As a major detoxicating enzyme in human liver, hydroxysteroid sulfotransferase (SULT2A) catalyzes the sulfonation of biologically important endogenous and xenobiotic substrates, including hormones, cholesterol intermediates, pharmaceuticals and procarcinogens. Sulfonated sterol metabolites are emerging as novel candidates for the modulation of nuclear receptor activity in the liver. We previously demonstrated that SULT2A transcription is regulated by lipid-sensing nuclear receptors in human and rodent liver. Recently, hyposulfatemic mice with nullified expression of a renal sulfate transporter were found to develop altered hepatic lipid and cholesterol metabolism along with selectively induced expression of hepatic SULT2A. These results suggest a role for sulfate homeostasis as an under-studied facet of metabolic disease. Our hypothesis is that hepatic SULT2A1 is an environmentally-sensitive determinant of liver X receptor (LXR) signaling. SULT2A1 catalyzes the sulfonation of endogenous sterols, thereby modulating the expression of LXR target genes, including SULT2A1 itself. SULT2A1 transcription is regulated (1) by the xenobiotic-sensing receptor, pregnane X receptor (PXR), through interactions involving hepatocyte nuclear factor 4? (HNF4?) and (2) under conditions of sulfate depletion, through the above-described LXR-mediated autoregulatory mechanism.
The specific aims of the proposed research are to: (1) Define the roles of HNF4? and PXR in the modulation of human hepatic SULT2A1 transcription by rifampicin, (2) Define the mechanism mediating SULT2A up-regulation in response to hyposulfatemia, (3) Identify endogenous hepatic sterols that represent physiological substrates for SULT2A1, and (4) Determine the abilities of sulfonated sterols, relative to their unsulfonated counterparts, to function as modulators of human LXR activity. Overall, this work has implications for metabolic disturbances in cholesterol and sulfate metabolism in humans, and will provide new insights into the interactive roles of nuclear receptors and endogenous intermediates as modulators of xenobiotic detoxication and metabolism in human liver.

Public Health Relevance

Atherosclerosis has been aptly called a liver disease of the heart (Davis and Hui, 2004). The environmental modifiers of hepatic lipid metabolism that favor the genesis of insulin resistant diabetes and coronary artery disease are presently unknown. However, a prime candidate is cholesterol sulfotransferase (SULT2A1), a drug- and hormone-metabolizing enzyme in human liver that we hypothesize plays a major role in the control of the essential lipid metabolism pathways leading to heart disease. The proposed research will shed new light on the environmentally-sensitive components of cholesterol metabolism in human liver that serve as a prelude to diabetes, liver and heart disease in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES005823-19
Application #
8277357
Study Section
Special Emphasis Panel (ZRG1-DIG-F (02))
Program Officer
Carlin, Danielle J
Project Start
1992-03-01
Project End
2013-08-31
Budget Start
2012-06-01
Budget End
2013-08-31
Support Year
19
Fiscal Year
2012
Total Cost
$330,673
Indirect Cost
$100,227
Name
Wayne State University
Department
Type
Organized Research Units
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Barrett, Kathleen G; Fang, Hailin; Cukovic, Daniela et al. (2015) Upregulation of UGT2B4 Expression by 3'-Phosphoadenosine-5'-Phosphosulfate Synthase Knockdown: Implications for Coordinated Control of Bile Acid Conjugation. Drug Metab Dispos 43:1061-70
Rondini, Elizabeth A; Fang, Hailin; Runge-Morris, Melissa et al. (2014) Regulation of human cytosolic sulfotransferases 1C2 and 1C3 by nuclear signaling pathways in LS180 colorectal adenocarcinoma cells. Drug Metab Dispos 42:361-8
Duniec-Dmuchowski, Zofia; Rondini, Elizabeth A; Tibbs, Zachary E et al. (2014) Expression of the orphan cytosolic sulfotransferase SULT1C3 in human intestine: characterization of the transcript variant and implications for function. Drug Metab Dispos 42:352-60
Barrett, Kathleen G; Fang, Hailin; Gargano, Mary D et al. (2013) Regulation of murine hepatic hydroxysteroid sulfotransferase expression in hyposulfatemic mice and in a cell model of 3'-phosphoadenosine-5'-phosphosulfate deficiency. Drug Metab Dispos 41:1505-13
Runge-Morris, Melissa; Kocarek, Thomas A; Falany, Charles N (2013) Regulation of the cytosolic sulfotransferases by nuclear receptors. Drug Metab Rev 45:15-33
Fu, Jiaqi; Fang, Hailin; Paulsen, Michelle et al. (2011) Regulation of estrogen sulfotransferase expression by confluence of MCF10A breast epithelial cells: role of the aryl hydrocarbon receptor. J Pharmacol Exp Ther 339:597-606
Salman, Emily D; He, Dongning; Runge-Morris, Melissa et al. (2011) Site-directed mutagenesis of human cytosolic sulfotransferase (SULT) 2B1b to phospho-mimetic Ser348Asp results in an isoform with increased catalytic activity. J Steroid Biochem Mol Biol 127:315-23
Bai, Qianming; Xu, Leyuan; Kakiyama, Genta et al. (2011) Sulfation of 25-hydroxycholesterol by SULT2B1b decreases cellular lipids via the LXR/SREBP-1c signaling pathway in human aortic endothelial cells. Atherosclerosis 214:350-6
Fu, Jiaqi; Weise, Amy M; Falany, Josie L et al. (2010) Expression of estrogenicity genes in a lineage cell culture model of human breast cancer progression. Breast Cancer Res Treat 120:35-45