Hormonal regulation of the human sterol 27-hydroxylase gene CYP27A1

The mitochondrial sterol 27-hydroxylase (CYP27A1) is a multifunctional cytochrome P450 enzyme that catalyses important hydroxylations in the biosynthesis of bile acids and bioactivation of vitamin D-3. Previous results [Babiker, Andersson, Lund, Xiu, Deeb, Reshef, Leitersdorf, Diczfalusy and Bjorkhem (1997) J. Biol. Chem. 272, 26253-26261] suggest that CYP27A1 plays an important role in cholesterol homoeostasis and affects atherogenesis. In the present study, the regulation of the human CYP27A1 gene by growth hormone (GH), insulin-like growth factor-1 (IGF-1), dexamethasone, thyroid hormones and PMA was studied. HepG2 cells were transfected transiently with luciferase reporter gene constructs containing DNA fragments flanking the 5'-region of the human CYP27A1 gene. GH, IGF-1 and dexamethasone increased the promoter activity by 2-3-fold, whereas thyroxine (T-4) and PMA repressed the activity significantly when measured with luciferase activity expressed in the cells. The endogenous CYP27A1 enzyme activity in the cells was stimulated by GH, IGF-1 and dexamethasone, whereas T-4 and PMA inhibited the activity. Experiments with progressive deletion/luciferase reporter gene constructs indicated that the response elements for GH may be localized in a region upstream to position - 1094 bp. The putative response elements for dexamethasone were mapped to positions between - 792 and - 1095 bp. The - 451 bp fragment of the human CYP27A1 gene was found to confer the activation by IGF-1, and the inhibition by T-4 and PMA. Results of the present study suggest that CYP27A1 is regulated in human cells by hormones and signal-transduction pathways.