Nutreogenomics and Antioxidants Flashcards
1
Q
Diseases associated with obesity
A
- osteoarthritis
- insulin resistance/diabeteds mellitus
- hypertension
- cardiovascular disease
- bladder/urinary tract disease
- chronic kidney disease
2
Q
Effect of obesity on gene expression
A
- obesity in dog cause change in expression of over 1000 genes
- upregulated or downregulated
- prevelently in hepatic, adipose, skeletal tissue
- most associated with glucose and fat metabolism, appetite regulation and fat cell production
e.g. adiponectin = protein secreted by adipose tissue when eaten enough/stop hunger. Obese = downregulated gene, less adiponectin protein, constant hunger, eat more calories, put on more weight - (2011 Grant et al) female beagles fed ab lib or maintenance diet for 24 weeks
~ increased body weight ad lib = +14.1kg
~ altered expression of 1665 genes in adipose tissue
(glucose met, oxidative stress, cell differentiation, growth)
3
Q
Transcription
A
= synthesis of mRNA from DNA
4
Q
Translation
A
= synthesis of protein from DNA
5
Q
Gene expression via transcription factors
- promotor region
- transcription factor
A
- specific sequences of DNA adjacent to the genes that they regulate
- before coding region of gene
- bind to promotor region via binding domains to regulate gene expression
- activate or block RNA polymerase which copies DNA to mRNA
- TFs are main agent by which nutrients influence gene expression
- nuclear receptor super family of TFs has 48 members (human) all of which bind nutrients and their metabolites
- nutrients bind to tell TF to turn on and bind to gene
6
Q
Why are some animals susceptible to diseases that others are not (nutrigenetics)
A
e. g. obesity can cause diabetes, doesnt cause diabetes in every animal
- genetic variation in response to nutrients
- nutrigenetics = study of how people respond to nutrients depending on their genetic variation
- genetic progile of individual impacts response to body to nutrients
- absorpton, metabolism and effect at site of action
7
Q
How can we use nutrigenetics for health management and limitations
A
- personalised nutrition
~ aware which genes have high heritability and dams/sires genes passed down
~ animals susceptible to disease due to genetics fed diet to prevent disease - need to sequence genome and look for specific markers
- other lifestyle factor may have an impact (not just nutrition)
e. g cancer is linked to nutrition and lifestyle and enviro factors
8
Q
Nutrigenomics
A
= how nutrients (or their metabolites) interact with the genome to regulate the expression of genes
- which may inturn alter the the progression of or alleviate disease
- “the effect of the diet on gene expression and how that modulates health”
9
Q
Regulation of glucose
A
- animal eats = increase glucose levels
- increase detected by pancreas
- insulin hormone secreted which acts in liver or adipose tissue
- encourages glucoe to be converted to glycogen and stored in liver and stimulate glucose uptake in cells at level of adipose tissue
- glucose levels fall to normal levels
- animal fast
- decrease in glucose detected by pancreas
- glucagon enzyme secreted
- acts upon liver to convert glycogen to glucose
- blood glucose increase level and back to homeostasis
10
Q
The insulin gene
A
- enzyme that is secreted by pancreas to convert glucose to glycogen and stimulate glucose to be taken up by cells
- almost exclusve to pancreatic beta cells
- promotor region 340bp upstream of transcription
- 3 major binding domains within promotor region A3 C1 E1
- 3 major TFs that are glucose responsive
~ pancreatic/duodenal homeobox-1 (PDX-1)
~ MafA
~ E47/beta-2 homeodimer
11
Q
Stimulation of insulin expression by glucose
A
- glucose stimulates insulin transcription through its end products of catabolism
- glucose dtected by Glut 2 receptors
- 3 identified pathways of insulin gene transcription by glucose
1. glucose metabolised. products activate E47 (E)-BETA2/neuroD1 B2 complex. Complex binds to E elements and encourage to pass from the nuclear wall into nucleus to bind to E promotor region
2. glucose stimulates phosphorylation of PDX1 by PI3K (kinase) and Stress-activated protein kinase 2. PDX1 moves to nucleus and bind to A element
3. glucose directly stimulates binding of MafA to C1 element - once all TFs bound to specific binding sites = gene can be transcribed
12
Q
Regulation of insulin by glucose
A
- intake of glucose
~ increase glucokinase = 1st enzyme involved in glucose metabolism in hepatocytes
~ increase sterol-regulated element binding protein-1 (SREBP-1) transcription factor that mediates insulin action - SREBP-2 expression doesn’t change in response to feeding, always present
13
Q
Fatty acids in gene expression
A
- FAs affect insulin gene expression and genes involved in insulin synthesis/action
- FAS (fatty acid synthase) converts extra glucose to lipid
- transcription increases when fed a high fat diet by 20x
- protein expression increases by almost 4x in high fat diet
- SREBP1 (sterol-regulated element binding protein) mediates insulin action
- transcription increases by 11x in high fat diet
- protein expression increases by 3x in high fat diet
14
Q
insulin gene expression and diabetes - not under normal conditions
A
- prolonged exposure
~ to elevated glucose = glucotoxicity
~ to elevated FAs = lipotoxicity - deterioration of pancreatic beta cell func (synth insulin)
- impaired insulin gene expression and insulin synthesis
- elevated exposure over weeks impaires insulin gene expression
- direct link between impaired gene function and diabetes remains to be elucidated
15
Q
Glucotoxicity and lipotoxicity affect gene expression
A
- glucotoxicity
~ causes oxidative stress
~ decrease PDX1 binding ability and PDX1 expression (less protein)
~ decrease MafA protein but not mRNA (expression of gene)
MafA cant bind to its element as less of it
~ formation of E47/B2 activator complex inhibited - dont switch on insulin gene
- lipotoxicity
~ inhibition of translocation of PDX1 from cytoplasm to nucleus
~ decrease MafA mRNA expression (TF not transcribed) - high glucose/FA conc prevent binding of TF to promorto region on gene
- gene not transcribed or translated = no insulin
- no insulin = glucose level cant fall
- help animal lose weight, less adipose tissue, lower fatty acid diet, glucose in diet decline
- allows regulation of TFs returned to normal and insulin synthasised agian
