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14/01/12 12:44
Bile Acid Synthesis Regulation of Bile Acid Homeostasis Bile Acids as Metabolic Regulators Inborn Errors in Bile Acids Synthesis
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14/01/12 12:44
Synthesis of the 2 primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA). The reaction catalyzed by the 7!-hydroxylase (CYP7A1) is the rate limiting step in bile acid synthesis. Expression of CYP7A1 occurs only in the liver. Conversion of 7!-hydroxycholesterol to the bile acids requires several steps not shown in detail in this image. Only the relevant co-factors needed for the synthesis steps are shown. Sterol 12!hydroxylase (CYB8B1) controls the synthesis of cholic acid and as such is under tight transcriptional control (see text). The most abundant bile acids in human bile are chenodeoxycholic acid (45%) and cholic acid (31%). These are referred to as the primary bile acids. Before the primary bile acids are secreted into the canalicular lumen they are conjugated via an amide bond at the terminal carboxyl group with either of the amino acids glycine or taurine. These conjugation reactions yield glycoconjugates and tauroconjugates, respectively. This conjugation process increases the amphipathic nature of the bile acids making them more easily secretable as well as less cytotoxic. The conjugated bile acids are the major solutes in human bile.
Structure of the conjugated cholic acids Following secretion by the liver the bile acids enter the bile canaliculi which join with the bile ductules which then form the bile ducts. Bile acids are carried from the liver through these ducts to the gallbladder, where they are stored for future use. In the gallbladder bile acids are concentrated up to 1000 fold. Following stimulation by food intake the gallbladder releases the bile into the duodenum, via the action of the gut hormone cholecystokinin (CCK), where they aid in the emulsification of dietary lipids. Within the intestines the primary bile acids are acted upon by bacteria and undergo a deconjugation process that removes the glycine and taurine residues. The deconjugated bile acids are either excreted (only a small percentage) or reabsorbed by the gut and returned to the liver. Anaerobic bacteria present in the colon modify the primary bile acids converting them to the secondary bile acids, identified as deoxycholate (from cholate) and lithocholate (from chenodeoxycholate). Both primary and secondary bile acids are reabsorbed by the intestines and delivered back to the liver via the portal circulation. Indeed, as much as 95% of total bile acid synthesized by the liver is absorbed by the distal ileum and returned to the liver. This process of secretion from the liver to the gallbladder, to the intestines and finally reabsorption is termed the enterohepatic circulation.
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1. their synthesis and subsequent excretion in the feces represent the only significant mechanism for the elimination of excess cholesterol. 2. bile acids and phospholipids solubilize cholesterol in the bile, thereby preventing the precipitation of cholesterol in the gallbladder. 3. they facilitate the digestion of dietary triacylglycerols by acting as emulsifying agents that render fats accessible to pancreatic lipases. 4. they facilitate the intestinal absorption of fat-soluble vitamins. However, over the past several years new insights into the biological activities of the bile acids have been elucidated. Recent findings have demonstrated that bile acids are involved in the control of their own metabolism and transport via the enterohepatic circulation, regulate lipid metabolism, regulate glucose metabolism, control signaling events in liver regeneration, and the regulation of overall energy expenditure. Following the isolation and characterization of the farnesoid X receptors (FXRs), for which the bile acids are physiological ligands, the functions of bile acids in the regulation of lipid and glucose homeostasis has begun to emerge. As indicated above, the binding of bile acids to FXRs results in the attenuated expression of several genes involved in overall bile acid homeostasis. However, genes involved in bile acid metabolism are not the only ones that are regulated by FXR action as a consequence of binding bile acid. In the liver, FXR action is known to regulate the expression of genes involved in lipid metabolism (e.g. SREBP-1c), lipoprotein metabolism (e.g. apoCII), glucose metabolism (e.g. PEPCK), and hepatoprotection (e.g. CYP3A4, which was originally identified as nifedipine oxidase; nifedipine being a member of the calcium channel blocker drugs). In addition to their roles in lipid emulsification in the intestine and activating FXR, the bile acids participate in various signal transduction processes via activation of the c-JUN N-terminal kinase (JNK) as well as the mitogenactivated protein kinase (MAPK) pathways. Other members of the nuclear receptor family that are activated by bile acids are the pregnane X receptor (PXR), the constitutive androstane receptor (CAR), and the vitamin D receptor (VDR). An additional receptor activated in response to bile acids that may have implications for control of obesity is the transmembrane G-protein coupled bile acid receptor 1 (originally identified as TGR5 and also known as GPR131). Activation of TGR5 in brown adipose tissue results in activation of uncoupling protein 1, UCP1 (thermogenin) leading to enhanced energy expenditure. back to the top
Affected Enzyme
cholesterol 7!hydroxylase sterol 27hydroxylase
Gene Symbol
Phenotype / Comments
no liver dysfunction, clinical phenotype manifests with markedly elevated total cholesterol as well as LDL, premature gallstones, premature coronary and peripheral vascular disease, elevated serum cholesterol is not responsive to statin drug therapy progressive neurological dysfunction, neonatal cholestasis, bilateral cataracts, chronic diarrhea a single case was reported in 1998 of a 10-week-old boy presenting with severe progressive cholestasis, hepatosplenomegaly, cirrhosis, and liver failure, serum ALT and AST were markedly elevated; recently several individuals suffering from autosomal recessive hereditary spastic paraplegia 5A (SPG5A) have been shown to harbor mutations in the CYP7B1 gene although the number of cases only represents around 1% of all SPG cases most commonly reported defect in bile acid synthesis, heterogeneous clinical presentation that includes progressive jaundice, hepatomegaly, puritis, malabsorption with resultant steatorrhea (fatty diarrhea), fat soluble vitamin deficiency, rickets similar clinical manifestation to HSD3B7 deficiency although with earlier presentation afflicted infants will have a more severe liver disease with rapid progression to cirrhosis and death if no clinical intervention is undertaken, liver function tests will show marked elevation in AST and ALT, serum tests show
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CYP7A1
CYP27A1
oxysterol 7!hydroxylase
CYP7B1
3"-hydroxy-#5C27-steroid oxidoreductase
HSD3B7
#4-3oxosteroid 5"reductase
AKR1C4
http://themedicalbiochemistrypage.org/bileacids.html