Kinase/phosphatase regulation of CYP7A1.

Bile acid synthesis powerfully influences cholesterol homeostasis by providing an avenue for cholesterol disposal and by producing signaling molecules. Bile acids are multifaceted signals, regulating gene expression both by acting as a ligand for the nuclear hormone receptor, farnesoid X-receptor (FXR), and by activating cellular kinases. Though the exact identities and sequence of the signaling events are under investigation, there is mounting evidence for the involvement of c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK) 1/2 pathway. The rate of bile acid synthesis is controlled by the activity of the enzyme, cholesterol 7alpha-hydroxylase, encoded on the CYP7A1 gene. Cholesterol 7alpha-hydroxylase activity and transcription of CYP7A1 gene promoter have been reported to be affected by protein kinases and phosphatases. Cellular protein kinases may provide the mechanisms for coordinate regulation of cholesterol transport, synthesis and breakdown to bile acids. Investigations into the interrelationships between various kinases/phosphatases and nuclear hormone receptors will clarify the roles that these pathways play in bile acid gene regulation and coordinate regulation of lipid metabolism, as well as in the connection of lipid metabolism with disease onset and progression of several human diseases.