Androgen receptor-mediated regulation of the anti-atherogenic enzyme CYP27A1 involves the JNK/c-jun pathway.
CYP27A1, an enzyme with several important roles in cholesterol homeostasis and vitamin D₃ metabolism, has been ascribed anti-atherogenic properties. This study addresses an important problem regarding how this enzyme, involved in cholesterol metabolism in the liver and peripheral tissues, is regulated. Our results identify the human CYP27A1 gene as a new target for the JNK/c-jun pathway. Initial experiments showed that an inhibitor of c-Jun N-terminal kinase (JNK) downregulated basal CYP27A1 promoter activity whereas overexpression of JNK slightly enhanced promoter activity. Androgen receptor (AR)-mediated upregulation of mRNA levels and endogenous enzyme activity was recently reported. In the present study, the AR antagonist nilutamide blocked the androgen induction of CYP27A1. The present data revealed that inhibition of the JNK/c-jun pathway abolishes the AR-mediated effect on CYP27A1 transcription and enzyme activity, whereas overexpression of JNK markedly increased androgenic upregulation of CYP27A1. In conclusion, the current results indicate involvement of the JNK/c-jun pathway in AR-mediated upregulation of human CYP27A1. The link to JNK signaling is interesting since inflammatory processes may upregulate CYP27A1 to clear cholesterol from peripheral tissues.
Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Box 578, S-75123 Uppsala, Sweden.
Maria
M
Norlin
Hanna
H
Pettersson
Wanjin
W
Tang
Kjell
K
Wikvall
D000873:Anthracenes / Q000494:pharmacology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000873:Anthracenes; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D011944:Receptors, Androgen; C432165:pyrazolanthrone; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D048031:JNK Mitogen-Activated Protein Kinases