Bile acids: regulation of synthesis, 2009
Bile acid synthesis.
Bile acid synthesis. Bile acids are synthesized from cholesterol in the liver through two pathways: the classic pathway and the alternative pathway. In human liver, bile acid synthesis mainly produces two primary bile acids, cholic acid (CA), and chenodeoxycholic acid (CDCA). Key regulatory enzymes in both pathways are indicated. CYP7A1 catalyzes the first the rate-limiting step in the classic pathway to convert cholesterol into 7α-hydroxycholesterol, while CYP27A1 initiates the alternative pathway by converting cholesterol into 27-hydroxycholesterol, which is then 7α-hydroxylated by oxysterol 7α-hydroxylase (CYP7B1). CYP8B1 regulates the cholic acid synthesis in the classic pathway. In the intestine, primary bile acid CA and CDCA are dehydroxylated at the 7α-position by the bacterial enzymes to produce the secondary bile acids, deoxycholic acid (DCA), and lithocholic acid (LCA), respectively.
Regulation of Bile Acid and Cholesterol Metabolism by PPARs, 2009
Reverse cholesterol transport. In the intestine, dietary uptake of cholesterol is mediated by NPC1L1. ABCG5/G8 effluxes sitosterols and cholesterol back to the intestine lumen and limits intestinal sterol absorption. Oxysterols activate LXR, which induces ABCA1 and ABCG1 to transport cholesterol to ApoA1 and HDL, respectively. PPARα activation reduces NPC1L1 and fractional cholesterol absorption, and may promote cholesterol secretion by stimulating CYP27A1 and LXR activation of ABCA1 and ABCG1. In macrophages, LDLR and CD36 mediate LDL and oxidized-LDL uptake, respectively. CYP27A1 converts cholesterol into 27-hydroxycholesterol, which may activate LXR and cholesterol efflux via ABCA1 and ABCG1. Cholesterol can also be secreted in the form of 27-hydroxycholesterol. PPARγ induces CYP27A1 and LXR, and positively regulates the cholesterol efflux from macrophages. PPARα induces ApoA1 and inhibits CETP, and thus increases circulating HDL-C levels.
Kegg
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). (Role of NAC and Gly administration?)
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.
Classic
An inborn error of bile acid synthesis (3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency) presenting as malabsorption leading to rickets, 1999
Function
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
Central anorexigenic actions of bile acids are mediated by TGR5, 2021
