Hepatic biliary excretion is an essential process that exists to aid the in the elimination of foreign chemicals, and protects the body from accumulating chemicals and toxicants. Understanding the underlying processes by which specific transporters that aid in biliary excretion are regulated is integral for improving human health, predicting chemical exposure, and preventing disease associated with chemical exposure. Nutrition (i.e. dietary intake, fasting, and caloric restriction [CR]) is an important factor in the susceptibility/progression of a variety of diseases associated, especially those associated with aging and environmental exposure. Trans- resveratrol (RES) is an antioxidant in red wine with anti-aging effects that mimic CR, and is an agonist for the deacetylase Sirt1. Understanding how RES, fasting, and CR regulate the expression and function of liver transporters involved in hepatic excretion (i.e. Multidrug Resistance-Associated Proteins [MRPS]) is important for understanding mechanisms by which nutrition is beneficial against chemical exposure and disease. Preliminary data demonstrates that RES increases the mRNA and protein expression of Mrp1-4, 6 in human hepatocytes and mouse liver along with induction of genes regulated by the transcription factor Nuclear Factor- E2-Related Factor 2 (NRF2), suggesting that RES activates human and mouse NRF2. Additionally, liver Mrp1, 2, and 3 expression, along with Ho-1 expression is increased during fasting, in which liver cAMP is increased and Protein Kinase A (PKA) is activated. Furthermore, constitutive activation of NRF2 in livers of KEAP1-null mice results in increased Mrp1-5 expression. The hypothesis of this proposal is that RES, fasting, and CR induce expression of MRPs through Sirt1- and PKA- upstream regulation of NRF2-mediated transcription.
Specific aims will determine whether 1) RES treatment induces MRP expression in human hepatocytes and mouse liver through NRF2, 2) fasting and CR induce MRP expression via uptream activation of PKA and downstream activation of Nrf2, 3) RES, fasting, and CR induce MRP via Sirt1, and 4) RES, fasting, and CR affect bisphenol A and PBDE disposition in mice. Together, these studies will define mechanisms by which nutritional status alters expression of human and mouse MRPS, as well as demonstrate whether nutritional status enhances biliary excretion of environmental chemicals. Moreover, they will also provide novel insights into mechanisms that regulate NRF2-induction of human MRP genes. Project Narrative Nutritional status is an important factor for the development of many age-related diseases. Some environmental chemicals are thought to exacerbate or contribute to the development/progression of age- related diseases. The purpose of this project is to determine whether nutrition affects mechanisms involved in the liver's ability to uptake and clear environmental chemicals from the body.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES016042-05
Application #
8282836
Study Section
Special Emphasis Panel (ZES1-JAB-C (R2))
Program Officer
Shreffler, Carol K
Project Start
2008-09-08
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$361,672
Indirect Cost
$103,535
Name
University of Rhode Island
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
144017188
City
Kingston
State
RI
Country
United States
Zip Code
02881
Xu, Jialin; Donepudi, Ajay C; More, Vijay R et al. (2015) Deficiency in Nrf2 transcription factor decreases adipose tissue mass and hepatic lipid accumulation in leptin-deficient mice. Obesity (Silver Spring) 23:335-44
Kulkarni, Supriya R; Donepudi, Ajay C; Xu, Jialin et al. (2014) Fasting induces nuclear factor E2-related factor 2 and ATP-binding Cassette transporters via protein kinase A and Sirtuin-1 in mouse and human. Antioxid Redox Signal 20:15-30
Yalcin, Emine B; More, Vijay; Neira, Karissa L et al. (2013) Downregulation of sulfotransferase expression and activity in diseased human livers. Drug Metab Dispos 41:1642-50
Xu, Jialin; Donepudi, Ajay C; Moscovitz, Jamie E et al. (2013) Keap1-knockdown decreases fasting-induced fatty liver via altered lipid metabolism and decreased fatty acid mobilization from adipose tissue. PLoS One 8:e79841
More, Vijay R; Cheng, Qiuqiong; Donepudi, Ajay C et al. (2013) Alcohol cirrhosis alters nuclear receptor and drug transporter expression in human liver. Drug Metab Dispos 41:1148-55
Wen, Xia; Donepudi, Ajay C; Thomas, Paul E et al. (2013) Regulation of hepatic phase II metabolism in pregnant mice. J Pharmacol Exp Ther 344:244-52
Aleksunes, Lauren M; Xu, Jialin; Lin, Eugenia et al. (2013) Pregnancy represses induction of efflux transporters in livers of type I diabetic mice. Pharm Res 30:2209-20
Armstrong, Laura E; Driscoll, Maureen V; Donepudi, Ajay C et al. (2013) Effects of developmental deltamethrin exposure on white adipose tissue gene expression. J Biochem Mol Toxicol 27:165-71
Kulkarni, Supriya R; Xu, Jialin; Donepudi, Ajay C et al. (2013) Effect of caloric restriction and AMPK activation on hepatic nuclear receptor, biotransformation enzyme, and transporter expression in lean and obese mice. Pharm Res 30:2232-47
Chen, Yuan; Song, Xiulong; Valanejad, Leila et al. (2013) Bile salt export pump is dysregulated with altered farnesoid X receptor isoform expression in patients with hepatocellular carcinoma. Hepatology 57:1530-41

Showing the most recent 10 out of 15 publications