Bile Acids and Metabolic Regulation
For biliary lipid secretion and hepatic cholesterol and bile acid metabolism .. relationships between the roles of ABC1 and SR-BI in intestinal cholesterol. Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Synthesis of bile acids is a major route of cholesterol metabolism in most species other than humans. . The relationship of bile acids to cholesterol saturation in bile and cholesterol precipitation to produce gallstones has been. The metabolism of cholesterol and bile acids is tightly controlled but only partially characterized. The liver is responsible for most of the clearance and.
The structure is commonly drawn with A at the left and D at the right.
The hydroxyl groups can be in either of two configurations: All bile acids have a 3-hydroxyl group, derived from the parent molecule, cholesterol, in which the 3-hydroxyl is beta. The four rings A-D form a sterane core.
Bile acid - Wikipedia
There are multiple steps in bile acid synthesis requiring 14 enzymes in all. This bile acid was first isolated from the domestic goose, from which the " cheno " portion of the name was derived. The term "cholan" denotes a particular steroid structure of 24 carbons, and the "oic acid" indicates that the carboxylic acid is found at position 24, at the end of the side-chain.
Chenodeoxycholic acid is made by many species, and is the prototypic functional bile acid. CYP27A1 contributes significantly to total bile acid synthesis by catalyzing sterol side chain oxidation, after which cleavage of a three-carbon unit in the peroxisomes leads to formation of a C24 bile acid.
Minor pathways initiated by hydroxylase in the liver and hydroxylase in the brain also may contribute to bile acid synthesis. This review examines recent data exploring possible mechanisms involved in regulation of glucose metabolism by bile acids and the potential impact of disruption of their enterohepatic circulation on diabetes. We will also summarize the available clinical trial data that supported the regulatory approval of colesevelam for the treatment of hyperglycemia in type 2 diabetes.
The synthesis of bile acids occurs exclusively in the liver in a series of enzymatic reactions in the hepatocyte that convert hydrophobic cholesterol into more water-soluble amphiphatic compounds 2. The production of bile acids is localized primarily in the perivenous hepatocytes, that is, the cells surrounding the central hepatic vein The immediate products of the bile acid synthetic pathways are referred to as primary bile acids.
Cholic acid and chenodeoxycholic acid are the primary bile acids formed in humans.
Regulation and interaction of cholesterol, bile salt and lipoprotein synthesis in liver.
The action of intestinal bacterial flora on primary bile acids results in the formation of secondary bile acid species: The activity of CYP7A1 is subject to complex modes of control. The conversion of cholesterol to bile acids is primarily determined by this pathway 2. The subsequent conversion of bile acid intermediates from either the classical or alternative pathways to cholic acid or chenodeoxycholic acid is governed by CYP8B1; interaction of these intermediates with this enzyme determines the amount of cholic acid versus chenodeoxycholic acid formed.
Hydroxylation via CYP8B1 results in the formation of the more hydrophilic cholic acid molecule.
Regulation of Bile Acid and Cholesterol Metabolism by PPARs
Before their secretion into the bile canalicular lumen for storage in the gallbladder as mixed micelles with phospholipids and cholesterol, primary bile acids are conjugated with taurine or glycine, further enhancing their hydrophilicity 2.
Upon ingestion of a meal, gallbladder contraction releases micellar bile acids into the intestinal lumen to aid digestion. Interestingly, the perivenous hepatocytes, which account for the production of bile acids, are not involved in the reuptake of bile acids; bile acids are taken up and transported primarily by pericentral hepatocytes that surround the portal triads, where portal blood enters the liver acinus The zonation differences accounting for where bile acids are produced and reenter the liver are relatively unexplored; thus, the patho physiological relevance of these observations is unknown at this time 2.
This small amount of loss is replenished via de novo synthesis of bile acids in the liver 12. The size of the bile acid pool is tightly regulated within the liver and intestine to prevent cytotoxic accumulation of bile acids 2.
As the bile acid pool size increases, a feedback mechanism, governed by the interplay of several nuclear receptors, is activated to inhibit de novo bile acid synthesis.
Inbile acids were identified as the natural ligands for the farnesoid X receptor FXR.