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Physiology, Bile Acids
Introduction
Bile acids are steroidal acids found in bile. Primary bile acids are steroids produced via the liver, specifically in peroxisomes.[1][2][3] There, the acids conjugate/connect to hydrophilic amino acids, namely glycine/taurine (i.e., conjugated bile acids called glycocholic and taurocholic acids, respectively); alongside sodium/potassium, they are termed bile salts.[4][5] Secondary bile acids, however, are made via colonic bacteria. Of the organic compounds found in bile, bile acids constitute the large majority.[6][7] Right after being synthesized, bile acids are secreted into bile and concentrated for storage in the gallbladder. Eating then stimulates cholecystokinin release, which causes gallbladder contraction--releasing its bile acids into the duodenum through the sphincter of Oddi.[8][9] The more bile acid that gets secreted, the faster that bile flows. The primary purpose of bile acids is to facilitate the digestion of fat via its surfactant properties, which emulsify fats into micelles.[10] Hormonally, bile acids are also ligands for the farnesoid X receptor (FXR) and GPBAR1 (TGR5).[11] In sum, the three main functions of bile acids are to (1) emulsify fat, (2) excrete cholesterol, and (3) have an antimicrobial effect.[1]
Function
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Function
Bile acids get conjugated in the liver to increase their water solubility because bile salts have a decreased pK, which favors the basic anionic form in the acidic duodenum. As amphiphiles, conjugated bile salts have a hydrophobic and hydrophilic side that, hence, their function as surfactants. The hydrophobic portion faces lipids, the hydrophilic portion facing the water, which allows them to act as bridges at the lipid/water interface, where they can make micelles when sufficiently concentrated.[2] Micelles, with their bile acids, can support the function of lipases in digesting lipids and also bring them close to the intestine's brush border, augmenting their absorption. Lipids are normally water-insoluble, and the stomach and intestines are full of water. If not for the action of bile, dietary lipids and water would not separate, and water-soluble lipases would inefficiently exert their effects at the small interface between water and lipids. The emulsification of lipids by bile salts thus suspends lipid particles in water to dissolve them, accordingly granting significantly more surface area for lipase action.[10][11]
Other functions of bile acids include removing the body's cholesterol, powering bile flow to remove various metabolites (like bilirubin), and facilitating the removal of bacterial flora of the small bowel and biliary tree (e.g., by disrupting their cellular membranes).[6] Bile acids also hormonally act on the FXR and TGR5 receptors. Control over bile acid concentrations is important because of their potential cytotoxicity, so FXR elicits functions primarily in the liver/intestines that include feedback regulation of bile acid concentration, in addition to regulating triglyceride levels and other biochemical functions.[12][13][14][15] Secondary bile acids, e.g., deoxycholic acid, may have implications in more strongly downregulating bile acid synthesis than primary bile acids when it comes to negative feedback.[16] The TGR5 receptor is involved in the regulation of energy homeostasis by bile acids.[17][18] In addition to its effects on the above-mentioned hormone receptors, bile acids target other proteins like N-acyl phosphatidylethanolamine-specific phospholipase D, involved in pathways related to stress/pain responses, appetite, and lifespan via crosstalk between lipid amide signals with bile acids. Other miscellaneous functions under the purview of bile acids potentially include the regulation of particular enzymes/ion channels and the synthesis of various substances.[19][20][21][17]
Mechanism
Altogether, bile salts comprise a broad variety of different molecules, each being a steroid with the following basic components: (1) 4 rings, (2) a 5-/8-carbon side chain that ends with a carboxylic acid, and (3) a number of hydroxyl groups (whose position/number changes among the various salts). The rings are ascribed the letters A, B, C, and D based on their distance from the side chain with the -COOH group, the D ring being the most distant (as well as being 1 C smaller than the other rings). Beta hydroxyl groups face up/out, alpha groups down, and every bile acid has a 3-hydroxyl group that came from their cholesterol precursor.[1]
Primary bile acids are made by hepatocytes either by the classic or acidic pathway. The former, which constitutes 95% of bile acid synthesis, is via cytochrome P450-mediated oxidation of cholesterol that requires NADPH and oxygen and occurs in a series of steps, the most important of which is the rate-limiting hydroxylation of the 7th steroid nucleus of cholesterol by cholesterol 7alpha-hydroxylase (CYP7A1) to create 7alpha-hydroxycholesterol. That then gets metabolized into 7alpha-hydroxy-4 cholesten-3-one in the second step. In sum, primary bile acid synthesis requires 14 enzymatic steps. The most common bile acids are cholic and chenodeoxycholic acid (CDCA). Cholic acid (3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholan-24-oic acid) is the commonest bile acid, and CDCA is the prototypical and most basic of bile acids produced and is also known as 3alpha,7alpha-dihydroxy-5beta-cholan-24-oic acid.[4]
The alternative/acidic pathway acts via mitochondrial sterol 27-hydroxylase (CYP27A1), found in the liver, macrophages, and other tissues. Before secretion of bile acids, hepatocytes conjugate them with the amino acids taurine or glycine, thereby creating eight different conjugated bile acids/salts (including cholic and chenocholic acids). CYP27A1 significantly adds to bile acid synthesis by facilitating the oxidation of sterol side chains, followed by a peroxisomal cleavage of a 3-C unit to generate a C24 bile acid. Miscellaneous pathways, in addition to these two, include those started by the liver's 25-hydroxylase and the brain's 24-hydroxylase.
The purpose of conjugation is so that the bile acids can become water-soluble and thereby emulsify fats.[2] Secondary bile acids are formed from bacterial deconjugation/dehydroxylation and removal of those amino acid groups, creating four more different types of bile acids (including deoxycholic and lithocholic acids). These acids are absorbed through the bloodstream and brought back to the liver via the enterohepatic circulation to then be resecreted. Most triglyceride absorption occurs at the jejunum, but the conjugated bile acids do not get absorbed along with them. Instead, the bile salts remain in the small intestine, where most are later absorbed and recycled by active transport at the terminal ileum (the remaining undergo fecal elimination). The end of the small intestine acting the site of bile salt absorption allows for a high concentration of bile salts to exist throughout the entire organ, maximizing lipid digestion and absorption.[5]
Pathophysiology
Bile acid synthesis defects comprise about 1 to 2% of the cholestatic diseases found in children.[22] With an autosomal recessive inheritance pattern, these defects have a spectrum of disease severity based on what they affect. Most commonly, these manifest as progressive cholestasis of infancy, in addition to other disorders like an advanced liver disease at birth or neonatal hepatitis; patients may also develop a liver disease later in childhood. Typically, an earlier onset of liver disease occurs with those enzymatic defects that result in a buildup of oxo-bile acids, which tend to be cholestatic.[23] Adult liver disease may also have a connection to inherited defects in bile synthesis, as well.[24]
Clinical Significance
Impairing enterohepatic circulation of bile acids decreases cholesterol because the liver is driven to use more cholesterol to make more. This state is the basis behind treating hyperlipidemia with bile acid resins like cholestyramine, colestipol, and colesevelam, which bind bile acids in the gut, preventing their reabsorption in the intestines. The bound bile acids are then fecally removed. However, because bile acid sequestrants also interfere with the absorption of fat, the absorption of drugs and fat-soluble vitamins are impaired.[25]
Structural/functional abnormalities of the biliary tract can produce an increase in bilirubin, causing jaundice, as well as an increase in serum bile acids. This observed cholestasis (disrupted bile flow to intestines) may also present with primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, and primary biliary cholangitis, where the buildup of bile acids can lead to pruritus because of the bile salts in skin.[26] Treating these disorders has involved ursodeoxycholic acid (ursodiol), a non-toxic bile acid that increases bile secretion and decreases cholesterol secretion/absorption. Obeticholic acid is a semisynthetic bile acid that can also treat primary biliary cirrhosis by stimulating FXR.[27][28]
Bile that has diluted concentrations of bile acids or phospholipids, in addition to increased cholesterol, leads to a decrease in the solubilization of cholesterol. This situation increases the risk for microcrystal formation from this supersaturated bile--eventually leading to the formation of cholesterol stones. Fibrates like gemfibrozil, bezafibrate, and fenofibrate also increase the risk of cholesterol gallstones by inhibiting cholesterol-7alpha-hydroxylase, resulting in decreased bile acid production.[29] Dissolution or prevention of these gallstones occurs with bile acid administration, in the form of chenodeoxycholic and/or ursodeoxycholic acid.[30][31]
Too much bile acid in the colon may precipitate chronic diarrhea, which may occur in conditions that impair the ileal absorption of bile salts, as seen with surgical removal for Crohn disease (which normally causes fat malabsorption by affecting the terminal ileum). Such malabsorption of bile acids is treatable with bile acid resins.[32]
There may also exist a link between bile acids and colorectal cancer.[33] Specifically, low fecal concentrations of bile acids have correlations with lower rates of colorectal cancer.[34][35][36] One potential explanation is that high concentrations of deoxycholic acid, a type of bile acid, can increase the generation of reactive oxygen species that can go on to damage DNA.[37][34]
Bile acids have also been used to get rid of undesired fat, i.e., mesotherapy, with deoxycholic acid being one such drug.[38][39]
Media
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Recycling of bile Image courtesy: https://commons.wikimedia.org/wiki/File:Bile_recycling.png
References
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