Glucagon and cAMP inhibit cholesterol 7alpha-hydroxylase (CYP7A1) gene expression in human hepatocytes: discordant regulation of bile acid synthesis and gluconeogenesis.

Glucagon and cAMP inhibit cholesterol 7alpha-hydroxylase (CYP7A1) gene expression in human hepatocytes: discordant regulation of bile acid synthesis and gluconeogenesis.

Song Kwang-Hoon; Chiang John Y L

Hepatology (Baltimore, Md.)

2006

2006-01

The gene encoding cholesterol 7alpha-hydroxylase (CYP7A1) is tightly regulated to control bile acid synthesis and maintain lipid homeostasis. Recent studies in mice suggest that bile acid synthesis is regulated by the fasted-to-fed cycle, and fasting induces CYP7A1 gene expression in parallel to the induction of peroxisome proliferators-activated receptor gamma co-activator 1alpha (PGC-1alpha) and phosphoenolpyruvate carboxykinase (PEPCK). How glucagon regulates CYP7A1 gene expression in the human liver is not clear. Here we show that glucagon and cyclic adenosine monophosphate (cAMP) strongly repressed CYP7A1 mRNA expression in human primary hepatocytes. Reporter assays confirmed that cAMP and protein kinase A (PKA) inhibited human CYP7A1 gene transcription, in contrast to their stimulation of the PEPCK gene. Mutagenesis analysis identified a

*Gluconeogenesis; 8-Bromo Cyclic Adenosine Monophosphate/*pharmacology; Adolescent; Bile Acids and Salts/*biosynthesis; Cells; Cholesterol 7-alpha-Hydroxylase/*genetics; Chromatin/metabolism; Cultured; Cyclic AMP-Dependent Protein Kinases/physiology; Enzymologic/*drug effects; Female; Gene Expression Regulation; Genetic/drug effects; Glucagon/*pharmacology; Hepatocyte Nuclear Factor 4/genetics/metabolism; Hepatocytes/*enzymology; Humans; Male; Messenger/analysis; Middle Aged; Organ Specificity; Phosphorylation; RNA; Transcription

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