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Inflammation and Nutritional Genomics

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DNA

  • every cell contains DNA

  • 6.5 ft in each nucleus 

  • 22 pairs of chromosomes plus an XX or XY

  • DNA contains

    • nitrogenous bases ​

      • C,G,T,A​

      • sugar

      • phosphate group

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Gene

  • regions with the DNA sequence

    • code for protein​

    • code for regulation of the protein

  • 30,000-40,000 in the human genome

  • basic unit of heredity

    • 1-2% of the sequence

    • 1-2% controls when, how much and frequency with which a gene is read

    • 96-98% has no known function

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Genotyping

  • We inherit genes from each parent but the result is unique

  • Inheritance of some characteristics is simple, e.g. eye color

  • Others interact to give a result that is a mixture, e.g. hair color

  • The genes that you inherit make up your genotype

  • The resulting product is your phenotype

  • Genotyping determines the genes you inherited but not the result

  • Predictable phenotypes include those associated with disease, e.g. cystic fibrosis

  • Age-related diseases are controlled by many genes

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study questions:

  • describe transcription and translation

  • what is the start codon and what are the end codons?

RNA

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  • identical to DNA

    • uracil instead of thymine​

  • able to leave nucleus

  • study of all RNA sequences from a cell is called transcriptomics

study questions:

  • name the three main differences between DNA and RNA

  • label the chart to the right

DNA --> RNA --> Protein

  • DNA --> RNA (transcription)

  • RNA --> protein (translation)

  • protein consists of 20 unique AAs

    • click here for review​

  • the collection of proteins coded by a genome is called the proteome

    • study of the proteome is proteomics

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Metabolism and Metabolites

  • protein responsibilities

    • structure​

    • growth

    • reproduction

    • coordination of activities

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Individuality

  • Differences from the published sequence between individuals

  • These are known as polymorphisms

  • Single nucleotide polymorphism (SNP) =  a swap of a single letter in the code

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study question:

  • describe SNPs and how they contribute to genetic variation

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Transcription Factor Pathways

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Transcriptional Regulation by Vitamin A
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Transcriptional Regulation by Vitamin D
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PPARs are ligand activated transcription factors
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PUFA effect

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Estrogen and Phytoestrogens

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  • Cancer prevention

  • Post-menopausal supplement

  • Prevention of osteoporosis

  • Cardiovascular health

  • Fertility

Diet Influence on Epigenetics

  • Epigenetics is the study of heritable changes in gene expression that occur without a change in DNA sequence.

  • DNA methylation- CpG islands

  • Histone posttranslational modifications:

    •   Acetylation of lysines

    •   Methylation of lysines and arginines

    •   Phosphorylations of serines and threonines

    •   ADP-ribosylation of glutamic acids

    •   Ubiquitination of lysine residues

    •   Biotinylation of lysines

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Nutrigenomics

  • Nutrigenomics attempts to study the genome-wide influences of nutrition

  • Nutrients are dietary signals that are detected by the cellular sensor systems that influence gene and protein expression and therefore metabolite production.

  • Patterns of gene expression, protein expression and metabolite production in response to particular nutrients or nutritional regimes can be viewed as 'dietary signatures

  • Nutrigenomics seeks to examine these dietary signatures in specific cells, tissues and organisms, and to understand how nutrition influences homeostasis.

  • Nutrigenomics aims to identify the genes that influence the risk of diet-related diseases on a genome-wide scale, and to understand the mechanisms that underlie these genetic predispositions.

study question:

  • how does nutrigenomics explore the interaction between diet and genes in terms of health and disease risk?

Immune System                       Inflammation

  • Components of Natural resistance

  • Innate immunity (non-specific)

    • defense system you were born with​

  • Acquired immunity (specific)

    • Different types of cells involved and their functions

    • Major cytokines (what is a cytokine?) and their function

  • Process of immune response following an invasion by microorganism

  • view here for in depth review

  • Inflammation is mediated by cytokines

    • Pro-inflammatory cytokines

  • The symptoms of inflammation

  • Causes for chronic inflammation

  • Diseases and conditions linked to chronic inflammation

Inflammatory Response

  • Inter-related to immune system

  • Cytokines involved

  • Primary function is to increase blood circulation around site of infection

    • Blood vessels dilate

    • Blood flow increased

    • Gaps appear in cell walls around infected area—allows large cells to pass though

    • Increases presence of immune cells at site of inflammation

    • Increased temperature shifts balance of chemical reactions to favor host

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study questions:

  • explain the implications of this response

  • what is the difference between inflammation and the inflammatory response?

  • Ending inflammatory responses

    • May involve apoptosis

    • Induced by signals

    • Can be “die” signal or not receiving a “stay alive” signal

    • Activated immune cells are supposed to commit suicide when finished

    • Helper T cells emit the “stay alive” signal as long as they see antigens and prolong the inflammatory response

study question:

  • what signals cause this response?

Chronic Inflammation

  • Chronic inflammation may occur

    • If the antigen is not eradicated, or Helper T cells think it’s still there, or if immune cells receive the “stay alive” signal from another source

    • After repeated episodes of acute inflammation​

  • Chronic inflammation may result from

    • Repeated exposure to free radicals generated by oxidants

      • Dietary pro-oxidants (e.g., Fe, too much vitamin E?, n-6 PUFA?)

      • UV radiation

      • Exposure to chemicals

      • Overeating??? Too much ETS activity?  Exercise???

    • Psychological Stress

      • Catacholamines are inducers of cytokines, esp IL-6

      • Glucocorticoids tend to prevent glucagon

study question:

  • explain how overeating, ETS activity and exercise can contribute to chronic inflammation

  • Stress has been shown to induce an acute phase response

    • Associated with exaggerated sympathetic nervous system stimuli (increased blood pressure, heart rate, etc)

      • Cause endothelial cells to produce cytokines

      • Increases in TNF-alpha

    • May activate the innate immune response and suppress the adaptive response

    • Chronic stress may lead to chronic acute phase response

    • Inflammatory response mounted towards a perceived invader

  • Causes of chronic inflammation

    • Persistent invaders (perceived invaders?) who hide from immune cells

    • Irritant, non-living foreign materials that can’t be removed by immune cells

      • Wood splinters

      • Particles or fibers

    • Abnormality of regulation of immune response

      • Autoimmune diseases

        • E.g. Crohn’s disease

    • Chronic oxidative damage (free radicals)

  • Chronic inflammation may be linked to:

    • Cardiovascular disease

      • Endothelial cell damage leads to increased cytokines

    • Rheumatoid arthritis

    • Cancers

    • Obesity

    • Insulin resistance

    • Diabetes

    • Possibly Alzheimer’s Disease

Interleukin-6

  • Acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine

  • Is secreted by T cells and macrophages to stimulate immune response

  • Osteoblasts secrete IL-6 to stimulate osteoclast formation.

  • Smooth muscle cells in the tunica media of many blood vessels also produce IL-6 as a pro-inflammatory cytokine.

  • IL-6's role as an anti-inflammatory cytokine is mediated through its inhibitory effects on TNF-alpha and IL-1.

  • Is an important mediator of fever and of the acute phase response.

    • IL-6 stimulates acute phase protein synthesis, as well as the production of neutrophils in the bone marrow. It supports the growth of B cells and is antagonistic to regulatory T cells.

  • Inhibitors of IL-6 (including estrogen) are used to treat postmenopausal osteoporosis. IL-6 is also produced by adipocytes and is thought to be a reason why obese individuals have higher endogeneous levels of CRP.

  • When psychologically stressed, the human body produces stress hormones like cortisol, which are able to trigger IL-6 release into the circulation.

  • IL-6 seems to play a major role in the process of acute or chronic stress (e.g. depression, anxiety) suppressing the immune system.

  • High levels of IL-6 in cancer patients or in children with encephalitis could therefore be explained by the high levels of psychological stress these diseases trigger in the patients’ minds.

  • IL-6 stimulates the inflammatory and auto-immune processes in many diseases such as diabetes, atherosclerosis, depression, Alzheimer's Disease, systemic lupus, multiple myeloma, prostate cancer, and rheumatoid arthritis.

study question:

  • What are some of the roles of interleukin-6 (IL-6) in the body, and how does its secretion impact various physiological processes and diseases?

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Infection and Inflammation

  • Infection --> Immune response --> change in cytokine profile -> inflammation

  • Some cytokines can serve as inflammation markers, eg

    • CRP

    • TNF-alpha

    • IL-6

Diet and Inflammation

  • NF-kB

    • Nuclear factor kappa B

  • Endothelial function/activation (nitric oxide, NO)

  • Circulating cytokines

  • C-reactive protein (CRP)

  • Cellular adhesion molecules (CAMs)

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  • These markers play a beneficial role in inflammation when you need a response (e.g., bacterial infection)

  • The problem in health/disease is when it’s chronic & markers become detrimental

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  • NF- kB pathway: Activation and inhibition

  • Major cytokines/markers from adipose tissue

  • Different PUFA --> different PGs with opposite effects

  • Regulation by diet, esp. dietary fat

    • Pro-inflammatory

      • sat fat​

      • N6

    • Anti-inflammatory

      • N3​

      • MUFAs

study question:

  • what fat is anti-inflammatory? pro-inflammatory?

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  • Nutrient modulation of inflammatory response

    • Antioxidants

      • Free radicals are pro-inflammatory, also cause DNA damage

      • Flavonoids

        • Modulate signal transduction related to inflammation

        • Possibly directly or as antioxidants

      • Vitamin E and flavonoids may modulate acute phase response

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Healthy dietary patterns:

  • Low in refined starches, sugar, and saturated and trans-fatty acids

  • High in natural antioxidants and fiber from fruits, vegetables, and whole grains​

Gene Expression of Inflammatory Markers

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NF-kB is a transcription factor

  • Involved in transcription of many genes

  • Inflammatory processes

    • CAMs

    • Cyclooxygenase-2 (COX-2)

    • Cytokines (TNF, IL 1, IL8 , IL6)

  • Cell proliferation

  • Cell differentiation

  • Apoptosis (repair after mutations)

NFKB Pathway Regulation

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  • Activation of NF-KB may block insulin from working

    • TNFa shown to activate NF-KB

    • Aspirin has been shown to relieve insulin resistance in Type 2 DM and reduce circulating glucose and insulin levels

    • Aspirin inhibits the system that activates NF-KB

  • Several nutrients may block activation of NF- KB (protective)

    • so genes coding for harmful things are not transcribed

      • PUFA—especially n-3 (eg. DHA, EPA)

      • MUFA

      • Some flavonoids and other antioxidants

study question:

  • describe the relationship between NFKB and insulin

Glucocorticoids

  • Glucocorticoids may inhibit activation of NF- kB

    • Glucocorticoids increase I KB mRNA --> increase of I KB protein --> more efficient sequestration of NF- KB in the cytoplasm.

    • The glucocorticoid receptor competes with NF- KB for binding to coactivators

    • The glucocorticoid receptor directly binds to one of the subunits of NF- KB and inhibits its activation

Stress, Inflammation, and Insulin Resistance

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  • Under stress, metabolism is controlled by stress hormones

    • Usually those opposed by insulin

    • Often get insulin resistance

    • Hyperglycemia induces IL-6 release from endothelium

    • Other cytokines elevated in insulin resistance

    • TNF-alpha and IL-6 elevated in obese persons

study question:

  • describe how stress impacts metabolism

Cytokines

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  • Increased trans fats associated with increased circulating concentrations of CRP and TNF

  • Diets high in whole grains and low in SFA and dairy associated with lower CRP

  • But better results seen with diets high in plant sterols, soy protein, viscous fiber and almonds

  • N-3 fatty acids associated with lower levels of CRP  and IL-6

  • Fiber in diet has been shown to reduce IL-18 and stimulate adiponectin

study question:

  • what are some dietary interventions to combat this?

Prostaglandins

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Series 1 & 3 PGs

  • Increased vasodilatation

  • Decreased pain

  • Increased endurance

  • Enhanced immune system

  • Increased oxygen flow

  • Decrease in cellular proliferation

  • Prevents platelet aggregation

  • Dilates airways

Series 2 PGs

  • Increased vasoconstriction

  • Increased pain

  • Decreased endurance

  • Immune system suppression

  • Decreased oxygen flow

  • Increases cellular proliferation

  • Creates platelet aggregation

  • Constricts airways

study question:

  • describe the relationship between prostglandins and different fats

©2023 by Syracuse University Dr.Margaret Voss

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