Bile acid

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Bile acids are steroid acids found predominantly in the bile of mammals.[1] Bile salts are bile acids compounded with a cation, usually sodium. In humans, the salts of taurocholic acid and glycocholic acid (derivatives of cholic acid) represent approximately eighty percent of all bile salts. Bile acids, glycine and taurine conjugates, and 7-alpha-dehydroxylated derivatives (deoxycholic acid and lithocholic acid) are all found in human intestinal bile. An increase in bile flow is exhibited with an increased secretion of bile acids. The main function of bile acid is to facilitate the formation of micelles, which promotes processing of dietary fat.[2]

Production and function[edit]

Structure of cholic acid showing relationship to other bile acids
Synthesis of the remaining 10 bile acids (2 secondary, 8 conjugated) from the two primary bile acids.

In humans, bile acid synthesis begins when liver cells synthesize the two primary bile acids, cholic acid and chenodeoxycholic acid,[3]:357-358 via the cytochrome P450-mediated oxidation of cholesterol. Approximately 600 mg of bile salts are synthesized daily to replace bile acids lost in the feces.[3]:359 In humans, the rate-limiting step is the addition of a hydroxyl group on position 7 of the steroid nucleus by the enzyme cholesterol 7 alpha-hydroxylase. This enzyme is down-regulated by cholic acid and up-regulated by cholesterol.

When these two bile acids are secreted into the lumen of the intestine, intestinal bacteria dehydroxylate a portion of each of them to form the secondary bile acids, deoxycholic acid and lithocholic acid.[3]:358 (Cholic acid becomes deoxycholic acid. Chenodeoxycholic acid becomes lithocholic acid.) All four of these bile acids can be taken back up into the blood stream, return to the liver, and be re-secreted in a process known as enterohepatic circulation.

Prior to secreting any of the four bile acids, the liver cells may also conjugate them with one of two amino acids, glycine or taurine, to form a total of 8 possible conjugated bile acids.[3]:358 These conjugated bile acids are usually referred to as bile salts[3]:358 because of their physiologically-important acid-base properties. The pKa of each of the unconjugated bile acids is 7, and the pH of the duodenum ranges between 3 and 5,[3]:358 so when unconjugated bile acids are in the duodenum, they are almost always protonated (HA form), which makes them relatively insoluble in water. Conjugating bile acids with amino acids lowers the pKa of the bile-acid/amino-acid conjugate to between 1 and 4.[3]:358 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 fulfill their physiologic function of emulsifying fats.[4]

One way this added solubility aids in bile salt function is by preventing passive re-absorption once secreted into the small intestine. As a result, the concentration of bile acids/salts in the small intestine can stay high enough to form micelles and solubilize lipids. "Critical micellar concentration" refers to both an intrinsic property of the bile acid itself and amount of bile acid necessary to function in the spontaneous and dynamic formation of micelles.[citation needed]

Bile acids also serve other functions, including eliminating cholesterol from the body, driving the flow of bile to eliminate catabolites from the liver, emulsifying lipids and fat-soluble vitamins in the intestine to form micelles that can be transported via the lacteal system, and aiding in the reduction of the bacteria flora found in the small intestine and biliary tract.[citation needed]

Synthesis of bile acids is a major route of cholesterol metabolism in most species other than humans. The body produces about 800 mg of cholesterol per day and about half of that is used for bile acid synthesis. In total about 20-30 grams of bile acids are secreted into the intestine daily. About 90% of excreted bile acids are reabsorbed by active transport in the ileum and recycled in what is referred to as the enterohepatic circulation, which moves the bile salts from the intestinal system back to the liver and the gallbladder. This allows a low rate of daily synthesis, but high secretion to the digestive system.[2]

Types[edit]

IUPAC recommended ring lettering (left) and atom numbering (right) of the steroid skeleton. The four rings A-D form a sterane core.
Cholesterol with numbering

Bile salts constitute a large family of molecules, composed of a steroid structure with four rings, a five- or eight-carbon side-chain terminating in a carboxylic acid, and the presence and orientation of different numbers of hydroxyl groups. The four rings are labeled from left to right (as commonly drawn) A, B, C, and D, with the D-ring being smaller by one carbon than the other three. The hydroxyl groups have a choice of being in 2 positions, either up (or out), termed beta (often drawn by convention as a solid line), or down, termed alpha (seen as a dashed line in drawings). All bile acids have a hydroxyl group on position 3, which was derived from the parent molecule, cholesterol. In cholesterol, the 4 steroid rings are flat and the position of the 3-hydroxyl is beta.[citation needed]

In many species, the initial step in the formation of a bile acid is the addition of a 7-alpha hydroxyl group. In the subsequent step, in the conversion from cholesterol to a bile acid, the junction between the first two steroid rings (A and B) is altered, making the molecule bent, and, in this process, the 3-hydroxyl is converted to the alpha orientation. Thus, the default simplest bile acid (of 24 carbons) has two hydroxyl groups at positions 3-alpha and 7-alpha. The chemical name for this compound is 3-alpha,7-alpha-dihydroxy-5-beta-cholan-24-oic acid, or, as it is commonly known, chenodeoxycholic acid. This bile acid was first isolated from the domestic goose, from which the "cheno" portion of the name was derived.[citation needed]

Another bile acid, cholic acid (with 3 hydroxyl groups) had already been described, so the discovery of chenodeoxcholic acid (with 2 hydroxyl groups) made the new bile acid a "deoxycholic acid" in that it had one fewer hydroxyl group than cholic acid. The 5-beta portion of the name denotes the orientation of the junction between rings A and B of the steroid nucleus (in this case, they are bent). The term "cholan" denotes a particular steroid structure of 24 carbons, and the "24-oic acid" indicates that the carboxylic acid is found at position 24, which happens to be at the end of the side-chain. Chenodeoxycholic acid is made by many species, and is quite a functional bile acid. Its chief drawback lies in the ability of intestinal bacteria to remove the 7-alpha hydroxyl group, a process termed dehydroxylation. The resulting bile acid has only a 3-alpha hydroxyl group and is termed lithocholic acid (litho = stone). It is poorly water-soluble and rather toxic to cells. Bile acids formed by synthesis in the liver are termed "primary" bile acids, and those made by bacteria are termed "secondary" bile acids. As a result, chenodeoxycholic acid is a primary bile acid, and lithocholic acid is a secondary bile acid.[citation needed]

To avoid the problems associated with the production of lithocholic acid, most species add a third hydroxyl group to chenodeoxycholic acid. In this manner, the subsequent removal of the 7-alpha hydroxyl group by intestinal bacteria will result in a less toxic, still-functional dihydroxy bile acid. Over the course of vertebrate evolution, a number of positions have been chosen for placement of the third hydroxyl group. Initially, the 16-alpha position was favored, in particular in birds. Later, this position was superseded by a large number of species selecting position 12-alpha. Primates (including humans) utilize 12-alpha for their third hydroxyl group position. The resulting primary bile acid in humans is 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholan-24-oic acid, or, as it is commonly called, cholic acid.[citation needed]

In the intestine, cholic acid is dehydroxylated to form the dihydroxy bile acid deoxycholic acid. In many vertebrate orders still subject to speciation, new species are discarding 12-alpha hydroxylation in favor of a hydroxy group on position 23 of the side-chain. Vertebrate families and species exist that have experimented with and utilize just about every position on the steroid nucleus and side-chain.[citation needed]

The principal bile acids are[citation needed]:

Bile acids can also be thought of as steroid hormones, secreted from the liver and having direct metabolic actions in the body through the nuclear receptor FXR, or the cell membrane receptor TGR5.[5][citation needed]

Regulation[edit]

As surfactants or detergents, bile acids are potentially toxic to cells, and their concentrations are tightly regulated. They function as a signaling molecule in the liver and the intestines by activating a nuclear hormone receptor, FXR, also known by its gene name NR1H4. Activation of FXR in the liver inhibits synthesis of bile acids, and is one mechanism of feedback control when bile acid levels are too high. FXR activation by bile acids during absorption in the intestine increases transcription and synthesis of FGF19, which will then inhibit bile acid synthesis in the liver.[6] Emerging evidence associates FXR activation with alterations in triglyceride metabolism, glucose metabolism, and liver growth.[citation needed]

Clinical significance[edit]

Since bile acids are made from endogenous cholesterol, the enterohepatic circulation of bile acids may be disrupted to lower cholesterol. Bile acid sequestrants bind bile acids in the gut, preventing reabsorption. In so doing, more endogenous cholesterol is shunted into the production of bile acids, thereby lowering cholesterol levels. The sequestered bile acids are then excreted in the feces.[citation needed]

Tests for bile acids are useful in both human and veterinary medicine, as they help to diagnose a number of conditions, including cholestasis, portosystemic shunt, and hepatic microvascular dysplasia.[citation needed]

Excess concentrations of bile acids in the colon are a cause of chronic diarrhea. This condition of bile acid malabsorption can be diagnosed by the SeHCAT test and treated with bile acid sequestrants.[7]

Bile acids and colon cancer[edit]

Bile acids appear to be of particular importance in colon cancer. The bile acid deoxycholic acid (DOC) is increased in the colonic contents of humans in response to a high fat diet.[8] In populations with a high incidence of colorectal cancer, fecal concentrations of bile acids are increased (e.g. Hill, 1990; Cheah, 1990),[9][10] suggesting that increased exposure of the colonic lumen to high levels of bile acids plays a role in the natural course of development of colon cancer.

In a particular comparison, the concentration of DOC in the feces of Native Africans in South Africa (who eat a low fat diet) is 7.30 nmol/g wet weight stool while that of African Americans (who eat a higher fat diet) is 37.51 nmol/g wet weight stool.[11] Native Africans in South Africa have a low incidence rate of colon cancer in their population of <1:100,000,[12] compared to the high incidence rate for male African Americans of 72:100,000.[13]

Experimental studies, in addition to epidemiological studies, also indicate a role of bile acids in colon cancer. As reviewed by Bernstein et al., twelve studies show that exposure of colon cells to high human level concentrations of DOC increases formation of reactive oxygen species, causing oxidative stress and 14 studies show that exposure of cells to bile acids increases DNA damage.[14] Surviving cells that retain un-repaired DNA damage, upon replication, may give rise to daughter cells with carcinogenic mutations.

In an experimental study, mice were fed a diet with an added level of DOC that resulted in the same level of DOC in their colons as in the colons of humans on a high fat diet. Among the 18 mice fed diet+DOC for 8 to 10 months, 17 developed colonic tumors, including 10 with colon cancers. Mice fed a control diet, with one-tenth the level of DOC in their colons, had no colonic tumors. [15]

References[edit]

  1. ^ "Bile Acids". 
  2. ^ a b Hofmann, Alan F.; Borgström, Bengt (1964). "The Intraluminal Phase of Fat Digestion in Man: The Lipid Content of the Micellar and Oil Phases of Intestinal Content Obtained during Fat Digestion and Absorption*". Journal of Clinical Investigation 43 (2): 247. doi:10.1172/JCI104909. PMC 289518. 
  3. ^ a b c d e f g Costanzo, Linda S. (2010). Physiology (4th ed.). Philadelphia, PA: Saunders/Elsevier. ISBN 978-1-4160-6216-5. 
  4. ^ 'Essentials of Medical Biochemistry, Lieberman, Marks and Smith, eds, p432, 2007'
  5. ^ Fiorucci, S; Mencarelli, A, Palladino, G, Cipriani, S (2009). "Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders". Trends in pharmacological sciences 30 (11): 570–80. doi:10.1016/j.tips.2009.08.001. PMID 19758712. 
  6. ^ Kim, I; Ahn, SH, Inagaki, T, Choi, M, Ito, S, Guo, GL, Kliewer, SA, Gonzalez, FJ (2007). "Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine". Journal of lipid research 48 (12): 2664–72. doi:10.1194/jlr.M700330-JLR200. PMID 17720959. 
  7. ^ Pattni, S; Walters, JR (2009). "Recent advances in the understanding of bile acid malabsorption". British medical bulletin 92: 79–93. doi:10.1093/bmb/ldp032. PMID 19900947. 
  8. ^ Reddy BS, Hanson D, Mangat S, et al. (September 1980). "Effect of high-fat, high-beef diet and of mode of cooking of beef in the diet on fecal bacterial enzymes and fecal bile acids and neutral sterols". J. Nutr. 110 (9): 1880–7. PMID 7411244. 
  9. ^ Hill MJ (May 1990). "Bile flow and colon cancer". Mutat. Res. 238 (3): 313–20. PMID 2188127. 
  10. ^ Cheah PY (1990). "Hypotheses for the etiology of colorectal cancer--an overview". Nutr Cancer 14 (1): 5–13. doi:10.1080/01635589009514073. PMID 2195469. 
  11. ^ Ou J, DeLany JP, Zhang M, Sharma S, O'Keefe SJ (2012). "Association between low colonic short-chain fatty acids and high bile acids in high colon cancer risk populations". Nutr Cancer 64 (1): 34–40. doi:10.1080/01635581.2012.630164. PMID 22136517. 
  12. ^ O'Keefe SJ, Kidd M, Espitalier-Noel G, Owira P (May 1999). "Rarity of colon cancer in Africans is associated with low animal product consumption, not fiber". Am. J. Gastroenterol. 94 (5): 1373–80. doi:10.1111/j.1572-0241.1999.01089.x. PMID 10235221. 
  13. ^ American Cancer Society. Cancer Facts and Figures 2009. http://www.cancer.org/Research/CancerFactsFigures/cancer-facts-figures-2009
  14. ^ Bernstein H, Bernstein C, Payne CM, Dvorak K (July 2009). "Bile acids as endogenous etiologic agents in gastrointestinal cancer". World J. Gastroenterol. 15 (27): 3329–40. PMC 2712893. PMID 19610133. 
  15. ^ Bernstein C, Holubec H, Bhattacharyya AK, et al. (August 2011). "Carcinogenicity of deoxycholate, a secondary bile acid". Arch. Toxicol. 85 (8): 863–71. doi:10.1007/s00204-011-0648-7. PMC 3149672. PMID 21267546. 

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