RT Journal Article
SR Electronic
T1 Regulation of Human Hepatic Hydroxysteroid Sulfotransferase Gene Expression by the Peroxisome Proliferator-Activated Receptor α Transcription Factor
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1257
OP 1267
DO 10.1124/mol.104.005389
VO 67
IS 4
A1 Hai-Lin Fang
A1 Stephen C. Strom
A1 Hongbo Cai
A1 Charles N. Falany
A1 Thomas A. Kocarek
A1 Melissa Runge-Morris
YR 2005
UL http://molpharm.aspetjournals.org/content/67/4/1257.abstract
AB Human hydroxysteroid sulfotransferase or (HUMAN)SULT2A1 catalyzes the sulfonation of procarcinogen xenobiotics, hydroxysteroids, and bile acids and plays a dynamic role in hepatic cholesterol homeostasis. The treatment of primary cultured human hepatocytes with a peroxisome proliferator-activated receptor α (PPARα)-activating concentration of ciprofibrate (10- 4 M) increased (HUMAN)SULT2A1 mRNA, immunoreactive protein, and enzymatic activity levels by ∼2-fold. By contrast, expression of (RAT)SULT2A3, the rat counterpart to (HUMAN)SULT2A1, was induced by treatment of primary hepatocyte cultures with an activator of the pregnane X receptor, but not PPARα. In HepG2 cells, transient transfection analyses of luciferase reporter constructs containing upstream regions of the (HUMAN)SULT2A1 gene implicated a candidate peroxisome proliferator response element (PPRE) at nucleotides (nt) -5949 to -5929 relative to the transcription start site. Site-directed mutagenesis and electrophoretic mobility shift assay studies confirmed that this distal PPRE (dPPRE), a direct repeat nuclear receptor motif containing one intervening nt, represented a functional PPRE. Chromatin immunoprecipitation analysis indicated that the (HUMAN)SULT2A1 dPPRE was also a functional element in the context of the human genome. These data support a major role for the PPARα transcription factor in the regulation of hepatic (HUMAN)SULT2A1. Results also indicate that important species differences govern the transactivation of SULT2A gene transcription by nuclear receptors.