RDL340

Food & Genes

Term Paper by: Phurpa D. Thungon 2008BB50035 Group: 1 Mehul Bhardwaj 2008BB50021 Group: 2

Table of Contents:

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Abstract................................................................................ Introduction.......................................................................... Nutrigenomics...................................................................... Nutrient Regulation of Gene Expression............................. Cancer Cardiovascular disease Hyperinsulinemia and diabetes Obesity Pregnancy Food and Gene..................................................................... Conclusion........................................................................... Appendices.......................................................................... References...........................................................................

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Abstract

In recent studies scientists across the world have found convincing evidence that the food we eat affects our gene expression, repression and various metabolic activities. Experiments have suggested that each person requires a different diet with a different (for each person) composition of nutrients depending upon their genetic makeup. Things like these have been known in the past but with little knowledge of what goes on at molecular level, for e.g. Diabetics are advised to have a low carbohydrate diet because their insulin machinery is defunct. This has led the scientists from fields like molecular biology, medicine, genomics, and bioinformatics to come together and form a new branch of science called Nutrigenomics. This paper gives a brief introduction to this branch and gives an overview of how food can control gene expression. Several examples have been included to exhibit the strong connection between the nutrient intake and the subsequent gene regulation. Nutrigenomics still has a long way to go before people can choose their food based on their gene map.

Introduction

Till recent years it was thought that a persons disease state is a result of some metabolic syndrome which can be cured only by pharmaceuticals. But new studies have found and established that the first stage of disease is metabolic stress which is caused by lack of proper nutrition. This is opened up new arenas of research related to disease prevention by intake of a proper diet which depends upon a persons genetic makeup (Muller, 2006).

Food
There are 5 major components of food: Carbohydrates, proteins, fats, vitamins, minerals. Each of them is required in different quantities by the body and each serves a different purpose. Carbohydrates turn to glucose which acts as starting point in the glycolytic pathway1. This provides energy to the cell. Proteins get broken down into amino acids which are then used by the cell to form new useful proteins. Similarly, fats provide energy, vitamins acts as co-factors2, minerals act as ligands to stabilize proteins and catalysts for various biochemical reactions. The abundance or scarcity of any of these will disrupt the way in which the numerous machineries in the body work and result in a disease. So it becomes necessary to check on whether our body is getting the right nutrients in the right amount. Genetic and metabolic analysis of the ways in which each nutrient is utilized by the body will lead to a better understanding of the importance of each nutrient. The regulation of gene expression by specific nutrients has become a major frontier for the next generation of nutrition scientists. The techniques of molecular biology help in defining nutrient needs along with outcomes of nutrient excesses. This results can be concluded by events that govern gene transcription, mRNA processing, mRNA stability, and mRNA translation. (JEAN GETZ, 2010)
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Details in Appendix (a) Details in Appendix (b)

Food may impact the cell by interacting directly with DNA (genes), RNA, protein, or other metabolites. Knowing these roles of nutrients and how each of these cell components may cause diseases will allow food to be tailored to an individuals genetic make-up. (JEAN GETZ, 2010)

Genes
A gene is a unit of the DNA or RNA molecule that codes for a protein. It can also be a RNA molecule that has some function in the body. Genes code for proteins in two stages: transcription and translation. During transcription a certain molecule called a RNA polymerase3 binds to the promoter region of the gene and assembles a complimentary RNA strand (called mRNA). Thus to block gene expression, we can either use a repressor to prevent the RNA polymerase to bind to the DNA or make the promoter region inaccessible. During translation the mRNA enters a ribosome machinery and codes for a protein. The functioning of a gene depends upon whether it can be expressed or not. The whole mechanism involves several molecules and a particular nutrient molecule can thus either act as a repressor or promoter and control gene expression. In the remaining paper, several examples will be used to establish how nutrient molecules become a part of the whole gene machinery in the cell. But before that, nutrigenomics will be introduced as a new branch of science.

Details in Appendix(c)

Nutrigenomics

Nutrigenomics is the study that combines molecular biology, genetics, and nutrition. It focuses on the role of nutritional status or specific nutrients in the regulation of gene expression. The greater knowledge of how diet may influence disease state at the gene or molecular levels is very significant in nutrigenomics. The current threats to public health includes cancer, diabetes, obesity and other chronic diseases, are influenced to a certain extent by genetic factors. Lower fat intake for a population is due to a link between fat intake and heart disease. However, not all individuals who consume a high-fat diet will develop heart disease. Hence, if we know who has a genetic susceptibility to a type of heart disease associated with elevated blood cholesterol, then perhaps diets can be tailored to suit those individuals. It has also been noticed that those with family history of various chronic diseases such as diabetes increases an individuals risk for developing such diseases. So the best explanation for this phenomenon is that many chronic diseases are regulated not only by lifestyle factors and environmental influences, but also by some genetic component. By studying the effect of specific nutrients, we can define a relationship which governs the nutritional effects on our health. It (nutrigenomics) sees the nutrient molecules as signals to the cell which can induce several phenomena ranging from controlling gene expression to cell death (apoptosis).

Nutrient Regulation of Gene Expression

In this section we will look upon some examples of nutrients controlling pre and post translational events. Some major nutrients whose effects have been studied are cholesterol, glucose/fructose, minerals e.g. iron, fat soluble vitamins e.g. retinoic acid. These molecules can target nuclear proteins and cis-acting elements, which regulate transcription; nuclear RNA processing events such as splicing and editing; and cytosolic proteins that modify mRNA stability and mRNA translation rates (Steven D. Clarke, 2002). High intakes of carbohydrate induce the lipogenic capacity of liver and adipose tissue by increasing the level of glycolytic and lipogenic enzymes. These enzymes are directly involved in gene transcription, mRNA processing, mRNA editing, and mRNA stability (Steven D. Clarke, 2002). If a carbohydrate diet is replaced with a high fat diet, there will be a reduction in the biosynthesis of fatty acids in hepatic and adipose tissues (Steven D. Clarke, 2002). It has been found that retinoic acid alters the processes of cell differentiation. It can bind to intracellular nuclear retinoic acid receptors and regulate gene expression (Steven D. Clarke, 2002). The above examples are findings of various experiments performed by different research groups. But, it is not yet clear as to what is the exact mechanism for the control of gene expression by a nutrient. A generalized way has been described below which is applicable in most cases. Nutrients have been shown to directly impact gene expression. Often, this occurs by means of transcription factors. Transcription factors are biochemical entities which bind to the DNA and either promoter or inhibit transcription of genes. Several nutrients are known to bind to transcription factors and regulate gene expression in this manner.
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Figure 1 The above figure shows two transcription factors binding to the promoter region; this will either activate or de-activate the promoter and lead to transcription or no transcription of the gene. Thus, the presence or absence of these transcription factors will have diverse effect on the protein synthesis. The next section has been dedicated to the effect of specific nutrients in cases of disease or other phenomenon.

Cancer Oncogenes are genes which code for proteins that control cell death, or apoptosis; or which control cell division and proliferation. Rapid cell proliferation or inhibition of apoptosis may cause a cell to become cancerous, and begin the growth of lesions which may, in turn, become tumors. Which mechanism causes the onset of cancer is dependent on the specific oncogene and tissue type involved. (Muller, 2006) The role of vitamin D appears to favor pathways and gene involved with cell differentiation and inhibits path-ways favoring cell proliferation. Hence, this may have an impact on cancer as cell proliferation versus differentiation must be kept in balance. (JEAN GETZ, 2010)

Cardiovascular disease This is one of the most frequently occurring diseases. The common biochemical markers for high cardiovascular risk include different nonspecific indices of the general inflammation system, whose elevation is associated with cardiovascular risk. There also chances that the risk may elevate due to more acute conditions such as infection. It has been demonstrated that the circulating levels of these markers may be influenced, at least in part, by various genetic factors. (Muller, 2006) These genetic factors may be taken as nutrients.

Hyperinsulinemia and diabetes Defective genetic regulation of several proteins which respond to the presence of insulin may be implicated in the etiology of type 2 diabetes. Ducluzeau et al. (2001) found decreased expression of key proteins and their mRNA in type 2 diabetic patients, and observed a lack of response to the presence of insulin by upregulation of key response proteins. This lack of response is linked to defective expression of the genes for these proteins in response to insulin. Type 1 diabetes is reliant on genetic components to a greater degree than type 2 diabetes because the genetic regulation of type 1 diabetes is polygenic, or accomplished by several genes. Glucose consumption is a crucial determinant of the rate of transcription in the liver of genes for several glycolytic enzymes and enzymes for fatty acid synthesis, as well as lipoproteins and insulin. (JEAN GETZ, 2010)

Obesity Major pathway by which fatty acids modulate gene expression is the peroxisome proliferator-activated receptors (PPARs4), which activate gene transcription when fatty acids bind to them. (Steven D. Clarke, 2002)

Details in Appendix(d)

Fasting Circulating fatty acid concentrations are increased during fasting. These fastinginduced amplified fatty acid concentrations increase the expression of several genes involved in -oxidation of fatty acids. Fatty acids can act as ligands to PPAR, such as oleic acid, to enhance activity. Also, PPAR activity activation may lead to weight loss. (JEAN GETZ, 2010)

Pregnancy Retinoic acid, a form of vitamin A, forms part of transcription factors which may bind to the promoter region of genes involved in embryonic development and cell differentiation. When there is a mutation in one nucleotide base pair that alters the function of the protein that occurs in more than 1% of the population, this is termed a single nucleotide polymorphism or SNP. Folate synthesis in some populations may be limited due to SNP and thus more dietary folate may be required. A lack of folate during pregnancy can lead to spina bifida birth defects5.

Details in Appendix(e)

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Food and Gene

Dysfunctional PPAR activity has been implicated in diabetes and thus it is not inconceivable that providing a diet to enhance PPAR activity may prove beneficial. Indeed, oleic acid and peanut oil high in oleic acid have been shown to reverse the inhibitory effect upon insulin production and can have a beneficial effect in type 2 diabetes. Flavonoids have been shown to enhance PPAR expression and normalize blood triglycerides in high-fat-fed diabetic rats. Divalent minerals, such as iron, copper, and zinc, alter the transcription rates of genes for proteins such as metallothionein, a crucial transport and storage protein for these minerals. These minerals are not produced by our body and should be taken from other sources which are food. So depending on the type of disorder one faces their diet should be structured. Following table shows the different nutrients and its food sources. NUTRIENTS Vitamin A Vitamin B1 (thiamine) Vitamin B6 (pyridoxine) Vitamin B9 (Folic acid) Flavonoids Vitamin C Vitamin D Oleic acid FOOD SOURCES Egg, Leafy vegetables, Milk and dairy products, Intense coloured fruits Meat, milk, cereals Beans, legumes, nuts, Fish, meat Citrus food and juices, beans, leafy vegetables, whole grains Colourful berries and fruits Citrus fruits, amla Exposure to Sun, cheese, butter Vegetable and animal oil

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Conclusion

Nutrigenomics involves tailoring diets to someone's genetic makeup. It is expected that in the coming 5-10 years, a genetic counselor or physician would introduce us to our genetic makeup and then our diet could accordingly be customized by a nutritionist. But this expectation is weighed down by the challenges faced in this field as of today. Firstly, there is very little research going on in this field and the small groups working around the globe are uncoordinated. Secondary, there is very little knowledge to exact mechanism in which a nutrient molecule acts as far as gene expression is concerned. Without this knowledge no prediction methods can be designed. We have an answer to what is happening but not to how is it happening. Thirdly, the human genome is in itself very complex and it is difficult to understand the chemistry of all the molecules involved in the gene to protein journey. Thus we need to have a definite strategy to move forward in this field. This strategy will require a large consortium, considerable research funding and excellent multidisciplinary and multinational collaboration.

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Appendix (a)- Glycolytic Pathway Glycolysis is the sequence of enzymatic reactions that oxidize the six-carbon sugar glucose into two three-carbon compounds with the production of a small amount of adenosine triphosphate (ATP). Glycolysis has two basic functions in the cell. First, it metabolizes simple six-carbon sugars to smaller three-carbon compounds that are then either fully metabolized by the mitochondria to produce carbon dioxide and a large amount of ATP or used for the synthesis of fat for storage. Second, glycolysis functions to produce a small amount of ATP, which is essential for some cells solely dependent on that pathway for the generation of energy.

Figure 1 The glycolytic pathway.

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Appendix (b) - Cofactors

Cofactors are non-protein molecules which bind to a protein to activate it and perform its required function. Such proteins are mostly enzymes and thus cofactors can be viewed as helper molecules which help enzymes perform their function.

Appendix (c) RNA Polymerase

RNA polymerases are proteins that bind to a strand of DNA and help in replication of that strand (used as template) into a complimentary strand (RNA) which is further coded into proteins. They have parts which unwound the DNA and help the mRNA transcript and template strand to hold together.

Appendix (d) - Peroxisome proliferator-activated receptors PPARs are nuclear receptor proteins that function as transcriptional factor. They are of three types: , , and which are expressed in different parts of the body.

Appendix (e) - Spina bifida birth defects

Spina bifida is Latin for split spine. It is a developmental disorder wherein an embryos central nervous system doesnt close fully. This leads to protrusion outside the body in the back. It can also lead to severe paralysis, bladder problems etc. 14

References
JEAN GETZ, K. A. (2010, January). Nutrigenomics and Public Health. Food Technology , pp. 28-33. Muller, L. A. (2006). Nutrigenomics: From Molecular Nutritionto. Journal of the AMERICAN DIETETIC ASSOCIATION , 569-576. S.D. Clarke, a. S. (1992). Gene Expression: Nutrient control of pre- and post translational events. FASEBJ , 3146-3152. Steven D. Clarke, D. G. (2002). Fatty Acid Regulation of Gene Expression. Annals of the New York Academy of Science , 283-298. Wikipedia. (n.d.). Retrieved from http://en.wikipedia.org/wiki/Nutrigenomics

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