Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Pharmacy (PharmD)

First Advisor

Angela L. Slitt

Abstract

Steatosis is fat deposition in liver arising from conditions like obesity, diabetes, and/or alcohol consumption. It is a benign condition with normal liver function, and can often be reversed. Both alcoholic and non-alcoholic liver steatosis can further progress to irreversible steatohepatitis to cirrhosis and substantial loss of liver function. Nuclear factor E2 related factor 2 (Nrf2) is a transcription factor known to combat oxidative stress in the cell. The contribution of Nrf2 to other cellular functions, such as lipid homeostasis is emerging. The work herein assessed how enhanced Nrf2 activity impacts progression of hepatic steatosis with long-term high fat diet (HFD) feeding. C57BL/6 and Keap1- Knockdown (Keap1-KD) mice, which exhibit enhanced Nrf2 activity, were fed a HFD for 24 weeks. Keap1-KD mice had higher body weight, liver weight and higher hepatic fat deposition. Lipogenic gene expression was also higher in livers of Keap1-KD mice fed HFD. Next, the work herein studied effect of steatosis and cirrhosis on Nrf2 and drug transporter expression in human livers. Transporters aid in hepatobiliary excretion of many drugs and toxic chemicals, and can be determinants of drug-induced liver injury. Alcohol cirrhosis increased efflux transporter mRNA and protein expression in human livers as compared to normal non-steatotic livers. It was observed that transporter expression alterations with steatosis were much less severe as compared to cirrhosis. In order to demonstrate the effects of these drug transporter and metabolizing enzyme alterations on pharmacokinetics, we conducted oral Bisphenol A (BPA) disposition study in diet-induced obese mice. The mice were administered deuterated BPA orally and blood levels were detected for BPA and BPA metabolites at times after BPA administration. Increased BPA clearance was observed in DIO mice, as compared to lean controls, attributed to increased phase II conjugation enzyme Ugt and biliary efflux transporter Abcc2 expression. In conclusion, constitutive activity of Nrf2 increases susceptibility to mice to develop liver steatosis; and human livers with steatosis and alcohol cirrhosis have altered expression of drug transporters, which may result in xenobiotic disposition alterations.

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