Bile acids: regulation of synthesis, 2009
Bile acid synthesis.
Cholesterol is converted to two primary bile acids in human liver, CA and CDCA (Key regulated enzymes, CYP7A1, CYP8B1, CYP27A1, and CYP7B1, in the pathways are indicated)
- CYP7A1 initiates the classic (neutral) bile acid biosynthetic pathway in the liver.
- CYP27A1 initiates the alternative (acidic) pathway in the liver and macrophages.
CA and CDCA are conjugated to glycine (G) and taurine (T).
BACS and BAT are two key enzymes involved in amino conjugation of bile acids.
In the intestine, conjugated CA and CDCA are deconjugated and then dehydroxylated at the 7α-position to the secondary bile acids DCA and LCA, respectively.
An inborn error of bile acid synthesis (3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency) presenting as malabsorption leading to rickets, 1999
Regulation of bile acid synthesis by an ileal bile acid sensing system. Bile acids are synthesized from cholesterol in the liver. The rate-limiting enzyme in the pathway is cholesterol-7α-hydroxylase (Cyp7a1). Bile acids are secreted across the apical (canalicular) membrane into the bile canaliculus via the Bsep transporter). Bile is then released into the duodenum and flows through the intestinal lumen, where it emulsifies lipids. Lipids are primarily absorbed by enterocytes in the jejunum. The bile acids are transported through the apical Asbt transporter across into ileal enterocytes. Bile acids activate the farnesoid X receptor/retinoid X receptor (FXR/RXR), leading the induction of Fgf15 and Ostαβ. The bile acids are then released into the portal circulation via basolateral Ostα/β and reabsorbed by the hepatic basolateral transporter, Ntcp. FGF15 binds to the FGF4 receptor, leading to the repression of Cyp7a1 expression and reduced bile acid synthesis.
Deletion of the ileal basolateral bile acid transporter identifies the cellular sentinels that regulate the bile acid pool, 2008