Human Biochemistry, Volume 1 - Murray R. 1993

Bioenergetics and Carbohydrate and Lipid Metabolism
Synthesis, Transport, and Excretion of Cholesterol
Cholesterol Elimination and Bile Acid Synthesis — Enterohepatic Circulation of Bile Acids

Lipid Digestion products, including Cholesterol, are absorbed in the upper part of the Small Intestine (the first 100 cm). However, Primary and secondary Bile acids are absorbed almost exclusively in the ileum, and 98–99% of the bile acids entering the intestine return to the Liver via the PORTAL VEIN SYSTEM. This cycle of bile acids is known as the enterohepatic Circulation. It is worth noting that due to its poor solubility, lithocholic acid is virtually not reabsorbed in the intestine.

A small fraction of bile acid salts, approximately 500 mg/day, is not absorbed and is excreted from the body in the feces. Although a relatively small amount of bile acids is excreted via this pathway, it serves as the primary route for cholesterol elimination. The enterohepatic circulation of bile acid salts operates very efficiently. Although a relatively small pool of bile acids circulates in the body (about 3–5 g), it passes through the intestine 6–10 times per day. Meanwhile, the proportion of excreted bile acids is small—approximately 1–2% per single cycle within the enterohepatic circulation system. To replenish the loss of bile acids excreted in the feces, the liver continuously synthesizes bile acids de novo from cholesterol in an amount equivalent to the excreted loss, thereby maintaining a constant bile acid pool. The regulation of this process occurs via a feedback mechanism.

Regulation of Bile Acid Synthesis

The rate-limiting step in bile acid Biosynthesis is the reaction catalyzed by 7α-hydroxylase, whereas in Cholesterol Biosynthesis, it is the reaction catalyzed by HMG-CoA reductase (Fig. 27.1). Often, the activities of these two Enzymes change simultaneously, making it quite difficult to determine at which exact stage bile acid synthesis is inhibited: the stage catalyzed by HMG-CoA reductase or the one catalyzed by 7α-hydroxylase. Throughout the day, the activities of both enzymes fluctuate in a similar manner. It remains unclear whether cholesterol exerts a direct stimulatory effect on 7α-hydroxylase. Conversely, bile acids inhibit 7α-hydroxylase via a feedback mechanism (though this inhibition is unlikely to occur through a direct allosteric mechanism). Therefore, the return of bile acids to the liver via the enterohepatic circulation plays a crucial regulatory role; interruption of this circulation leads to the activation of 7α-hydroxylase. It is important to note that both 7α-hydroxylase and HMG-CoA reductase can be regulated by phosphorylation-dephosphorylation. Phosphorylation of 7α-hydroxylase increases its activity; in contrast, HMG-CoA reductase is more active in its dephosphorylated state.