Primary hepatocytes treated with non-esterified polyunsaturated fatty acids have been used as a model for describing the inhibitory effects of dietary polyunsaturated fats on lipogenic gene expression. This model resembles starvation or uncontrolled diabetes but not dietary fat ingestion, which is delivered to liver via chylomicron remnants. Chylomicron remnants enriched with polyunsaturated fatty acids stimulate a unique pattern of intracellular signaling. These remnants enhance p38 mitogen activated protein kinase (MAPK) activity but do not inhibit insulin signaling or induce extracellular-signal related kinase (ERK) or AMP-activated protein kinase (AMPK) activation as do non-esterified polyunsaturated fatty acids. Polyunsaturated fatty acids-enriched remnants and non-esterified polyunsaturated fatty acids both inhibit the rate of fatty acid synthesis and the expression of the lipogenic genes, particularly those regulated by sterol response element binding protein-1c (SREBP-1c). Saturated fatty acid-enriched remnants fail to inhibit the lipogenic genes indicating that the inhibitory action of dietary polyunsaturated fats involves regulatory mechanisms in liver. In contrast, polyunsaturated fatty acids-enriched remnants fail to inhibit malic enzyme, glucokinase, L-pyruvate kinase, and cytochrome P450-7α (Cyp-7α) expression despite their inhibition by non-esterified fatty acids. These genes are regulated independently of SREBP-1c. Therefore, non-esterified polyunsaturated fatty acids do not accurately model all aspects of regulation of hepatic metabolism by dietary fat. Alison Bloom Kohan Mechanism by which Dietary Polyunsaturated Fat Regulates Lipogenic Gene Expression iii ACKNOWLEDGEMENTS I would like to thank all those people who have supported me throughout my Ph.D training. First, I am very thankful for all the help and advice that I have received from my advisor Dr. Lisa Salati in these last 6 years. I have learned how best to teach, learn, and participate in scientific endeavors through her. I appreciate all the time and effort she took to train me from an inexperienced graduate student to the doctoral graduate I am today. I also want to thank all of my lab mates who have made my work in the lab so much more fulfilling. Callee, Viola, and Sushant have at times been my biggest fan club, my most helpful reviewers, and my best critics. At all times, they have been my friends. Without them, I'm not sure how I could have made it through to my defense. I'll miss our scientific discussions, but also they're daily friendship as I start in a new lab. Finally, I want to thank my family. Without the continuous support of my parents, my inlaws, and my husband I could not have succeeded at this goal. My husband Mark, especially, has been an incredible source of strength, support, and love throughout this process. He has always reminded me why I chose this path, and he has always helped me to stay on it. Without him, this would not be possible. ABSTRACT iii. TABLE OF CONTENTS iv. ABBREVIATIONS vi. CHAPTER 1. 1 I. SIGNIF...