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.
Bile acid synthesis regulation
The first step is cholesterol 7α hydroxylase (CYP7A1/CYP7B1) a cytochrome
Effect of thyroid hormone on hepatic cholesterol 7α hydroxylase, LDL receptor, HMG-CoA reductase, farnesyl pyrophosphate synthetase and apolipoprotein A-I mRNA levels in hypophysectomized rats, 1990
THE GENE
CP7A1_HUMAN (Kegg)
- Functions as a critical regulatory enzyme of bile acid biosynthesis and cholesterol homeostasis. Catalyzes the hydroxylation of carbon hydrogen bond at 7-alpha position of cholesterol, a rate-limiting step in cholesterol catabolism and bile acid biosynthesis (PubMed:12077124, PubMed:19965590, PubMed:2384150).
CP7B1_HUMAN (Kegg)
- Usually metabolizes steroids carrying a hydroxy group at position 3, functioning as a 3-hydroxy steroid 7-alpha hydroxylase (PubMed:24491228).
Hydroxylates oxysterols, including 25-hydroxycholesterol and (25R)-cholest-5-ene-3beta,26-diol toward 7-alpha hydroxy derivatives, which may be transported to the liver and converted to bile acids (PubMed:9802883, PubMed:10588945).
Via its product 7-alpha,25-dihydroxycholesterol, a ligand for the chemotactic G protein-coupled receptor GPR183/EBI2, regulates B cell migration in germinal centers of lymphoid organs, thus guiding efficient maturation of plasma B cells and overall antigen-specific humoral immune response (By similarity).
7-alpha hydroxylates neurosteroids, including 3beta-hydroxyandrost-5-en-17-one (dehydroepiandrosterone) and pregnenolone, both involved in hippocampus-associated memory and learning (PubMed:24491228).
- Abstract
The effects of thyroid hormone on cholesterol 7α hydroxylase, LDL receptor, HMG-CoA reductase, apo A-I and farnesyl pyrophosphate synthetase hepatic mRNA levels were investigated in hypophysectomized rats. Of these mRNAs cholesterol 7α hydroxylase responded the most rapidly and required the lowest dose of T3. Maximal mRNA levels were reached one hr after T3 administration and required 10 μg/100g of body weight. These results suggest that the hypocholesterolemic effect of thyroid hormone may be mediated by a primary effect on cholesterol 7α hydroxylase gene expression.
Bile acids: regulation of synthesis, 2009
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
