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High-Yield Terms

  • Classic (neutral) pathway: major pathway for bile acid synthesis, initiated from cholesterol via the action of CYP7A1, both cholic and chenodeoxycholic acid synthesized via the classic pathway

  • Acidic pathway: alternative, minor pathway for bile acid synthesis initiated via the action of sterol 27-hydroxylase (CYP27A1), only chenodeoxycholic acid synthesized via the acidic pathway

  • CYP7A1: 7α-hydroxylase, rate-limiting enzyme in the classic pathway of bile acid synthesis

  • Primary bile acids: the end products of hepatic bile acid synthesis and includes cholic acid and chenodeoxycholic acid

  • Secondary bile acids: products of the actions of intestinal bacteria on the primary bile acids generating deoxycholate (from cholate) and lithocholate (from chenodeoxycholate)

  • Enterohepatic circulation: the circulation of bile acids, or other substances, from the liver to the gallbladder, followed by secretion into the small intestine, absorption by intestinal enterocytes, and transport back to the liver

  • Farnesoid X receptors (FXR): nuclear receptors for bile acids and bile acid metabolites; regulate the expression of genes involved in bile acid synthesis

  • Guggulsterone: the term for any resin collected by tapping the trunk of a tree is called guggul (or guggal) and the lipid component of this extract is called guggulsterone (also called guggul lipid)

High-Yield Concept

Although the acidic pathway is not a major route for human bile acid synthesis, it is an important one as demonstrated by the phenotype presenting in a newborn harboring a mutation in the CYP7B1 gene. This infant presented with severe cholestasis (blockage in bile flow from liver) with cirrhosis and liver dysfunction.

Bile Acid Synthesis Pathways

The end products of cholesterol utilization are the bile acids. Indeed, synthesis of bile acids is one of the predominant mechanisms for the excretion of excess cholesterol. However, the excretion of cholesterol in the form of bile acids is insufficient to compensate for an excess dietary intake of cholesterol.

Although several of the enzymes involved in bile acid synthesis are active in many cell types, the liver is the only organ where their complete biosynthesis can occur. Although bile acid synthesis constitutes the route of catabolism of cholesterol, these compounds are also important in the solubilization of dietary cholesterol, lipids, and essential nutrients, thus promoting their delivery to the liver. Synthesis of a full complement of bile acids requires 17 individual enzymes and occurs in multiple intracellular compartments that include the cytosol, endoplasmic reticulum (ER), mitochondria, and peroxisomes. The genes encoding several of the enzymes of bile acid synthesis are under tight regulatory control to ensure that the necessary level of bile acid production is coordinated to changing metabolic conditions. Given the fact that many bile acid metabolites are cytotoxic, it is understandable why their synthesis needs to be tightly controlled.

The major pathway for the synthesis of the bile acids is initiated via hydroxylation of cholesterol at the 7 position via the action of cholesterol 7α-hydroxylase (CYP7A1) which is ...

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