Bile acid
The rate-limiting step in synthesis is the addition of a hydroxyl group of the 7th position of the steroid nucleus by the enzyme cholesterol 7 alpha-hydroxylase.
This enzyme is down-regulated by cholic acid, up-regulated by cholesterol and is inhibited by the actions of the ileal hormone FGF15/19.
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 fulfil their physiologic function of emulsifying fats.
[2][3] As molecules with hydrophobic and hydrophilic regions, conjugated bile salts sit at the lipid/water interface and, above the right concentration, form micelles.
[9] The added solubility of conjugated bile salts aids in their function by preventing passive re-absorption in the small intestine.
As a result, the concentration of bile acids/salts in the small intestine is high enough to form micelles and solubilize lipids.
[9] Bile acid-containing micelles aid lipases to digest lipids and bring them near the intestinal brush border membrane, which results in fat absorption.
About 95% of bile acids are reabsorbed by active transport in the ileum and recycled back to the liver for further secretion into the biliary system and gallbladder.
This enterohepatic circulation of bile acids allows a low rate of synthesis, only about 0.3 g/day, but with large amounts being secreted into the intestine.
[5] Bile acids have other functions, including eliminating cholesterol from the body, driving the flow of bile to eliminate certain catabolites (including bilirubin), emulsifying fat-soluble vitamins to enable their absorption, and aiding in motility and the reduction of the bacteria flora found in the small intestine and biliary tract.
[7][10] They bind less specifically to some other receptors and have been reported to regulate the activity of certain enzymes [11] and ion channels [12] and the synthesis of diverse substances including endogenous fatty acid ethanolamides.
[1] The initial step in the classical pathway of hepatic synthesis of bile acids is the enzymatic addition of a 7α hydroxyl group by cholesterol 7α-hydroxylase (CYP7A1) forming 7α-hydroxycholesterol.
[3] These result in the junction between the first two steroid rings (A and B) being altered, making the molecule bent; in this process, the 3-hydroxyl is converted to the α orientation.
[2][3] Different vertebrate families have evolved to use modifications of most positions on the steroid nucleus and side-chain of the bile acid structure.
The subsequent removal of the 7α hydroxyl group by intestinal bacteria will then result in a less toxic but still-functional dihydroxy bile acid.
Primates (including humans) utilize 12α for their third hydroxyl group position, producing cholic acid.
[7][19] As surfactants or detergents, bile acids are potentially toxic to cells, and so their concentrations are tightly regulated.
Among these protein targets, the enzyme N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) generates bioactive lipid amides (e.g. the endogenous cannabinoid anandamide) that play important roles in several physiological pathways including stress and pain responses, appetite, and lifespan.
NAPE-PLD orchestrates a direct cross-talk between lipid amide signals and bile acid physiology.
[23] Structural or functional abnormalities of the biliary system result in an increase in bilirubin (jaundice) and in bile acids in the blood.
It is commonly found when the ileum is abnormal or has been surgically removed, as in Crohn's disease, or cause a condition that resembles diarrhea-predominant irritable bowel syndrome (IBS-D).
[32] Deoxycholic acid (DCA) is increased in the colonic contents of humans in response to a high fat diet.
[40][41] The effects of ursodeoxycholic acid (UDCA) in modifying the risk of colorectal cancer has been looked at in several studies, particularly in primary sclerosing cholangitis and inflammatory bowel disease, with varying results partly related to dosage.
[42][43] Genetic variation in the key bile acid synthesis enzyme, CYP7A1, influenced the effectiveness of UDCA in colorectal adenoma prevention in a large trial.
[45] Phase III trials showed significant responses although many subjects had mild adverse reactions of bruising, swelling, pain, numbness, erythema, and firmness around the treated area.
