MD140: Metabolism, Nutrition and Health Lecture Notes PDF

MD140: Metabolism, Nutrition and Health L1 & 2 16/17 Jan, 2024 Dr. Lynn O’Connor Module Coordinator Lynn O’Connor : Module Coordinator Contributors to module Lectures: Lynn O’Connor Muriel Grenon Geraldine Nolan Project: Muriel Genon Recommended Textbooks “Lippincott Illustrated Reviews Biochemistry...

MD140: Metabolism, Nutrition and Health L1 & 2 16/17 Jan, 2024 Dr. Lynn O’Connor Module Coordinator Lynn O’Connor : Module Coordinator Contributors to module Lectures: Lynn O’Connor Muriel Grenon Geraldine Nolan Project: Muriel Genon Recommended Textbooks “Lippincott Illustrated Reviews Biochemistry” 7th ed “Introduction to Nutrition and Metabolism” 5th ed David A. Bender CRC press- multiple library copies available “Introduction to Human Nutrition” 2nd ed ed Gibney, Lanham-New, Cassidy and Vorster -multiple library copies available “Nutrition and Metabolism” 2nd ed Lanham-New, MacDonald and Roche Food Composition? What are Nutrients How Nutrients Contribute to DISEASE NUTRITION How nutrients affect Health Fate of Food And Nutrients What is Food ? Food vs Nutrients Macronutrients Micronutrients Why do we eat? Because we feel hungry We are what we eat?? not correct The human body can synthesize most of its component molecules non-essential vs. essential nutrients Protein CHO Fat Nucleotides + Urea (N from protein) Nutrient usage – quantified –O2 usage and Nitrogen excretion CO2 correlates with energy production N excretion – reflects amount protein degraded Growing body (child) – nutrient uptake must be higher than nutrients used for ATP production and protein degradation – to achieve net body mass growth The need for Energy/Raw Materials Nutrients are required to provide: 1. The energy to synthesize body components (energy nutrition) 2. The energy for transport of molecules, heat production (to maintain body temperature) and motility 3. The essential (non-synthesizable) body components Fate of Food Physiological Level Fate of Food Molecular Level Maintain Health Nutrients Contribute to Disease “Complex, multifaceted scientific domain indicating how substances in food provide essential nourishment for the maintenance of life” Epidemiology and Physiology Molecular Biology Nature Reviews Genetics Vol 4 April 2003 Genetics Developments that drove the change of focus 1. Completion of several large genome projects 2. Macronutrients and Micronutrients - potent dietary signals that influence the metabolic programming of cells - Have an important role in the control of homeostasis 3. Genetic predisposition – links diet related disease e.g.CVD, diabetes type 11 and cancers 4. Integration of Genetics and epigenetics in Nutrition E.g ABCA1 common genetic variant (involved with HDL metabolism) Example Methylation depends on A) what you eat B) your genome The ABCA1 – common genetic variant that sits atop a differentially methylated 5’CpG region of the genome Can change the methylation of that CpG but also neighbouring CpGs Study 10000 people – a change in EPA in the diet resulted in either decreased methylation and increased HDL cholesterol or the opposite depending on the ABCA1 genotype So increasing EPA - =ive effect on some individuals and -ive effect in others (https://ncbi.nlm.nih.gov/books/NBK518613#sec_000019) New Tools Real-time PCR: changes in gene expression even at the single-cell level High-density microarray analysis: allows the entire nutrition-relevant TRANSCRIPTOME to be studied simultaneously New tools ctd Transgenic Mouse Models Allows identification of new genes and pathways Establish how a TF mediates the effect of a specific nutrient NUTRIGENOMICS Journal Preventative Medicine and Hygiene J Prev Med Hyg. 2022 Jun:63(2 Suppl 3) Nutrigenomics I. Nutritional Genetics (nutrigenetics) II. Nutritional epigenetics III. Nutritional transcriptomics Nutritional genetics (Nutrigenetics) Describes how the response to nutrients in the diet is influenced by individual genetic differences Genes involved in the metabolism or utilization of most nutrients are being systematically screened for commonly occurring polymorphisms. Polymorphisms that affect nutrient status and disease have been identified – a work in progress Nutritional Epigenetics Describes nutrient induced changes in DNA methylation, histone post-translational modifications and other chromatin alterations This is an important property of those nutrients involved in cellular methylation reactions e.g. folate, vit B12,choline, and methionine Nutritional Transcriptomics Describes the effects of nutrients on gene expression An important property of fat-soluble vitamins (A & D) that bind to nuclear receptors and directly affect gene expression May also involve antioxidant vitamins that affect redox signalling pathways which regulate gene expression Basic Tenets of Nutrigenomics 1. Improper diets are risk factors for disease 2. Dietary chemicals alter gene expression and/or change genome structure 3. The degree to which diet influences the balance between healthy and disease states may depend on an individuals genetic makeup 4. Some diet-regulated genes are likely to play a role in the onset, incidence, progression and/or severity of chronic diseases Nutrients are dietary signals that are detected by the cellular sensor systems These influence - Gene expression - Protein expression - Metabolite production Expression Patterns become “dietary signatures” Nutrigenomics also aims to Identify the genes that influence the risk of diet-related diseases on a genome-wide scale Understand the mechanisms that underlie these genetic predispositions Nutrients Modulate Gene Expression Both macronutrients (carbohydrates, fatty acids and amino acids) and micronutrients (Minerals, vitamins) are involved They regulate a) the activity of transcription factors or b) the secretion of hormones that in turn interfere with a transcription factor 1) Carbohydrate-rich diet modifies hepatic gene expression Glucose increases the transcription of glucokinase Fe increases translation for the synthesis of ferritin Vitamin K increases postranslational carboxylation of glutamic acid residues for the synthesis of prothrombin Nutrients influence the synthesis of structural and functional proteins, by influencing gene expression within the cell Gene Polymorphisms and Nutrient Metabolism Phenotypic variablility: is based on interindividual genetic variation Polymorphisms may be a) Qualitative –affect the sequence itself i.e. basepair changes i) SNP – single nucleotide polymorphisms ii) SND- single nucleotide deletions iii) Deletions iv) Duplications v) Insertions b) Quantitative – i.e. affect the copy number The inherited genotype differences in DNA sequence contribute to phenotypic variation and to differences in disease risk in response to the environment Individual genotype variations can alter nutrient metabolism from Relatively minor conditions --- Lactose Intolerance Severe pathological conditions – phenylketonuria (PKU) or Obesity -sickle-cell anemia, -thalassemia and CF result from SNPs SNPs underlie differences in our susceptibility to disease; a wide range of human diseases, e.g sickle-cell anemia, -thalassemia and CF result from SNPs The severity of illness and the way our body responds to treatments are also manifestations of genetic variations E.g a single-base mutation in the APOE (apolipoprotein E) gene is associated with a higher risk for Alzheimer’s disease Summary: Nutrient-Gene Interaction 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 so that gene expression is chronically altered 3. GENETIC VARIATION: common genetic variations such as single-nucleotide polymorphisms (SNPs) can alter the expression or functionality of genes Lactose intolerance in Different Population groups Population Group/Country of Origin Lactose intolerance % UK white 4.7 Northern Germany 7.5 Tuareg (nomads of the central Sahara) 12.7 Western Austria 15 Southern Germany 23 Eastern Austria 25 US Black 26.2 Sri Lankan 71.2 Italy 72.5 Greece 75 South African black 78 Japan 89 Singapore-born Chinese 92 Canadian-born Chinese 97.9 Papua New Guinea 98 Approx 10% of the population are sensitive to the hypersensitive effect of excessive salt intake Approx 10% of the population are genetically at risk of iron overload as a result of polymorphisms in the HFE gene, hepcidin or the transferrin receptor 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 Polymorphism of the IRS explain much of the inherited susceptibility to T2D Polymorphisms of the Vit 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 CVD A number of polymorphisms occur in the untranscribed regions of genes, affecting the extent of gene expression rather than the activity of the protein product HapMap (Haplotype Map) Describes the common patterns of human sequence variation A resource to find genes affecting health, disease and responses to drugs and nutrients Human Genome contains approx 10 million SNPs https://ghr.nlm.nih.gov/primer/ genomicresearch/hapmap During meiosis DNA strands break at “hot-spots” Long stretches of DNA move from generation to generation unbroken –these stretches are called haplotypes Haplotypes contain SNPs that travel together Identifying one SNP allows prediction of others Average- haplotypes span approx 20 kb and contain 30-40 SNPs International HapMap – examined 4 populations for SNP variability Holds enormous potential for nutrigenomics Health and disease state of the different organs and systems will determine the nutrient requirements of the body as a whole Epigenetics and Nutrition Recall – The study of changes in gene function that are mitotically and/or meiotically heritable and do not entail a change in the sequence of DNA (flexible def – does not take into account that epigenetic mechanisms can control the functions of noncoding sequences of DNA) e.g. Methylation is dependent on 2 factors 1. What we eat 2. The nature of the genome Epigenetics -an important tool for Nutrition How Nutrients interact at the molecular level with the genome to create long-lasting signals How the genome interacts with the environment The transmission of information through meiosis or mitosis that is not just based on the DNA sequence A mechanism for the stable maintenance of gene expression states that involve physically marking the DNA or its associated proteins Dietary factors and the regulation of DNA methylation Journal of the American Dietetic Association, March 2006 Journal of the American Dietetic Association, March 2006 Reading Material These papers are intended to provide you with a reading resource on the topics covered in these lectures. It is not provided as examinable material. Polymorphisms, diet and nutrigenomics J Prev Med Hyg. 2022 jun; 63 (2 Suppl 3): E125-E141 Nutrigenomics, Proteomics, Metabolomics, and the Practice of Dietetics. J Am Diet. Ass. 2006 Trends in Molecular Medicine, January 2018, Vol. 24, No. 1 Trends in Food Science & Technology 31 (2013) 6e12 Eur J Clin Nutr 2022 April 20 Opportunities to integrate nutrigenomics into clinical practice and patient counselling - SAMPLE MCQs 1. (i) Alb, FAS, GK, PEPCK, SREBP-1c (ii) SREB-1c, Alb. FAS, PEPCK, GK (iii) PEPCK, SREBP-1c, Alb. FAS, GK (iv) Alb, PEPCK, FAS, GK, SREB-1c, ((v) Alb, SREB-1c, PEPCK,GK, FAS 2. Which of the following statements is TRUE? Glucose increases the transcription of glucokinase Glucose increases the translation of glucokinase Fe increases transcription for the synthesis of Ferritin Fe increases post-translational modification for the synthesis of Ferritin Vit K increases translation for the synthesis of prothrombin Body composition “Introduction to Human Nutrition” Gibney, Lanham-New, Cassidy and Vorster Body Composition Used to evaluate nutritional status Growth and Development Water homeostasis Specific disease states Body Compostion 5 levels Atomic Molecular Cellular Tissue Whole body Body Composition at the atomic level ( 70kg reference man) Atomic Level Amount (kg) Oxygen 43 Amount (% body weight) 61 Carbon 16 23 Hydrogen 7 10 Nitrogen 1.8 2.6 Calcium 1.0 1.4 Phosphorus 0.6 0.8 TOTAL 69.4 98.8 Body Composition at the Molecular Level (70kg reference man) Component Amount (kg) Amount (% body weight) Extracellular 18 26 Intracellular 24 34 Essential 1.5 2.1 Non-essential 12 17 Protein 10.1 14.4 Minerals 3.7 5.3 Carbohydrate 0.5 0.6 TOTAL 69.8 99.4 Water Lipid Body Composition at the Cellular Level Described in terms of Body cell mass: Includes the cell with contents – water, proteins and minerals Extracellular fluids: approx 95% water i.e. plasma in the intravascular space and interstitial fluid in the extravascular space Extracellular solids: Mainly proteins e.g. collagen and minerals (bone minerals and soluble minerals) Difficult to measure Body Composition at the Tissue Level (70kg reference man) Tissue/Organ Amount (kg) Amount (% body weight) Muscle 28 40 Adipose Tissue 15 21.4 Blood 5.5 7.9 Bone 5 7.1 Skin 2.6 3.7 Liver 1.8 2.6 TOTAL 57.9 82.7 CT or MRI can measure adipose tissue Creatinine excretion in urine for skeletal muscle DXA for bones MRI or ultrasound for organs Whole Body Composition DIRECT METHODS: Components measured directly INDIRECT METHODS: e.g.(i) determination of body protein from body nitrogen – using conversion factor of 6.25 from N to protein. (ii) determination of body cell mass using 40K. DOUBLY INDIRECT METHODS: Rely on a statistical relationship between easily measured body parameter(s) and the component of interest e.g. Assessment of (i) skeletal muscle mass by creatinine excretion and the (ii) assessment of body fat from skin-fold thickness. Methods used to Determine Body Composition Direct Indirect Doubly Indirect Carcass analysis Densitometry (fat Weight/height indices mass and fat-free mass) IVNAA Measures elements IVNAA: In vivo neutron activation analysis 40K counting Skinfolds/ultrasound (FFM calculation) Lower in obese Prob age dependent More useful as Body cell mass CT/MRI scans Creatinine excretion 1g equiv to 18-22kg muscle -variation approx 20% HYDRODENSITOMETRY Bod Pod Air displacement PLETHYSMOGRAPHY (ADP) DXA scan The body or part of the body is scanned with X-rays of two distinct energy levels The attenuation of the tissues for the 2 different levels of radiation depends on its chemical composition and is detected by photocells Software calculates Bone mineral content and bone mineral density, lean mass and adipose tissue fat mass MRI imaging Measurement of Biceps Skinfold Skin folds from 4 sites usual Accuracy in individuals in poor Quickest and cheapest method Equations to predict body fat from the sum of skin folds use a log transformation of thickness Note: body fat is not linearly related to skin fold thickness, age and gender of a patient Body Mass Index (Kg/m2) can determine if your weight is in the healthy range Body Mass Index (BMI) is an index of weight in relation to height that is used to compare body size with a standard