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, INDIA
E-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 β -
cell mass lower response of remaining β -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 PKAα .

• Increased ATP to ADP ratio achieved through

glucose metabolism, close the K+ ATP
channel, which leads to depolarization of β -
cells.

• Depolarized β -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