Bile acid metabolism doc. Ing. Zenóbia Chavková, CSc.
Bile acid metabolism Importance: Availability for fat & cholesterol absorption Regulates total body pool of cholesterol Factors that synthesis promote mobilization of cholesterol Factors that synthesis increase total body pool of cholesterol Factors that decrease reabsorption increase synthesis
Bile acids from cholesterol The conversion of cholesterol in bile acids significantly changes properties of cholesterol Cholesterol is a hydrophobic compound, while bile acids are amphipathic Bile acids contain 24C atoms, 2-3 O groups and side chain that terminates in a -COO group Bile salts have therefore both a polar and nonpolar face and can act as emulgifying agent They pass via the bile duct into the intestine, where they aid digestion of fats, and other lipid substances
Bile acids from cholesterol Formed from cholesterol in the liver Stored in the gall bladder in bile as bile salts (sodium and potassium) Utilized during digestion of fats and other lipid substances (act as detergents) Rate limiting step is the conversion of cholesterol to 7- cholesterol by 7- -hydroxylase
Other function of bile salts Aid in the absorption of fat-soluble vitamins (especially vitamin K) Accelerate the action of pancreatic lipase ave choleretic action stimulate the liver to secrete bile Stimulate intestinal motility Keep cholesterol in solution (as micelles)
Enterohepatic cycle Conversion of cholesterol into bile acids (salts) constitutes the major route for elimination of cholesterol from the body Most bile acids are reabsorbed, returned to the liver by the portal vein, and re-secreted This is the enterohepatic cycle
Recycling of bile acids Enterohepatic circulation 98% recycling of bile acids Cholestyramine treatment Resin binds bile acids Prevents recycling Increased uptake of LDL-C for bile acid synthesis
Bile salts are divided into 2 classes: Primary Secondary Primary salts are synthesized in the liver (by humans) Secondary bile salts result from the action of intestinal bacteria on the primary bile salts
The first and rate-limiting step in conversion of cholesterol to bile salts is catalysed by cholesterol-7-hydroxylase The enzyme catalyses insertion of O group at C7 at position The reaction involves NADP, molecular oxygen, cytochrom P-450 Cholesterol 7- -hydroxylase is monooxygenase and the activity of this enzyme is decreased by bile salts In subsequent steps 3 -O group changes its position at 3 -O group and additional hydroxylation may occur
Two different sets of compounds are produced: One set has -O groups at position 3, 7 and 12 and produces the cholic acid series of bile salts The other set has -O groups only at position 3 and 7 and produces the chenodeoxycholic acid series
NADP + + NADP O O O 7a-hydroxylase cholesterol O 12a-hydroxylase O 2 ; NADP + + 2 CoA-S 7a-hydroxycholesterol O 2 NADP + + 2 CoA-S C O S CoA C S CoA O O O cholyl-coa O O chenodeoxycholyl- CoA
Before cholic and chenodeoxycholic acid leave the liver, they are conjugated to a molecule of either glycine or taurine by amino bond between carboxyl and N 2 group of added compound These new structures are called glycocholic and taurocholic acid and they are primary bile acids (salts)
Conversion of cholyl-coa to glycocholic acid C S CoA O glycine CoA-S C N C 2 COO O cholyl-coa O O glycocholic acid
Conversion of cholyl CoA to taurocholic acid C O S CoA O cholyl-coa taurine CoA-S C C 2 C 2 SO 3 O O taurocholic acid (primary bile acid)
Taurine Taurine is formed by the decarboxylation of cysteic acid, which in turn is made by oxidation of cysteine COO COO 3 N C + O 2 + O2 - CO 2 3 N C 3 N C 2 C 2 S cysteine C 2 SO 2 cysteine sulfinate C 2 SO 3 taurine
C O S CoA O O chenodeoxycholyl- CoA Conversion of glyco-(tauro-) chenodeoxycholic acid to lithocholic acid tauro- and glyco-chenodeoxycholic acids (primary bile acids) deconjugation + 7a-dehydrxylation (catalyzed by microbial enzymes) COO O lithocholic acid (secondary bile acid)
Conversion of glycocholic acid to deoxycholic acid O C O N C 2 COO glycocholic acid (primary bile acid) deconjugation + 7 -dehydroxylation catalyzed by microbial enzymes) Deoxycholic acid (secondary bile acid) COO O
Bile acids Cholic acid is the bile acid found in the largest amount in bile Cholic acid and chenodeoxycholic acid are referred to as primary bile acids Bile acids are converted to either glycine or taurine conjugates (in humans the ratio of glycine to taurine conjugates is 3:1)
Approximate composition of bile salts Glycocholate 24% Glycochenodeoxycholate 24% Taurocholate 12% Taurochenodeoxycholate 12% Glycodeoxycholate- 16% Taurodeoxycholate 8% Various lithocholate 4%
Bile acids Fat digestion products are absorbed in the first 100 cm of small intestine The primary and secondary bile acids are reabsorbed almost exclusively in the ileum returning to the liver by way of the portal circulation (98 to 99%) known as the enterohepatic circulation Less than 500 mg a day escapes reabsorption and is excreted in the feces
Bile salts Detergent character of bile salts is due to the hydrophobic-hydrophilic nature of the molecules The presence of -O (or sulfate) and the terminal -COO group on the tail gives the molecule its hydrophilic face The steroid ring with its puckered plane provides the hydrophobic face
Mixed micelle formed by bile salts, triacylglycerols and pancreatic lipase
Medications Bile Acid Sequestrants (Resins) Anion exchange resins Prevents reabsorption of bile salts Effects additive when used with statins May inhibit absorption of fat soluble vitamins (use multi-vitamin supplement) Cholestryramine (Questran) Cholestipol (Cholestid) Cholesavelem (Welchol) Newest resin, better tolerated than traditional resins
GALLSTONE TERAPEUTIC AGENTS Chenodeoxycholic acid (chenodiol; Chenix) Ursodeoxycholic acid (ursodiol; Actigall) MAO: Reduce hepatic secretion of cholesterol into bile Inhibition of MGCoA reductase: inhibit cholesterol biosynthesis Increase cholesterol solubility
Chenodiol and ursodiol Both are effective in dissolving cholesterol stones in some patients Ursodiol is the 7- epimer of chenodiol Most effective in dissolving small (<5 mm) floating stones in a functioning gallbladder Cannot dissolve stones that are more than 4% calcium by weight
BILE ACIDS C 3 C 3 O C 3 12 C 3 COO C 3 C 3 COO 3 7 COLANIC ACID O COLIC ACID O C 3 C 3 C 3 COO C 3 C 3 COO C 3 O O CENODEOXYCOLIC ACID (CENODIOL) (CENIX) O O URSODEOXYCOLIC ACID (URSODIOL) (ACTIGALL)