Activation of bile acid biosynthesis by the p38 mitogen-activated protein kinase (MAPK) -: Hepatocyte nuclear factor-4α phosphorylation by the p38 MAPK is required for cholesterol 7α-hydroxylase expression

Bile acids are required for intestinal absorption and biliary solubilization of cholesterol and lipids. In addition, bile acids play a crucial role in cholesterol homeostasis. One of the key enzymes in the bile acid biosynthetic pathways is cholesterol 7 alpha-hydroxylase/cytochrome P450 7 alpha-hydroxylase (7 alpha-hydroxylase), which is the rate-limiting and regulatory step of the "classic" pathway. Transcription of the 7 alpha-hydroxylase gene is highly regulated. Two nuclear receptors, hepatocyte nuclear factor 4 alpha (HNF-4 alpha) and alpha(1)-fetoprotein transcription factor, are required for both transcription and regulation by different physiological events. It has been shown that some mitogen-activated protein kinases, such as the c-Jun N-terminal kinase and the ERK, play important roles in the regulation of 7 alpha-hydroxylase transcription. In this study, we show evidence that the p38 kinase pathway plays an important role in 7 alpha-hydroxylase expression and hence in bile acid synthesis. Inhibition of p38 kinase activity in primary hepatocytes results in similar to 5-10-fold reduction of 7 alpha-hydroxylase mRNA. This suppression is mediated, at least in part, through HNF-4 alpha. Inhibition of p38 kinase activity diminishes HNF-4 alpha nuclear protein levels and its phosphorylation in vivo and in vitro, and it renders a less stable protein. Induction of the p38 kinase pathway by insulin results in an increase in HNF-4 alpha protein and a concomitant induction of 7 alpha-hydroxylase expression that is blocked by inhibiting the p38 pathway. These studies show a functional link between the p38 signaling pathway, HNF-4 alpha, and bile acid synthesis.