Symposium: Dietary Fat and Gene Expression Diet-Disease Interactions at the Molecular Level: An Experimental Paradigm1'2 JIM KAPUT, DEBORAH SWARTZ, ELIZABETH PAISLEY, HEATHER MANG1AN, WILLIAM L. DANIEL AND WILLARD J. VISEK Department of Internal Medicine, University of Illinois College of Medicine, Urbana, Illinois 61801 ABSTRACT High levels of dietary fat enhance the severity of certain cancers, obesity, and cardiovascular diseases in susceptible individuals usually after prolonged exposure. We have been developing methods for identifying and characterizing genes regulated by the level of dietary fat for the purpose of determining their role in diseases promoted by high levels of dietary fat, particularly cancer and atherosclerosis. Our protocol employs semi-purified diets of reproducible composition fed to normal inbred mice to obtain reagents for studying of molecular events that lead to pathology. Our early studies demonstrated that different levels of dietary fat cause the accumulation or change in expression of two genes, designated Lfm-1 and Lfm-2 (low fat mammary) in mouse mammary glands and selected other tissues. The Lfm-2 gene is stearoyl CoA desaturase, a gene known to be regulated by dietary fat and insulin levels. The Lfm-1 gene is highly similar to the e subunits of bovine and rat FjFo-ATPases. A Lfm-1 restriction fragment length polymorphism located on chromosome 8 is associated with atherosclerosis in certain inbred strains of mice warranting additional tests to determine whether it is involved in initiation or promotion of heart disease. The experimental approach has the potential for analyzing genes regulated by approximately 50 essential nutrients or other dietary constituents. A potential outcome of this research is the development of reagents which can be used to predict the risk of diet-related diseases in individuals. J. Nutr. 124: 1296S-1305S, 1994. INDEXING KEY WORDS: •gene expression •atherosclerosis •cancer •genetics Obesity, cancer, and cardiovascular diseases de velop following abnormal changes in the expression of unknown numbers of genes (Bishop 1991, Coleman 1978, MacCluer and Kammerer 1991). Because long term consumption of high fat diets is associated with these conditions (reviewed in Committee on Diet and Health 1989, Henderson et al. 1991, Public Health Service 1988), it is likely that diet directly or in- 0022-3166/94 $3.00 ©1994 American Institute of Nutrition. directly regulates the expression of genes involved in initiation or promotion of pathological conditions. Identifying and characterizing these genes should en hance our understanding of the role that diet plays in these processes and may reveal aspects of the molecular mechanisms underlying normal and ab normal metabolism. Some of the genes involved in chronic, noninfec- tious diseases have been identified because they play a major role in specific physiological processes (reviewed in MacCluer and Kammerer 1991). Muta tions in the LDL receptor, for example, result in atherosclerosis. However, only 5% of cardiac patients have this type of familial hypercholesterolemia (reviewed in MacCluer and Kammerer 1991). It is unlikely that every gene contributing to a disease will be identified by searching for mutations of single genes in the general population because some genes involved in these diseases may be essential for life, normal development, or have pleiotropic effects. Apolipoprotein B deficient mice, for example, show lipid profiles similar to hypobetalipoproteinemia but develop exencephalus and hydrocephalus (Homanics et al. 1992). 'This research was supported by funds from a USD A Grant (91- 01631], the Department of Food Sciences, and the Colleges of Agriculture and Medicine at the University of Illinois. D.S. was supported by NIH Training Grant (PHS 5T32-AM07497) and an American Institute of Nutrition Predoctoral Fellowship. E.P. is an American Institute of Nutrition Predoctoral Fellow. 2Presented as part of the symposium "Dietary Fat and Gene Expression," given at the Experimental Biology '93 meeting, New Orleans, LA March 28-April 1, 1993. The symposium was spon sored by the American Institute of Nutrition and the American Society for Clinical Nutrition. The guest editor for this symposium was Willard f. Visek, Department of Internal Medicine, University of Illinois College of Medicine, Urbana, IL. Abbreviations used: A x B and B x A, A x C57B46; B x H, C57B46 x C3H; C x B, BALB/c x C57BL/6; cM, centimorgan; Lfm, low fat mammary; RFLP, restriction fragment length polymor phisms. 1296S by guest on April 13, 2012 jn.nutrition.org Downloaded from