Biochemistry of Nutrition PDF

Biochemistry of Nutrition BIOC1305  Topic 9 Nutrigenomics By: Dr Rehab Almasabi 3  Nutrigenetics and Nutrigenomics: Nutrigenetics studies how genetic differences affect nutrient needs and dietary impacts on health. Nutrigenomics studies how naturally occurring chemicals in foo...

Biochemistry of Nutrition BIOC1305  Topic 9 Nutrigenomics By: Dr Rehab Almasabi 3  Nutrigenetics and Nutrigenomics: Nutrigenetics studies how genetic differences affect nutrient needs and dietary impacts on health. Nutrigenomics studies how naturally occurring chemicals in foods impact the expression of genetic information, influencing health. When a gene is expressed, it leads to the production of a protein, which plays roles in various bodily functions, including nutrition. Genomics and Nutritional Proteins: Scientists have identified specific genes that produce nutritionally relevant proteins, such as digestive enzymes and nutrient transport molecules. Gene Expression and Phenotype:The pattern of gene expression shapes the phenotype, which encompasses observable traits like hair color, body weight, and disease susceptibility.  Genetic Polymorphisms: common genetic variants, affect how individuals respond to diet and environmental factors, influencing health risks. Phenotypic expression is influenced by nutrition; for example, diets alter cholesterol levels and types (LDL, HDL, and their ratios), homocysteine levels, and obesity (nutritional component), and these responses differ among individuals (genetic component) Examples include: Polymorphisms of various apo-proteins of the plasma lipoproteins, and of LDL receptor and cholesterol ester transfer protein account for much of the variance in atherosclerosis Polymorphisms of the insulin receptor substrate explain much of the inherited susceptibility to type II diabetes mellitus. Polymorphisms of the vitamin D receptor explain much of the susceptibility to osteoporosis. Polymorphisms of methylene tetrahydrofolate reductase are associated with elevated blood homocysteine and a higher-than-normal requirement for folic acid, a factor in neural tube defects and cardiovascular disease  Nutrition and Gene Regulation Nutrition affects more than gene expression; it influences every step from gene activity to protein production and metabolic processes, including signal transduction and post- translational protein modifications. There is connection between diet and diseases, such as cancer, that is well-established, providing a foundation for further exploration through advanced genomic studies. New technologies, such as nutrigenomics, transcriptomics (mRNA expression analysis), metabolomics (study of chemical fingerprints of cellular processes), and epigenomics (study of epigenetic modifications), allow in-depth investigation of nutrition's role in disease processes.  Nutrients primarily influence gene expression through transcription factors, particularly the nuclear receptor superfamily, which includes 48 receptors in humans. Many of these receptors bind nutrients or their metabolites. For example, peroxisome proliferators activator receptor (PPAR) binds fatty acids, while the liver X receptor binds cholesterol metabolites. These receptors, bind as heterodimers together with retinoid X receptor, attach to specific nucleotide sequences (response elements) in the promoter regions of a large number of genes. Upon nutrient binding, nuclear receptors change shape, shedding co-repressors and attracting co-activators to activate transcription. In metabolically active organ like the liver, intestine, and adipose tissue, these transcription factors act as nutrient sensors by changing the level of DNA transcription of specific genes in response to nutrient changes  Effects of Nutrients on Gene Expression Nutrient-Gene Interactions There are three types of nutrient gene-interactions that occur: 1. Direct interactions: Nutrients, sometimes after interacting with a receptor, behave as transcription factors that can bind to DNA and acutely induce gene expression. 2. Epigenetic interactions: Nutrients can alter the structure of DNA (or of histone proteins in chromatin) so that gene expression is chronically altered. 3. Genetic variations: Common genetic variations such as single-nucleotide polymorphisms (SNPs) can alter the expression or functionality of genes. All of these mechanisms can result in altered metabolism and altered dietary requirements for nutrients. Acute Effects of Nutrients on Gene Transcription Nutrients as Transcription Modifiers: Certain nutrients can act as transcription factors, altering gene expression by interacting with specific receptors. Examples of Nutrient-Receptor Interactions: Vitamin A binds with retinoic acid receptors to regulate transcription. Vitamin D interacts with the vitamin D receptor, calcium with calcineurin, and zinc with metal- responsive transcription factor 1 to impact gene transcription. Temporary Signaling:These nutrient-receptor interactions act as short-term signals, ceasing to affect gene expression once nutrient exposure stops. Epigenetics and Nutrition Epigenetic Modifications: Epigenetic effects occur through DNA methylation or modification of histones (methylation, acetylation, or biotinylation), impacting gene expression. Long-lasting and Heritable Effects:These modifications can last throughout a person’s life and may persist across generations. DNA Methylation Mechanism: DNA methylation typically occurs at CpG islands (cytosine followed by guanine) and can alter gene transcription and genomic stability. Methylation in promoter regions generally silences or reduces gene expression by blocking transcription factors, although there are rare cases where it can derepress genes. Reproducibility: Once DNA methylation occurs, it is replicated in new cells, making its effects persistent over time.  Histone Modifications: DNA wraps around histones, which, when tightly packed, restrict access to genes. Histone modifications can loosen this structure, allowing transcription factors to access gene promoters and activate gene expression. Diet can influence these epigenetic changes; for example, dietary methyl group availability can cause stable alterations in DNA methylation, affecting gene expression and phenotype. 12  Dietary factors that are involved in one-carbon metabolism provide the most compelling data for the interactions of nutrients and DNA methylation because they influence the supply of methyl groups and therefore the biochemical pathways of methylation processes. These nutrients include folate, vitamin B-12, vitamin B-6, methionine, and choline. In fact, dietary methyl (folate, choline, and methionine) deficiency in combination causes global hypomethylation, hepatic steatosis, cirrhosis, and ultimately hepatic tumorigenesis in rodents in the absence of carcinogen treatment. Because epigenetic events are reversible, they offer an important mechanism whereby environmental factors, e.g., diet, can influence biological processes and disease-related phenotypes.  Genetic Variation Humans have around 50,000 single nucleotide polymorphisms (SNPs) across their genes. Some SNPs alter gene expression or the structure and function of proteins, impacting nutrient needs. Challenges of Genotyping: Though genotyping costs have decreased, covering all SNPs is still expensive. Researchers select key markers, or “haplotype blocks,” which are linked SNPs inherited across generations, to reduce costs.  Examples of SNPs Affecting Nutrient Requirements MTHFR C677T SNP: In about 15-30% of the population, this SNP reduces the enzyme’s activity (methylenetetrahydrofolate reductase) (MTHFR) in folate metabolism, raising homocysteine levels unless folate intake is high. MTHFD1-G1958A SNP: Premenopausal women with this SNP have an increased risk of choline deficiency on low-choline diets and a fourfold higher risk of having a child with neural tube defects if they also consume low-choline diets. PEMT SNP (rs12325817): This SNP affects choline synthesis, particularly in women, increasing susceptibility to choline deficiency due to its interaction with estrogen. Studies aim to identify other SNPs that explain individual differences in nutrient needs, especially for choline, to further understand dietary impacts on organ health.  Gene Expression Process: Gene expression encompasses transcription, translation, and post-transcriptional and translational modifications, resulting in protein synthesis. The final protein product often serves as an enzyme, hormone, or other active molecule with specific physiological roles. Gene expression is affected by various factors, including transcriptional, translational, and post-transcriptional factors, along with their regulators. Environmental factors, particularly nutrients, significantly impact gene expression by influencing various stages in the gene expression process.  Effect of Carbohydrate on Gene Expression Feeding high-energy diet to rats leads to early development of obesity and metabolic syndrome, through an inability to cope with energy density of the diet. Obesity in the face of reduced overall weight gain was associated with decrease in mRNA levels for the oxygenic neuropeptides, NPY (neuropeptides Y), Ag RP (Agouti Related Peptide) in the ARC (Arcuate nucleus). The effects of hyperglycemia on liver angiotensinogen (AGT) gene expression are found that hyperglycemia activated AGT gene expression in liver increased by approximately three-fold.  Feeding the glucose diet caused a slight increase in lactase activity, accompanied by an elevation of LPH (lactase/ phlorizin hydrolase) mRNA levels. By contrast, a-methylglucoside, a non-metabolizable sugar, was unable to induce an elevation in LPH mRNA levels. It has been demonstrated that LPH mRNA levels are elevated in rats given sucrose as a dietary carbohydrate source, but not in those given α–methylglucoside. A report also suggests that between the two constituent monosaccharides of sucrose, fructose is more active in enhancing LPH mRNA levels than glucose.(32) These results hypothesize that certain carbohydrates or their common metabolite(s) might play a pivotal role in the regulation of LPH gene expression.  Glucose Regulated Gene Expression Glucose, the most abundant monosaccharide in nature, provides a very good example of how organisms have developed regulatory mechanisms to cope with a fluctuating level of nutrient supply. In yeast, glucose facilitates its own use by inducing expression of genes involved in its metabolism while repressing that of those involved in the utilization of alternative carbon sources. The mechanisms by which glucose affects gene expression in yeast are now well understood. In mammals, the response to dietary glucose is more complex because it combines effects related to glucose metabolism itself and effects secondary to glucose- dependent hormonal modifications, mainly pancreatic stimulation of insulin secretion and inhibition of glucagon secretion  In the pancreatic b-cells, glucose is the primary physiological stimulus for the regulation of insulin synthesis and secretion. In the liver, glucose in the presence of insulin induces expression of genes encoding glucose transporters and glycolytic and lipogenic enzymes, e.g., L-type pyruvate kinase (L-PK), acetyl-CoA carboxylase (ACC), fatty acid synthase, and represses genes of the gluconeogenic pathway, such as the phosphoenolpyruvate carboxykinase gene. There is a study indicated that carbohydrates have a key role in transcriptional regulation. DNA sequences and DNA binding complexes involved in the glucose-regulated gene expression have been characterized recently in liver and b- cells.(35  Effect of Dietary Fat on Gene Expression Role of Dietary Fat: Dietary fat is an essential macronutrient necessary for growth and development across organisms. Beyond serving as an energy source, dietary fat influences membrane lipid composition and affects gene expression. Impact on Gene Expression: Dietary fat modulates gene expression, leading to changes in metabolism, growth, and cell differentiation as an adaptive response to the type and amount of fat consumed. Key Fatty Acid-Regulated Transcription Factors: Identified in bacteria, and mammals, these factors in mammals include: PPARs (peroxisome proliferator–activated receptors: PPARα, -β, and -γ)HNF4α (hepatocyte nuclear factor α) NFκB (nuclear factor kappa B) SREBP1c (sterol regulatory element binding protein 1c) Mechanisms of Regulation: These transcription factors are regulated by: Direct binding of fatty acids, fatty acyl–coenzyme A, or oxidized fatty acids.  Cellular Response to Fatty Acids: The response varies based on: 1. Quantity, chemistry, and duration of fat intake. 2. Cell-specific fatty acid metabolism, including oxidation pathways, reaction kinetics, and competing reactions. 3. Cellular levels of specific nuclear and membrane receptors. 4. Transcription factors involved in gene expression. Regulated Processes: These mechanisms control: 1. Carbohydrate and lipid metabolism. 2. Cell differentiation and growth. 3. Production of cytokines, adhesion molecules, and eicosanoids. Understanding the genomic effects of fatty acids sheds light on the potential role of dietary fat in health and disease. Polyunsaturated fatty acids (PUFA) and their effects on SREBP-1 and leptin: Suppression of SREBP-1: PUFA suppresses the expression of SREBP-1 and regulates it at the post-transcriptional level. Effect on SREBP-1 mRNA: PUFA induces changes in SREBP-1 mRNA levels Leptin Expression: PUFA does not reduce leptin mRNA levels in combination with increased mature SREBP-1, suggesting PUFA-induced leptin expression effects may involve reduced mature SREBP-1. Dietary Fatty Acid Influence on Leptin: Dietary FA composition can modify plasma leptin levels in humans.Reduction in Leptin Gene Expression: PUFA decreases leptin gene expression both in vivo and in vitro, linked to reduced expression of PPARγ and SREBP-1. Reduction in Leptin Gene Expression: PUFA decreases leptin gene expression both in vivo and in vitro, linked to reduced expression of PPARγ and SREBP-1.  Effect of Protein on Gene Expression Protein is essential for growth, to develop immunity, normal maintenance of body function and structure apart from reproduction and production (growth, milk, meat, egg, and wool). The function of protein in the body is not only at the macro level but it also at the gene level. A variety or number of genes responds to dietary protein. Both protein quantity as well as quality influences gene expression. Intrauterine deficiency of proteins during gestation and lactation affects the structure and function of several organs in the newborn.  Insulin secretion was reduced in rats, which were fed with low protein diet due to reduction in pancreatic b-cell mass, lower response of remaining b-cells to nutrients and lowered protein kinase activity (PKA). PKA is involved in potentiation of glucose induced insulin secretion by gastrointestinal hormones such as GIP (gastric inhibitory polypeptide) and GLP-1(glucagon like peptide-1). Low protein diet feeding to rats altered the expression of many genes, which are responsible for proteins related to insulin biosynthesis, secretion, and cellular remodeling. Genes encoding the insulin like growth factor (IGF) system are highly sensitive to nutritional status. Soy protein decreases cholesterol level acting through gene level. Prolonged feeding of a low-protein diet causes a decrease in the plasma level of most of the essential amino acids. For example, in plasma of children affected by kwashiorkor, leucine and methionine concentrations can be reduced.  Effect of Vitamins on Gene Expression Vitamins are micronutrients needed in very small quantity in human and non-ruminants diet. However, in ruminants certain vitamins are synthesized in their body system itself, provided pre vitamin constituents are present. Mostly all vitamins are involved in gene expression. Vitamin C and Vitamin E are helpful in prevention of oxidation to DNA and lipid oxidation while its deficiency is associated with increased baseline level of DNA strand breaks, chromosome breaks, and oxidative DNA lesions and lipid peroxide adducts on DNA. Vitamin A is involved in gene expression of PEPCK (phospho enol pyruvate kinase), IGF (insulin like growth factor). Biotin is involved in various essential proteins (enzymes) synthesis at gene level. Disease Control Occurrences of chronic diseases are “encoded” by a combination of factors, all acting on the body over time to create the disease phenotype of variable severity. These factors may include a number of genes, common genetic variants (i.e., SNPs, haplotypes), environmental factors, risk-conferring behaviors, and socioeconomic status. The genetic factors contributing to complex disease are difficult to identify because they typically exert small effects over long periods. Around 1,000 genes causing human diseases have been identified, 97% of them associated with monogenic diseases. However, most cases of cardiovascular diseases, diabetes, cancer, and other chronic diseases are due to complex interactions between several genes and environmental factors. Nutrients can influence the genome; however, there are some potential “candidate” or “susceptibility” genes that will have a heightened sensitivity to diet.  Nutrients are involved similarly in toxic substances present in feed, whether its toxicity starts at gene level, at post gene level is to be known to overcome its toxicity. Nutritional genomics technologies can be integrated with data bases of genomic sequences inter individual genetic variability, and disease susceptibility, the results of which, along with biomarkers to identify individuals at risk and predisposed to cancer, will be conducive to the development of cancer prevention strategies. “Genome Health Nutrigenomics” concept deals how nutritional deficiency or excess can cause genome mutations at the base sequence or chromosomal level. The main aim of this concept is to define the optimal dietary intake and tissue culture medium concentration to maintain damages to the genome at its lowest possible level.