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

Zhumei Xu,Olga L Tavares-Sanchez,Quanzhong Li,Josephine Fernando,Carmen M Rodriguez,Elaine J Studer,William M Pandak,Phillip B Hylemon,Gregorio Gil

doi:10.1074/jbc.m611481200

Zhumei Xu, Olga L Tavares-Sanchez + Show 7 more

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https://doi.org/10.1074/jbc.m611481200

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Abstract

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 7alpha-hydroxylase/cytochrome P450 7alpha-hydroxylase (7alpha-hydroxylase), which is the rate-limiting and regulatory step of the "classic" pathway. Transcription of the 7alpha-hydroxylase gene is highly regulated. Two nuclear receptors, hepatocyte nuclear factor 4alpha (HNF-4alpha) 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 7alpha-hydroxylase transcription. In this study, we show evidence that the p38 kinase pathway plays an important role in 7alpha-hydroxylase expression and hence in bile acid synthesis. Inhibition of p38 kinase activity in primary hepatocytes results in approximately 5-10-fold reduction of 7alpha-hydroxylase mRNA. This suppression is mediated, at least in part, through HNF-4alpha. Inhibition of p38 kinase activity diminishes HNF-4alpha 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-4alpha protein and a concomitant induction of 7alpha-hydroxylase expression that is blocked by inhibiting the p38 pathway. These studies show a functional link between the p38 signaling pathway, HNF-4alpha, and bile acid synthesis.

Highlights

Cholesterol is an important precursor of several compounds that provide key physiological requirements of mammals
Decreased 7␣-Hydroxylase Expression in Primary Rat Hepatocytes Treated with p38 Kinase Inhibitors—To investigate whether the p38 MAPK pathway plays a role in 7␣-hydroxylase expression and bile acid biosynthesis, we incubated primary rat hepatocytes with two specific chemical inhibitors of the p38 kinase, SB 202190 and SB 203580
We provide additional evidence for cross-talk between a nuclear receptor pathway and a signaling pathway, implicating, for the first time, the p38 kinase pathway in bile acid biosynthesis

Summary

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Interleukin-1␤ inhibits the expression of another important gene in bile acid synthesis, sterol 12␣-hydroxylase/CYP8B1, via the JNK pathway (15), presumably by phosphorylating HNF-4␣ and preventing binding to its recognition site in the sterol 12␣-hydroxylase promoter. Specific to bile acid biosynthesis, it has been reported that bile acids inhibit 7␣-hydroxylase gene transcription and HNF-4␣ transactivating potential via activating the JNK/c-Jun pathway (14) This suggests that MAPK phosphorylation of nuclear receptors may be an important regulatory mechanism for bile acid metabolism. A known activator of the p38 kinase pathway, increases nuclear HNF-4␣ protein levels, which results in an induction of 7␣-hydroxylase expression These studies show a functional connection between the p38 signaling pathway and a key liver nuclear receptor, HNF-4␣

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