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Original Article

Regulation of Human Hepatic Hydroxysteroid Sulfotransferase Gene Expression by the Peroxisome Proliferator-Activated Receptor Transcription Factor

Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan (H-L.F., T.A.K., M.R.M.); Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.C.S., H.C.); and the Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama (C.N.F.)

Abstract

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 (PPAR)-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 PPAR. 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 PPAR 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.

Address correspondence to: Dr. Melissa Runge-Morris, Institute of Environmental Health Sciences, Wayne State University, 2727 Second Ave., Room 4000, Detroit, MI 48201. E-mail: m.runge-morris{at}wayne.edu

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