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␣-hydroxylase/cytochrome P450 7␣-hydroxylase (7␣-hydroxylase), which is the rate-limiting and regulatory step of the "classic" pathway. Transcription of the 7␣-hydroxylase gene is highly regulated. Two nuclear receptors, hepatocyte nuclear factor 4␣ (HNF-4␣) and ␣ 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␣-hydroxylase transcription. In this study, we show evidence that the p38 kinase pathway plays an important role in 7␣-hydroxylase expression and hence in bile acid synthesis. Inhibition of p38 kinase activity in primary hepatocytes results in ϳ5-10-fold reduction of 7␣-hydroxylase mRNA. This suppression is mediated, at least in part, through HNF-4␣. Inhibition of p38 kinase activity diminishes HNF-4␣ 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␣ protein and a concomitant induction of 7␣-hydroxylase expression that is blocked by inhibiting the p38 pathway. These studies show a functional link between the p38 signaling pathway, HNF-4␣, and bile acid synthesis.
Cardiovascular diseases (CVDs), the leading cause of death worldwide, are associated with high plasma cholesterol levels. The conversion of cholesterol to bile acids (BAs) accounts for about 50% of total cholesterol elimination from the body. This phenomenon occurs in the liver and is regulated by nuclear receptors such as hepatocyte nuclear factor-4α (HNF-4α). Therefore, special emphasis is given to HNF-4α properties and its multifunctional role, particularly in the conversion of cholesterol to BAs. HNF-4α is a highly conserved transcription factor that has the potential capacity to transactivate a vast number of genes, including CYP7 which codes for cholesterol 7α-hydroxylase (CYP7A1; EC 1.14.13.17), the rate-limiting enzyme of BA biosynthesis. The fact that HNF-4α transactivation potential can be modulated via phosporylation is of particular interest. Additional findings on structural and functional characteristics of HNF-4α may eventually present alternatives to control the levels of cholesterol in the body and consequently reduce the risk of CVDs.
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