Bile acid synthesis

Bile acid synthesis from cholesterol is the prime pathway for cholesterol catabolism. Cholesterol is converted into bile acids via multiple pathways which involve 17 different enzymes. Many of these enzymes are predominantly expressed in the liver and are localized in several different subcellular... 

Russell DW (2003) The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 72 137-174... 

CYP7A1 catalyzes the 7a-hydroxylation of cholesterol, the first and rate limiting step of bile acid synthesis. This is also the principal way to eliminate cholesterol. CYP7B1 is primarily expressed in brain and catalyzes the synthesis of various neurosteroids and also the 7a-hydroxylation of oxysterols. 

CYP27A1 catalyzes the side chain oxidation (27-hydroxylation) in bile acid biosynthesis. Because bile acid synthesis is the only elimination pathway for cholesterol, mutations in the CYP27A1 gene lead to abnormal deposition of cholesterol and cholestanol in various tissues. This sterol storage disorder is known as cerebrotendinous xanthomatosis. CYP27B1 is the 1-alpha hydroxylase of vitamin D3 that converts it to the active vitamin form. The function of CYP27C1 is not yet known. 

Bile Acid Synthesis Is Regulated at the 7a-Hydroxylase Step... 

Princen HMG Regulation of bile acid synthesis. Curr Pharm Design 1997 3 59. 

Reihner E, Bjorkhem I, Angelin B, Ewerth S, Einarsson K. Bile acid synthesis in humans regulation of hepatic microsomal cholesterol 7 alpha-hydroxy-... 

Everson, G. T., Daggy, B. P., McKinley, C., and Story, J. A. (1992). Effects of psyllium hydrophilic mucilloid on LDL-cholesterol and bile acid synthesis in hypercholesterole-... 

Cholesterol is required for membrane synthesis, steroid synthesis, and in the liver, bile acid synthesis. Most cells derive their cholesterol from LDL or HDL, but some cholesterol may be synthesized de novo. Most de novo synthesis occurs in the liver, vfhere cholesterol is synthesized from acetyl CoA in the cytoplasm. The citrate shutde carries mitochondrial acetyl CoA into the cytoplasm, and NADPH is provided by the HMP shunt and malic enzyme. Important points are noted in Figure 1-15-9,... 

An Overview of Bile-Acid Synthesis, Chemistry and Function... 

Figure 1.1 illustrates a condensed version of the classical pathway of bile-acid synthesis, a series of 12 enzymatic reactions that convert cholesterol, which is insoluble, into BAs, which are water soluble. The cholesterol is first converted to 7 alpha-hydroxy cholesterol, followed by the series of enzymatic transformations, eventually producing cholic and chenodeoxycholic acids (not all steps shown). The rate-limiting enzyme in this pathway is cholesterol 7 alpha-hydroxylase (CYP 7A1), which originates from microsomal cytochrome P-450 enzymes, expressed only in the liver hepatocytes. 

M. Fuchs, Bile Regulation of Hepatic Physiology 3, Regulation of Bile-acid synthesis Past Progress and Future Challenges, Am. J. Physiol. Gas-trointest. Liver Physiol., 2003, 284, 551-557. 

ASBT has a complex regulatory system reflecting the importance of this transporter to bile-acid pool size and bile-acid synthesis rates. Hepatic nuclear factor la (HNF-la) is necessary for expression of ASBT as knockout mice showed no expression and had defective bile-acid transport.Conversely, FXR-null mice showed no difference in expression of ASBT, showing that FXR plays no part in regulation of ASBT. In man, HNF-la controls baseline promoter activity of the ASBT gene as the minimal construct with full promoter activity was found to have 3 HNF-la binding sites. These authors also showed that the promoter construct bound peroxisome proliferator activated receptor a (PPARa)/9 cis retinoic acid receptor heterodimer, demonstrating a link between bile-acid absorption and hepatic lipid metabolism mediated by PPARa. 

Assays have also made use of 7a-hydroxysteroid dehydrogenase that can measure the primary bile acids, or for more specialised purposes such as differentiating between pathways of bile-acid synthesis to determine the proportion derived from the acid pathway. 

Hepatic dysfunction leading to decreased bile acid synthesis. 

Bile acid synthesis stimulation. Fiber, administered in ration of male rats at a dose of 5% of the diet, produced a higher total bile acid pool size compared to rats fed cellulose. It also lowered the hydrophobicity of the bile acid pool """. 

In addition to treatment with the statins, hypercholesterolemia is sometimes treated with the use of nonabsorbable anion-exchange resins like cholestyramine (5.13) and colestipol, which sequester bile acid in the intestine, excrete them, and thus increase their synthesis in the liver by a feedback mechanism. Increased bile acid synthesis increases cholesterol metabolism and also decreases LDL concentrations. Unfortunately, these resins interfere with the absorption of other fats and fat-soluble vitamins (A, D, E, and K). They... 

Rationally, 5/3-reduclase deficiency would not be a cause of MPH, but it seems appropriate to place this disorder adjacent to its 5a-counterpart. 5/3-Reductase (AKR1D1) is an essential bile-acid biosynthetic enzyme and patients with disabling mutations in this enzyme have a clinical phenotype associated with cholestasis and fiver failure. In addition to its importance in bile-acid synthesis, this aldoketo-reductase is responsible for reducing approximately two-thirds of the mass of synthesized androgens, corticosteroids, and aldosterone prior to their excretion, so has a vital role in steroid metabolism. 

Mitochondrial system The function of the mitochondrial cyto chrome P450 monooxygenase system is to participate in the hydroxylation of steroids, a process that makes these hydropho bic compounds more water soluble. For example, in the steroid hormone-producing tissues, such as the placenta, ovaries, testes, and adrenal cortex, it is used to hydroxylate intermediates in the conversion of cholesterol to steroid hormones. The liver uses this system in bile acid synthesis (see p. 222), and the kidney uses it to hydroxylate vitamin 25-hydroxycholecalciferol (vitamin D, see p. 384) to its biologically active 1,25-hydroxylated form. 

Bile salts secreted into the intestine are efficiently reabsorbed (greater than 95 percent) and reused. The mixture of primary and secondary bile acids and bile salts is absorbed primarily in the ileum. They are actively transported from the intestinal mucosal cells into the portal blood, and are efficiently removed by the liver parenchymal cells. [Note Bile acids are hydrophobic and require a carrier in the portal blood. Albumin carries them in a noncovalent complex, just as it transports fatty acids in blood (see p. 179).] The liver converts both primary and secondary bile acids into bile salts by conjugation with glycine or taurine, and secretes them into the bile. The continuous process of secretion of bile salts into the bile, their passage through the duodenum where some are converted to bile acids, and their subsequent return to the liver as a mixture of bile acids and salts is termed the enterohepatic circulation (see Figure 18.11). Between 15 and 30 g of bile salts are secreted from the liver into the duodenum each day, yet only about 0.5 g is lost daily in the feces. Approximately 0.5 g per day is synthesized from cholesterol in the liver to replace the lost bile acids. Bile acid sequestrants, such as cholestyramine,2 bind bile acids in the gut, prevent their reabsorption, and so promote their excretion. They are used in the treatment of hypercholesterolemia because the removal of bile acids relieves the inhibition on bile acid synthesis in the liver, thereby diverting additional cholesterol into that pathway. [Note Dietary fiber also binds bile acids and increases their excretion.]... 

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