Fatty Acid Regulation of Gene Transcription

ABSTRACT

Dietary fat has a dual role in human physiology: a) it functions as a source of energy and structural components for cells; b) it functions as a regulator of gene expression that impacts lipid, carbohydrate, and protein metabolism, as well as cell growth and differentiation. Fatty acid effects on gene expression are cell-specific and influenced by fatty acid structure and metabolism. Fatty acids interact with the genome through several mechanisms. They regulate the activity or nuclear abundance of several transcription factors, including PPAR, LXR, HNF-4, NFκB, and SREBP. Fatty acids or their metabolites bind directly to specific transcription factors to regulate gene transcription. Alternatively, fatty acids indirectly act on gene expression through their effects on a) specific enzyme-mediated pathways, such as cyclooxygenase, lipoxygenase, protein kinase C, or sphingomyelinase signal transduction pathways; or b) pathways that involve changes in membrane lipid/lipid raft composition that affect G-protein receptor or tyrosine kinase-linked receptor signaling. Further definition of these fatty acid-regulated pathways will provide insight into the role dietary fat plays in human health and the onset and progression of several chronic diseases, like coronary artery disease and atherosclerosis, dyslipidemia and inflammation, obesity and diabetes, cancer, major depressive disorders, and schizophrenia.

Keywords :

• cell signaling
• eicosanoids
• HNF-4
• lipid rafts
• LXR
• NFκB
• PPAR
• PUFA
• SREBP
• transcription.

ACKNOWLEDGMENTS

I would like to thank members of my laboratory, past and present, for their many contributions to our understanding of fatty acid regulation of gene expression. I would also like to thank William Smith at the University of Michigan, Ann Arbor, MI, Norman Salem, Jr. at NIH, Bethesda, MD, and David Mangelsdorf at Southwestern Medical Center in Dallas, TX for many helpful discussions. A special thanks goes to my colleagues, Drs. Julia Busik and L. Karl Olson, for critical review of the manuscript. Our research has been supported by the National Institutes of Health (DK43220), the US Department of Agriculture (98-35200-6064 and 2003-00857), and the Michigan Agricultural Experiment Station.