycholic acid. The reaction catalyzed by the 7α-hydroxylase is the rate limiting step in bile acid synthesis. Conversion of 7α-hydroxycholesterol to the bile acids requires several steps not shown in detail in this image. Only the relevant co-factors needed for the synthesis steps are shown

The most abundant bile acids in human bile are chenodeoxycholic acid (45%) and cholic acid (31%). These are referred to as the primary bile acids. Within the intestines the primary bile acids are acted upon by bacteria and converted to the secondary bile acids, identified as deoxycholate (from cholate) and lithocholate (from chenodeoxycholate). Both primary and secondary bile acids are reabsorbed by the intestines and delivered back to the liver via the portal circulation.

Within the liver the carboxyl group of primary and secondary bile acids is conjugated via an amide bond to either glycine or taurine before their being re-secreted into the bile canaliculi. These conjugation reactions yield glycoconjugates and tauroconjugates, respectively. The bile canaliculi join with the bile ductules, which then form the bile ducts. Bile acids are carried from the liver through these ducts to the gallbladder, where they are stored for future use. The ultimate fate of bile acids is secretion into the intestine, where they aid in the emulsification of dietary lipids. In the gut the glycine and taurine residues are removed and the bile acids are either excreted (only a small percentage) or reabsorbed by the gut and returned to the liver. This process of secretion from the liver to the gallbladder, to the intestines and finally re-absorbtion is termed the enterohepatic circulation.

Regulation

As surfactants or detergents, bile acids are potentially toxic to cells and their levels are tightly regulated. They function directly as signaling molecules in the liver and the intestines by activating a nuclear hormone receptor known as FXR also known by its gene name . This results in inhibition of bile acid synthesis in the liver when bile acid levels are too high. Emerging evidence associates FXR activation with alterations in triglyceride metabolism, glucose metabolism and liver growth.

Clinical significance

Since bile acids are made from endogenous cholesterol, the enterohepatic circulation of bile acids may be disrupted as a way to lower cholesterol. This is the mechanism of action behind bile acid sequestrants. Bile acid sequestrants bind bile acids in the gut, preventing their reabsorption. The sequestered bile acids are then excreted in the feces.

Cholesterol Is Necessary for Digestion — Cholesterol Is a Precursor to Bile Acids

The human body uses cholesterol to synthesize bile acids, which are important for the digestion of fats. The primary bile acid, cholic acid, is very similar in structure to cholesterol. Cholic acid is missing the double bond in the second ring, has two more hydroxyl (OH) groups attached to the steroid ring structure, and has a shortened hydrocarbon tail, the ending of which has been converted to a carboxyl (COOH) group.

 

 

Bile Acids Are Emulsifying Agents

Bile acids are amphipathic. This means that they have both water-soluble and water-insoluble (or fat-soluble) parts. Emulsifying agents are amphipathic molecules that are able to mix fats with water. For example, eggs contain an amphipathic substance called lecithin that makes them useful as emulsifying agents in baking.
In order for the human digestive system to digest fats, they must be emulsified into the digestive juices, because the enzymes that break them down are water-soluble.
In bile acids, the hydroxyl (OH) groups are water-soluble, and the methyl (CH₃) groups are fat-soluble. The hydroxyl groups all face one direction — for example, toward you from the picture above — while the methyl groups face the opposite direction — for example, away from you from the picture above — making one side of the bile acid water-soluble and the other side fat-soluble.
This characteristic allows bile salts to break up large globs of fat, connecting to the fat on one side, and connecting to the water on the other, thus mixing the fats and water together.

Synthesis and Storage of Bile Acids

Bile acids are synthesized from cholesterol in the liver. First, hydroxyl (OH) groups are inserted at several points, shown in the above picture; second, the second ring of cholesterol loses its double-bond; finally, the hydrocarbon tail is shortened by three carbons, and a carboxyl group is added to the end.
The bile salt shown above is called cholic acid, which contains three hydroxyl groups. The other primary bile acid is called chenodeoxycholic acid, which contains only two hydroxyl groups. These are the "primary" bile acids, although there are other "secondary" bile acids synthesized from primary bile acids by intestinal bacteria as well.
Bile acid synthesis is up-regulated by cholesterol and down-regulated by cholic acid. This means that the higher the cholesterol to cholic acid ratio is, the faster bile acids will be produced. As bile acids are produced, and the concentration of cholesterol lowers and the concentration of cholic acid rises, bile acid synthesis slows down.

Bile Acids are Precursors to Bile Salts

Before bile acids leave the liver, they are converted to bile salts. This involves the replacement of the hydrogen on the end of the carboxyl group with either the amino acid glycine or the amino acid taurine. There are four primary bile salts formed from this reaction:

• Glycine + Cholic Acid --> Glycocholic Acid
• Glycine + Chenodeoxycholic Acid --> Glycochenodeoxycholic Acid
• Taurine + Cholic Acid --> Taurocholic Acid
• Taurine + Chenodeoxycholic Acid --> Taurochenodeoxycholic Acid

At the pH (a measure of acidity determined by the concentration of hydrogen ions in a solution) normally present in intestinal digestive juices, the glycine and taurine completely separate from the bile acids within the bile salts. On the other hand, bile acids alone, if not converted to bile salts, will contain a hydrogen ion that tends to stick to the carboxyl group.
Since the carboxyl group is more water-soluble when the hydrogen ion or amino acid is separated from it, bile salts, which have amino acids that completely separate from the carboxyl group, are more water-soluble than bile acids, which have a hydrogen ion that likes to stick to the carboxyl group.
This makes bile salts more effective than bile acids at mixing fats with water. Thus, bile salts are more effective at mixing fats with the water-soluble enzymes that digest them.
Glycine forms of bile salts outnumber taurine forms of bile salts by 3 to 1. After bile salts are produced in the liver, they either flow through the bile duct into the duodenum, which is the first of three sections of the small intestine, to be used immediately for digestion, or they are stored in the gall bladder, where they are saved for future digestive requirements.

Circulation of Bile Salts

Bile salts are produced in the liver, and secreted through the bile duct into the duodenum, the first section of the small intestine. 95% of bile salts are reabsorbed through the ileum, the third and final part of the small intestine, where they travel through the blood, attached to a blood protein called "albumin," back to the liver. This circulation is called enterohepatic circulation.
About 15 to 30 grams of bile salts are circulated through this sequence each day, while about 0.5 grams are lost in the feces and about 0.5 grams are synthesized anew by the liver.