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Glucagon and cAMP inhibit cholesterol 7α‐hydroxylase (CYP7a1) gene expression in human hepatocytes: Discordant regulation of bile acid synthesis and gluconeogenesis
Author(s) -
Song KwangHoon,
Chiang John Y. L.
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20919
Subject(s) - cholesterol 7 alpha hydroxylase , biology , phosphoenolpyruvate carboxykinase , g protein coupled bile acid receptor , glucagon , bile acid , endocrinology , medicine , small heterodimer partner , gluconeogenesis , regulation of gene expression , biochemistry , gene , transcription factor , nuclear receptor , metabolism , insulin
The gene encoding cholesterol 7α‐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 γ co‐activator 1α (PGC‐1α) 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 PKA‐responsive region located within the previously identified HNF4α binding site in the human CYP7A1 promoter. Glucagon and cAMP increased HNF4α phosphorylation and reduced the amount of HNF4α present in CYP7A1 chromatin. Our findings suggest that glucagon inhibited CYP7A1 gene expression via PKA phosphorylation of HNF4α, which lost its ability to bind the CYP7A1 gene and resulted in inhibition of human CYP7A1 gene transcription. In conclusion , this study unveils a species difference in nutrient regulation of the human and mouse CYP7A1 gene and suggests a discordant regulation of bile acid synthesis and gluconeogenesis by glucagon in human livers during fasting. (H EPATOLOGY 2005.)