Information - Concepts In Nutrigenomics - Macronutrients

Unbalanced Diets Contribute to Disease

Unbalanced intake of any of the three major macronutrients - fat, carbohydrates, or protein - contribute to the initiation, development, progression, and/or severity of chronic diseases.  Fad diets, which are often unbalanced, may produce short-term weight loss, but are often unhealthy over long time periods.

Fats (Dietary Lipids)

Intake of saturated fatty acids (SFA) and high fat diets are correlated with increased levels of LDL cholesterol, the principal target of intervention for coronary disease risk reduction.  In addition to cardiovascular diseases (CVD), SFA may contribute to obesity and diabetes because these diseases are also characterized by dyslipidemias.  Large numbers of human and laboratory animal experiments support the associations predicted from epidemiological studies.

Human studies showing associations between amount and type of fat and prostate, colorectal, breast cancers are inconsistent.  Laboratory animal studies in which genotype and environment can be more rigorously controlled consistently show that type and level of dietary fat are associated with incidence and strongly associated with promotion of certain cancers.  Molecular studies that rely upon candidate genes identified from diet- and genotype-controlled laboratory animal studies may provide better candidate genes for human molecular epidemiology studies examining the role of dietary fats in human cancers. 

Carbohydrates 

Dietary guidelines continue to emphasize diets low in saturated and total fat to reduction in the risk of obesity and its related comorbidities - diabetes and cardiovascular disease.  Spurred by the increase in obesity and diabetes while fat intake barely decreased (36.4 to 34.1% of total calories) between 1970 and 1990, a new focus of a number of epidemiological studies is carbohydrates.  Simple and complex carbohydrates are metabolized at different rates and therefore have differential effects on blood glucose concentrations.  Refined simple sugars or some polysaccharides that are cleaved rapidly to glucose produce higher blood glucose levels and a greater demand for insulin.

Protein

Analyzing the effect of protein intake on health is difficult because fat and micronutrients are significant and variable components of meat.  Broiling, frying, and baking differentially alters the chemical composition of meat and other foods and in some cases, creates nitrosamines and other carcinogens.  Different ways of preparing foods may produce different amounts and types of natural or heat-generated dietary chemicals thereby introducing confounding into epidemiological analyses.  With these caveats, meat consumption appears to be associated with increased chronic disease risk  including bowel and colorectal cancers, and Type 2 diabetes.  Molecular epidemiology suggests that certain genes, for example, epoxide hydrolase, glutathione-S-transferase, and other detoxifying enzymes may modify the effect of meat on disease risk.

Increased metabolism of protein also will increase the production of urea, with the corresponding increase in membrane permeable ammonia (NH3) and its ionized form NH4+.  Ammonia released in the alimentary tract of animals by microbial enzymes can disrupt metabolic pathways, alter the gastrointestinal mucosa, inhibit rates of growth in animals, alter brain function and promote cancer.

Caloric restriction

Early epidemiological studies neglected to account for the differences in energy content between carbohydrates and proteins (each at ~4 kcal/gr) and lipids (~9 kcal/gr).  Virtually all association studies show an increased risk for common diseases with increased energy intake.  Laboratory animal studies have consistently shown that reducing caloric intake is the most effective means to reduce the incidence and severity of chronic diseases, retard the effects of aging, and increase genetic fidelity.  Experiments in Saccharomyces cerevisiae suggest that caloric restriction may produce its largest effects by increasing respiration with the concomitant increase in the NAD:NADH.  Energy balance may be monitored through changes in reducing equivalents.  NAD also is a cofactor for Sir2, a histone deacetylase involved in chromatin silencing of nucleolar rDNA, telomere, and mating type locus.  In mammals, other cellular targets, such as uncoupling proteins, and neuroendocrine peptides (e.g., leptin) of the central nervous system (CNS) are potential targets of regulation by caloric restriction.

Summary

The hunt for a single macronutrient or micronutrient that will prevent chronic diseases is destined to fail.  It is more likely that dietary imbalances - from micronutrient deficiencies to overconsumption of macronutrients or dietary supplements - are the modifiers of metabolism and potentiators of chronic disease.  Although the complexity of food and genotypic variations appear daunting, molecular and genetic technologies may provide the means for identifying causative genes (or their variants) and the nutrients that regulate them.

Further reading

Kaput, J and Rodriguez, RL 2004.  Nutritional Genomics: the next frontier in the postgenomic era.  Physiological Genomics  16, 166-177. PMID: 14726599  (free access)

Krauss, RM and Siri, PW. 2006.  Dietary and Genetic Effects on Atherogenic Dyslipidemia.  In Nutritional Genomics: Discovering the Path to Personalized Nutrition.  Kaput, J and Rodriguz, R (eds). Wiley and Sons, Inc. NY. 2006. pp 153-173

Krauss, RM 2006. Dietary and Genetic Probes of Atherogenic DyslipidemiaArteriosclerosis, Thrombosis, and Vascular Biology 25, 2265-2272. PMID: 16166563

Liu S and Willett WC. 2002. Dietary glycemic load and atherothrombotic risk. Curr Atheroscler Rep. 4, 454 - 461. PMID: 12361493