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Metabolic Pathways

The major bile acids produced in the liver are the taurine and glycine conjugates (amidates) of chenodeoxycholic acid (CDCA) and cholic acid (CA). Secretion of these conjugated bile acids into the canaliculi by the bile salt export pump fuels bile flow out of the liver. They are powerful detergents. This property is important in keeping cholesterol in solution in bile, and it is also essential for the digestion and absorption of fats and fat-soluble vitamins. The conversion of cholesterol to bile acids and the secretion of cholesterol into bile represent the major routes for elimination of excess cholesterol from the body. Thus, individuals with disorders of bile acid synthesis can present with liver disease due to impaired bile secretion (cholestasis), with gallstones, steatorrhea, symptoms of fat-soluble vitamin malabsorption, and buildup of cholesterol in tissues (causing neurological impairment, atherosclerosis, and xanthomata).

The conversion of cholesterol to bile acids requires modifications to the sterol nucleus and to the sterol side chain.1 The major pathway for bile acid synthesis in adults (the “neutral” pathway) starts with conversion of cholesterol to 7α-hydroxycholesterol. A second pathway (the “acidic” pathway) starts with the conversion of cholesterol to 27-hydroxycholesterol, and the early steps can take place outside the liver. The neutral and acidic pathways share several enzymes; thus, inborn errors can disrupt both routes for the synthesis of bile acids. A simplified version of the major bile acid synthesis pathways is shown in Figure 165-1.

Figure 165-1.

Simplified representation of two major pathways for the synthesis of bile acids from cholesterol—the acidic pathway on the left, starting with formation of 27-hydroxycholesterol, and the neutral pathway(s) on the right, starting with formation of 7α-hydroxycholesterol. Several enzymes participate in both pathways. Deficiencies have been described in cholesterol 7α-hydroxylase (1); 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase (2); Δ4-3-oxosteroid-5β-reductase (3); sterol 27-hydroxylase (4); α-methyl-acyl-CoA racemase (5); peroxisomal D-bifunctional protein (6); peroxisomal sterol carrier protein X (thiolase) (7); bile acid CoA: amino acid N-acyltransferase deficiency (8); bile acyl-CoA synthetase (9); and oxysterol 7α-hydroxylase (10). Reactions thought to occur predominantly in the peroxisomes are included in the green brackets. Disorders of peroxisome biogenesis affect many steps, including the reactions of peroxisomal β-oxidation, which is depicted by blue arrows.

The modifications to the cholesterol side chain involve 27-hydroxylation, further oxidation to a C27 bile acid, alteration of the stereochemistry of the C27 bile acid CoA ester (racemization), and then β-oxidation in the peroxisomes to produce a C24 bile acid CoA ester that is conjugated with glycine or taurine.

Disorders of bile acid synthesis that affect transformation of the cholesterol nucleus produce hepatobiliary disease; those that affect the oxidation of the cholesterol side chain often also cause extrahepatic (particularly neurological) disease. This is probably because the early steps of the acidic pathway for bile acid synthesis play an important role in ...

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