Diet-Disease Interactions at the Molecular Level: An Experimental Paradigm ,

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 F1F0-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.

Lifestyle Changes May Prevent Cancer

“…Micronutrients, such as vitamins and minerals, are essential nutrients in maintaining good health, while other bioactive molecules, such as phytochemicals (substances of plant origin) and zoochemicals (substances of animal origin) are non-essential, but may improve human health (Kaput, 2006). Recommendations for vitamin and mineral intake exist for different population groups (Institute of Medicine, 1998Medicine, , 2000Medicine, , 2001), but it is not possible to quantify the need for phytochemicals (Smolin & Grosvenor, 2010).…”

Complexity of type 2 diabetes mellitus data sets emerging from nutrigenomic research: A case for dimensionality reduction?

“…Some of these genes are likely to be regulated by diet, since certain diets are risk factors for T2DM [28][29][30]. This means that the susceptibility to disease in each of these individuals will also vary depending upon nutrient intakes that alter expression of genetic information.…”

Nutrient selection through nutrigenomic approaches

“…Since dietary chemicals are regularly ingested and participate indirectly and directly in regulating gene expression, it follows that a subset of genes regulated by diet must be involved in disease initiation, progression, and severity (79,113). The clearest example of genotype-diet interactions in chronic disease is type 2 diabetes, a condition that frequently occurs in sedentary, obese individuals and certain minority groups (13,15).…”

“…The limitation of a unique genotype can be overcome by examining multiple strains of mice (159). One of our laboratories (79,113) introduced a comparative method for laboratory animals that identifies genes regulated differently by dietary variables between two or more genotypes. The genotypes (or inbred strains) of mice are selected based upon their susceptibility to disease caused by diet.…”

“…We found that certain genes were differentially regulated based upon genotype (in this case, A vy /A obese yellow vs. A/a agouti mice) and/or on caloric intake (100% vs. 70% calories) or by the interaction between diet and genotype (Kaput et al, unpublished observations). The criteria for identifying a candidate disease gene are 1) genes must be differentially regulated by diet and/or 2) differentially regulated by genotype and 3) must map to chromosomal regions [e.g., quantitative trait loci (QTL)] associated with the disease (79,113). This approach identifies candidate genes in an unbiased manner, and additional testing in humans or animal models is necessary to validate these.…”