Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

Abstract

Prevalence of non-alcoholic fatty liver disease (NAFLD) and obesity both in the young and adult population is increasing at an alarming rate globally. Along with traditional risk factors, such as diet and sedentary life style, exposure of environmental chemicals is suspected to be a risk factor for metabolic disruption. Moreover, the ‘fetal basis of adult disease’ hypothesis implicates that early life exposure to environmental chemicals is more impactful in causing lipid homeostasis disturbances than exposure in maturity. Nuclear factor E2 related factor 2 (Nrf2) is a cytoprotective transcription factor known to combat oxidative stress. The contribution of Nrf2 to other cellular functions, such as lipid homeostasis relevant to liver and adipose tissue is relatively new emerging area. The work herein assessed the role of Nrf2 in augmenting environmental chemical induced NAFLD and adipogenesis. CD-1 mice were exposed to bisphenol A (BPA) perinatally and peripubertally until age of 5 week at 25 ug/kg BW/day and effect of this exposure on hepatic lipid disturbances was evaluated at pubertal (week 5) and adult age (week 39). Developmental exposure of BPA increased hepatic lipid accumulation in both young, as well as adult mice. BPA also increased Nrf2 expression in these animals at both ages. Nrf2 binding to predicted anti-oxidant response elements on the Srebp-1c promoter, a master regulator of denovo lipogenesis, elucidated a potential regulatory role of Nrf2 in lipogenesis. BPA exposure also increased Nrf2 binding to this new putative ARE by about 2 fold. Epigenetic reprogramming of chromatin upon developmental exposure of environmental xenobiotics is a potential mechanism for increasing susceptibly to diseases, such as like NALFD. BPA exposure from gestation day 8 through purberty caused hypomethylation in select regions of promoters that encode for proteins involved in lipogenesis (e.g. Srebp-1c), as well as the antioxidant response (e.g. Nrf2). The work further depicts an undescribed role for Nrf2 in the regulation of lipogenesis via regulation of Srebp-1c.

In connection to the findings above, as well as other findings in our laboratory that pointed to Nrf2 having a role in promoting hepatic lipid accumulation, it was decided to evaluate whether chemicals that induce lipid accumulation can do so in association with Nrf2 activation. Next, the role of Nrf2 in lipid accumulation was further characterized using adipose tissue in presence of perfluorooctane sulfonic acid (PFOS). In rodent and human preadipocytes, PFOS exposure elevated adipogenic process by increasing expression of key regulators of adipose differentiation. PFOS-induced adipogenesis was associated with increase in Nrf2 expression and its transcriptional activity.

In conclusion, the environmental contaminants, BPA and PFOS alter lipid homeostasis in liver and adipose tissue respectively. Concurrent increase in Nrf2 expression, and its transcription regulation on lipogenic mediators was demonstrated.

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