Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology

Supervisor

Dr. Daniel B. Hardy

Abstract

Clinical studies have demonstrated that intrauterine growth restriction (IUGR) offspring, faced with a nutritional mismatch postpartum, have an increased risk of developing the metabolic syndrome. The maternal protein restriction (MPR) rat model has been extensively studied to investigate the adverse effects of a nutritional mismatch in postnatal life of IUGR offspring. Previous studies have demonstrated that MPR leads to impaired function of the liver, an important metabolic organ. However the underlying mechanisms which predispose these offspring to the metabolic syndrome remain elusive. In the following studies, low protein diet during pregnancy and lactation led to IUGR offspring with decreased liver to body weight ratios, followed by increased circulating and hepatic cholesterol levels in both sexes at day 21 and exclusively in the male offspring at day 130. This was attributed to long-term repressive changes in histone modifications at the promoter of cholesterol 7α-hydroxylase, a rate-limiting enzyme that catabolizes cholesterol to bile acids. It was later demonstrated that these IUGR offspring exhibited increased molecular markers of hepatic endoplasmic reticulum (ER) stress and insulin resistance. Finally, these offspring were observed to have an increase in activity of Phase I drug metabolizing hepatic cytochrome p450 (Cyp) dependent enzymes. Collectively, these findings suggest that stable promoter-specific changes to post-translational histone modifications and elevated ER stress in the liver, are key molecular mechanisms whereby IUGR offspring receiving a nutritional mismatch in postnatal life develop high cholesterol and insulin resistance. Moreover, these offspring may require augmented doses of drugs in order to alleviate these symptoms.

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