ReviewRegulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms
Section snippets
Pathways of bile acid synthesis
Cholesterol degradation to bile acids in the liver can be initiated by either cholesterol 7α-hydroxylase (CYP7A1) of the classic (neutral) pathway, or by mitochondrial sterol 27-hydroxylase (CYP27A1) of the alternative (or acidic) pathway. In the classic pathway, modification of the sterol nucleus including saturation of the double bond, epimerization of the 3β-hydroxyl group, and hydroxylation at the 7α and 12α-positions precedes oxidative cleavage of the side chain. In the alternative
Nuclear receptor regulation of bile acid synthesis
The enterohepatic circulation of bile acids is an important physiological process that generates bile flow and feedback controls bile acid synthesis. The rate of bile acid synthesis, bile acid composition, and bile acid pool size vary significantly depending on the species, sexes, genetics, pathophysiological conditions, and environmental factors such as diets and drugs [10], [11]. Many nuclear receptors have been found to play pivotal roles in regulating transcription of the genes involved in
Bile acid regulation of lipid metabolism
Bile acids not only regulate bile acid synthesis, but also regulate other pathways in the enterohepatic system including bile acid transport and absorption, RCT, lipoprotein metabolism, triglyceride metabolism, and drug metabolism. Ablation of the Fxr gene in mice increases serum bile acid, cholesterol and triglycerides, and results in a proatherogenic serum lipoprotein profile, consistent with the roles of FXR in bile acid synthesis, excretion and lipid metabolism [104]. Fig. 2 shows FXR, LXR,
Mechanisms of bile acid feedback inhibition of gene transcription
It has been very difficult to decipher the mechanism of bile acid inhibition of CYP7A1 gene transcription. Many lines of evidence suggest that multiple mechanisms are involved in bile acid feedback inhibition of CYP7A1 gene transcription. These multifaceted regulatory mechanisms may be separated to SHP-dependent and SHP-independent mechanisms illustrated in Fig. 3.
Conclusion and future perspectives
Cloning and genetic knockout of the CYP7A1 and other genes involved in bile acid synthesis and identification of human patients with mutations in these genes have greatly advanced our understanding of the regulatory mechanism of bile acid synthesis. A recent discovery that bile acids and oxysterols are the endogenous ligands of several nuclear receptors has generated a plethora of interest in bile acid research. These exciting advances have greatly improved our knowledge on hepatic lipid
Acknowledgements
This work is supported by grants NIH DK44442 and DK58379.
References (155)
Ursodeoxycholic acid for primary biliary cirrhosis: treat early to slow progression
J Hepatol
(2003)- et al.
Side chain hydroxylations in bile acid biosynthesis catalyzed by CYP3A are markedly up-regulated in Cyp27−/− mice but not in cerebrotendinous xanthomatosis
J Biol Chem
(2001) - et al.
cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytopic membrane proteins that synthesize a potent oxysterol regulator of lipid metabolism
J Biol Chem
(1998) - et al.
Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover
J Biol Chem
(2003) - et al.
Expression cloning of an oxysterol 7α-hydroxylase selective for 24- hydroxycholesterol
J Biol Chem
(2000) - et al.
Identification and characterization of a putative bile acid responsive element in cholesterol 7α-hydroxylase gene promoter
J Biol Chem
(1994) - et al.
The nuclear receptor superfamily: the second decade
Cell
(1995) - et al.
Orphan nuclear receptors: the exotics of xenobiotics
J Biol Chem
(2001) - et al.
Nuclear receptor coactivators
Curr Opin Cell Biol
(1997) - et al.
Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple functions
J Steroid Biochem Mol Biol
(1999)