Activation of bile acid biosynthesis by the p38 mitogen-activated protein kinase (MAPK): hepatocyte nuclear factor-4alpha phosphorylation by the p38 MAPK is required for cholesterol 7alpha-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 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.
Xu
Zhumei
Z
Department of Biochemistry and Molecular Biology, Microbiology, Medical College of Virginia at Virginia Commonwealth University, Richmond, Virginia 23298-0614, USA.
Tavares-Sanchez
Olga L
OL
Li
Quanzhong
Q
Fernando
Josephine
J
Rodriguez
Carmen M
CM
Studer
Elaine J
EJ
Pandak
William M
WM
Hylemon
Phillip B
PB
Gil
Gregorio
G
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002478:Cells, Cultured; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D001647:Bile Acids and Salts; D004791:Enzyme Inhibitors; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D012333:RNA, Messenger; D002790:Cholesterol 7-alpha-Hydroxylase; D048051:p38 Mitogen-Activated Protein Kinases