An Introduction on

EFFECT OF NUTRIENTS ON THE GENE EXPRESSION:

Nutri-genomics.

By:

Mayank Tandon1, R. A. Siddique1 and S. N. Rai2

1 Ph.D. Students, 2 Principal Scientist National Dairy Research Institute,

Karnal, Haryana, INDIAE-mail: mayanktandon1@gmail.com

• The gene expression in response to changes in the nutritional status is one of the well established events in Prokaryotes.

• Single cell organisms are able to adjust their metabolic capacity in response to variation in the nutrient supply in the culture medium e.g. nutrient dependent regulation of the lactose, histidine and tryptophane operons by their respective substrates has been well characterized in bacteria.

• In multi-cellular organism, the control of gene expression differs in many aspects from that operating in single cell organism, and involves complex interactions of hormonal, neural and nutritional factors.

• Although not as broadly appreciated, nutrients also play an important role in controlling gene expression in mammals.

• The response to a nutrient status seems in many cases to be specific for each genotype and specific nutrient impairment results in different gene expression depending on each genotype.

NUTRITION AND GENE REGULATION

• The genomic era of nutrition is upon us: the human genome and several plant genomes have been characterized, and genetically modified foods are now abundantly available.

• New genomic technologies have made possible the investigation of nutritional modulation of the carcinogenesis pathway with nutrients, micronutrients, and phytochemicals.

• Study of nutrient-modulated carcinogenesis involves:

a) effect of nutrients on DNA damage and repair mechanisms b) DNA methylation, which influences gene expression and cellular phenotypes, c) antioxidant rearranging and oxidative stress, target receptors and signal transduction pathways, d) cell cycle controls and check points, apoptosis and antiangiogenic processes etc.

EFFECT OF CARBOHYDRATE ON GENE EXPRESSION

• Feeding high-energy diet to rats leads to early development of obesity and metabolic syndrome, apparently through an inability to cope with energy density of the diet.

• Obesity is associated with decrease in mRNA levels for the oxygenic neuropeptides, NPY (neuropeptides Y), Ag RP (Agouti Related Peptide) etc.

• The effect of hyperglycemia on liver angiotensinogen (AGT) gene expression and found that hyperglycemia activated AGT gene expression in liver increased approximately 3 fold.

• 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 mammals the response to dietary glucose is 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 - 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), and fatty acid synthase, and represses genes of the gluconeogenic pathway, such as the phosphoenolpyruvate carboxykinase gene.

• Although insulin and glucagon were long known as critical in regulating gene expression, it is only recently that Glucose also have been shown to play a key role in transcriptional regulation.

REGULATION OF GENE EXPRESSION BY DIETARY FAT

• In addition to its role as an energy source and its effects on membrane lipid composition, dietary fat has profound effects on gene expression, leading to changes in metabolism, growth, and cell differentiation.

• The effects of dietary fat on gene expression reflect an adaptive response to changes in the quantity and type of fat ingested.

• In mammals, fatty acid regulated transcription factors include peroxisome proliferator–activated receptors (PPARα, -β, and -γ), HNF4α, NFκB, and SREBP1c.

• These factors are regulated by

(a) direct binding of fatty acids, fatty acyl– coenzyme A, or oxidized fatty acids

(b) oxidized fatty acid regulation of G-protein–linked cell surface receptors and activation of signaling cascades targeting the nucleus

(c) oxidized fatty acid regulation of intracellular calcium levels, which affect cell signaling cascades targeting the nucleus.

• At the cellular level, the physiological response to fatty acids will depend on:

(a) the quantity, chemistry, and duration of the fat ingested;

(b) cell-specific fatty acid metabolism (oxidative pathways, kinetics, and competing reactions);

( c) cellular abundance of specific nuclear and membrane receptors

(d) involvement of specific transcription factors in gene expression.

• These mechanisms are involved in the control of carbohydrate and lipid metabolism, cell differentiation and growth

Role of PUFA on Gene expression

• Lipogenic enzymes in liver decreased as result of feeding a diet containing 60 % linoleic acid.

• Fatty acids stimulated the expression of adipocyte fatty acid binding protein (ap2) mRNA

• In the 3T3 –L1 adipocyte cell line, arachidonic acid (n-6) decreased SCD1 m RNA stability in a dose depedent manner (80% maximum repression), as did linoleic and eicosapentanoic acids.

EFFECT OF PROTEIN ON GENE EXPRESSION

• Protein is very essential for growth, to develop immunity, normal maintenance of body function and structure apart from reproduction and production.

• In many developing countries protein insufficiency is still remains a major and serious problem.

• The function of protein in body is not only at macro level but it also function at gene level.

• A variety or number of genes responds to dietary protein both protein quantity as well as quality influences gene expression.

• Insulin secretion was reduced in rats, which are fed with low protein diet due to reduction in pancreatic -cell mass lower response of remaining -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 and GLP-1.

• Low protein diet feeding to rats altered the many gene expression, which are responsible for proteins related to insulin biosynthesis, secretion and cellular remodeling.

• Normal insulin secretion is influenced by level of Protein Kinase C (PKC), K+ channel protein, calcium ion (Ca 2+) and PKA.

• Increased ATP to ADP ratio achieved through glucose metabolism, close the K+ ATP channel, which leads to depolarization of -cells.

• Depolarized -cells opens the voltage dependent Ca 2+ channels which results in influx of calcium leads to exocytosis of insulin granules.

• Feeding low protein diet also increased expression of PFK in islets (teramers M, P, L, and C) results in defective glucose metabolism; it further leads to deceased glucose induced insulin secretion.

• Feeding low protein diet decreases insulin level, it also acts through decreased movement of intracellular calcium

Influence of Amino Acids

• The first step of protein translation is the formation of the 43s pre-initiation complex containing methionyl tRNA, eIF2, GTP.

• This is followed by the assocoiation of methionyl tRNA and eIF2 – GTP that bind to the 40s ribosomal sub unit.

• The GTP is hydrolyzed late in the initiation process, and eIF2 is released from the ribosome as an inactive eIF2 – GTP complex.

• Formation of eIF2 – GTP is mediated by the guanine –nucleotide exchange factor eIF2B.

• The mechanism to regulate eIF2B activity may be at the level of the ribosomal protein S6 and eukaroyotic elongation factor 2 (eEF-2) which is phosphorylated in response to many agents, including growth factors and hormones initiation process.

• Amino acids regulate protein translation through modulation of eIF2B activity, 4 E –BP phosphorylation and protein S6 phosphorylation.

EFFECT OF MINERALS ON GENE EXPRESSION

• As similar to other nutrients, mostly minerals are involved in several gene expressions

Effect of Zinc on gene expression.

• Zn is an essential trace element with cofactor functions in a large number of proteins of intermediary metabolism, hormone secretion pathways and immune defense mechanism.

• Zn is involved in regulation of small intestinal, thymus and hepatocytes gene expression.

• MTF-I (Metal Responsive element Factor- I) is a Zn dependent transcriptional activator regulates mettalothionin I and II through MRE.

• Zn depedent KLF4 transcription factor is involved in protein preparation of HT-29 cells.

• The other protein have Zn in it as constituents are ATP synathase, cytochrome c, a, NADP dehydrogenase I and II regulated by Zn.

• Deficiency of one or more mineral in diet lead to impaired body functions

• Geographical differences (either deficiency or excess) in mineral level of Soil / Plants (diet) have effects up to gene level

• Such as Iron, Iodine, Selenium deficiency

or excess of heavy metal ions

Example: Anaemia

EFFECT OF VITAMINS ON GENE EXPRESSION

• Vitamins are micronutrients needed in very small quantity and are involved in gene expression.

• Vit A is involved in gene expression of PEPCK (Phospho Enol Pyruvate Kinase), IGF 9insulin like growth factor).

• Biotin is involved in various essential proteins (enzymes) synthesis at gene level.

• Vitamin C is involved in hepatic gene expression.

Vitamin A and PEPCK gene expression

• PEPCK is vitamin A depedent enzyme.

• PEPCK is involved in conversion of oxaloacetate to phospho enol pyruvate, one of the important steps in gluconeogenesis.

• Vitamin A deficiency condition leads to changes in chromosomal structure of RARE (Retinoic Acid Responsive Element), which further leads to change in co regulator binding and activity.

• PEPCK –RARE and pre initiation complex interaction leads to RNA polymerase II association with PEPCK promoter is reduced, finally all results in insufficient PEPCK or no PEPCK leads to improvement of gluconeogenesis.

• In vitamin A sufficient mice PEPCK gene expression is highly induced in the food deprived state, when blood glucose levels are reduced.

• The above discussed role of various nutrients on gene expression is occurring normally in body.

• For any type of study in biological system is not complete until studied up to gene level.

• To exploit full genetic potential, its needs lots of nutrients to function at gene level

Other Factors Related to Nutrigenomics:

• Nutrition and Diet

• Modern life style Food (junk food)

• Nutritional Status (deficiency or excess)

• Nutritional Behaviour (preference or rejection of any food)

• Religious-nutritional behaviour

(Vegetarian or Non-vegetarian diet)

• Demographic Nutritional changes

• Area Specific Deficiencies

• Environmental Factors (Tropical or Temperate)

• House hold Income (less or more expenditure on Quality food)

CONCLUSION:

• Nutritional genomics technologies can be integrated with data bases of genomic sequences, inter individual genetic variability, and disease susceptibility etc.

• By this knowledge we can elucidate the role of nutrients on hypertension, cancer, cardiovascular and other life threatening diseases.

Future Prospects

• Will it then be possible from nutrigenomics research to develop food products that can prevent or reduce onset and impact of complex diseases, such as type 2 diabetes, cardiovascular diseases, and some forms of cancers?

• Can food products be tailored to promote the health and well-being of groups in the population identified on the basis of their individual genomes?

THANK YOU