Ch 12 - Regulation & Integration of Metabolism PDF

Chapter 12 Regulation and Integration of Metabolism Biochemistry First Edition John Tansey Lecture PowerPoints Tanea Reed Please Have iClickers Ready! Where Are We? Central Metabolism: The Important Pathways and Processes o Glycolysis & Gluconeogenesis o Fates of Pyruvate o Citric Acid Cycle o Elect...

Chapter 12 Regulation and Integration of Metabolism Biochemistry First Edition John Tansey Lecture PowerPoints Tanea Reed Please Have iClickers Ready! Where Are We? Central Metabolism: The Important Pathways and Processes o Glycolysis & Gluconeogenesis o Fates of Pyruvate o Citric Acid Cycle o Electron Transport and Coupled ATP Production o Carbohydrate Metabolism Lipid Metabolism: Key Pathways of Synthesis and Degradation o Fatty Acid Catabolism and Biosynthesis o Steroids and Eicosanoids o Fats and Phospholipids Amino Acid Metabolism: Important Pathways That Use Nitrogen o Amino Acid and Amine Biosynthesis and Breakdown o Urea Cycle Metabolic Regulation: Control of Biolochemical Processes o Overview and Theory of Metabolic Regulation & Integration o Organ Specialization and Communication Nucleic Acid Metabolism: Biochemistry of Information Storage & Processing o Nucleotide Biosynthesis & Degradation o DNA Replication & Repair o RNA Synthesis & Processing o Protein Synthesis Important “Nonhuman” Biochemistry: Global Biochemical Processes & The Key to Life o Photosynthesis o Nitrogen Fixation Copyright © 2019 John Wiley & Sons, Inc. Chapter 12 Outline 12.1 A review of the pathways and crossroads of metabolism 12.2 Organ specialization and metabolic states 12.3 Communication between organs 12.4 Metabolic disease Copyright © 2019 John Wiley & Sons, Inc. Learning Objectives § Analyze how metabolic pathways interact with one another. § Compare the functions of the organs of the body in different metabolic states. § Illustrate how organs can communicate with one another to regulate complex processes such as metabolism. § Describe how metabolic diseases function at the chemical level. Copyright © 2019 John Wiley & Sons, Inc. Section 12.1 Learning Objective § Analyze how metabolic pathways interact with one another. Copyright © 2019 John Wiley & Sons, Inc. Pathways and Crossroads of Metabolism Dynamic Figure 12.1 Copyright © 2019 John Wiley & Sons, Inc. The Pathways of Metabolism Are Interconnected Figure 12.2 Review of the major metabolic pathways. Copyright © 2019 John Wiley & Sons, Inc. Cellular Locations of Metabolism (in eukaryotic animal cells!) Figure 12.3 Overview of where metabolism occurs in the cell. Copyright © 2019 John Wiley & Sons, Inc. Major Metabolites Copyright © 2019 John Wiley & Sons, Inc. What is meant by “metabolic flux”? § The rate of flow through a pathway Usually measured as the quantity of a product made: Flux = J J = dq/dt where q is the quantity of product Things that complicate J include o o o Product of one process may be substrate of another One product/substrate (aka intermediate) may be used in more than one reaction, and some reactions are catalyzed by more than one enzyme Every reaction in a network has effects on all the other reactions! Copyright © 2019 John Wiley & Sons, Inc. Major Fuel Metabolism Pathways But where do these occur? Major Fuel Metabolism Pathways For NEXT TIME: Look ahead at Ch 12 Key Concepts (parts I and II) This will also be pre-work for TBL Module 03 J iClicker Test Question iClicker Test Question Maybe it is time for a change of scenery… 1. Should we rearrange the team map for the rest of the semester? A. NO WAY! B. YES! Enjoy your break, and stay safe! Please Have iClickers Ready! Major Fuel Metabolism Pathways Where do these occur? Location is important for interactions and regulation. Cellular Compartmentalization Organ Specialization Section 12.2 Learning Objective § Compare the functions of the organs of the body in different metabolic states. § Which is the most selfish organ? Liver Muscle Brain Other tissues Copyright © 2019 John Wiley & Sons, Inc. Section 12.2 Learning Objective § Compare the functions of the organs of the body in different metabolic states. § Organ Specialization: Different organs have different “jobs” in fuel metabolism Organs may respond differently to the same conditions We will compare key functions in o Liver o Muscle o Brain o Other tissues Copyright © 2019 John Wiley & Sons, Inc. The Need for Organ Specialization § The specialization of different cell types has further evolved into discrete organ systems with specific metabolic functions § Examples include muscle cells, adipocytes, and neurons o o all capable of conducting glycolysis, conditions under which the glycolysis will occur are regulated differently in the three cell types Copyright © 2019 John Wiley & Sons, Inc. Overview of Organ Fuel Metabolism Figure 12.4 Overview of where metabolism occurs in the body. Copyright © 2019 John Wiley & Sons, Inc. Metabolism: Organ Specialization § “All roads lead to pyruvate” Pyruvate and acetyl-CoA are key intermediates of all energy metabolism in mammals § Organs use one or more central pathways Glycolysis & gluconeogenesis Glycogen synthesis & breakdown Citric acid cycle Oxidative phosphorylation Amino Acid synthesis & breakdown § Only the (well-fed) liver does all of these of all the major organs We Will Consider Metabolic States: What happens in different organs? State Fuel Fed Mixed from diet Postprandial Fatty acids made from dietary sources in the liver; glucose Postabsorptive Fatty acids from adipose tissue; glucose from glycogen stores Re-fed Mixed from diet; use of liver gluconeogenesis to replenish glycogen Fasted Carbohydrates depleted, fatty acids, ketone bodies, gluconeogenesis Starved Ketone bodies and fatty acids, limited gluconeogenesis Table 12.2 Metabolic States Copyright © 2019 John Wiley & Sons, Inc. All rights reserved. The Liver § Responsible for the urea cycle, gluconeogenesis, and ketone body biosynthesis § Involved in detoxification of various metabolites and the balance of carbohydrate, lipid, and amino acid metabolism! § Stores 25% of body’s glycogen § Provides short-term energy Copyright © 2019 John Wiley & Sons, Inc. The Liver § Liver makes all other types of fuel available to other tissues in the body Major function of liver is blood glucose “buffer” Takes up & releases glucose to maintain constant blood glucose level o Glucose-6-phosphate is a key intermediate o o Glucokinase (hexokinase IV) could be called “trappase” Main function is to lower high blood glucose levels Glucose à glucose-6-phosphate o “Regular” hexokinase (hexokinase I) also in liver Main function is normal glycolysis at lower blood glucose levels Hexokinase vs. Glucokinase: Relative Enzyme Activities Metabolic Fates of Glucose-6-Phosphate Cori Cycle Carries lactate to liver for recycling – Gluconeogenesis primarily occurs in liver – Facilitates anaerobic metabolism in muscle Glucose-Alanine Cycle Carries alanine to liver for recycling – Gluconeogenesis primarily occurs in liver – Facilitates amino acid metabolism in muscle The Liver Figure 12.4 Overview of where metabolism occurs in the body. Copyright © 2019 John Wiley & Sons, Inc. The Brain § Regulates both appetite and metabolism § Does not store energy but depends on other organs Only stores a tiny amount of glycogen § Is separated from the rest of the body by the blood– brain barrier § Thinks it’s all special Copyright © 2019 John Wiley & Sons, Inc. The Brain § Brain requires steady supply of glucose § Uses glucose as fuel (but not typical glycolysis) ATP in brain provided by aerobic oxidation o glucoseàlactate in support cells (astrocytes, e.g.) o Lactate aerobically oxidized in primary signal cells 20% of resting O2 consumption done by 2% of body mass (brain!) – like when sitting in class thinking about brains o In the brain most ATP used for Na+/K+ ATPase (why?) § In starvation conditions Gradual switch to ketone bodies for fuel Copyright © 2019 John Wiley & Sons, Inc. The Brain Figure 12.4 Overview of where metabolism occurs in the body. Copyright © 2019 John Wiley & Sons, Inc. The Muscle § Does not normally contribute to the metabolic needs of other organs; instead makes demands on other organs (liver and adipose tissue) § Carries out glycolysis § Stores 75% of body’s glycogen § Uses carbohydrates as fuel but can catabolize amino acids for fuel (i.e., alanine transmination) Copyright © 2019 John Wiley & Sons, Inc. The Muscle § Muscles have versatile fuel sources Rested, well-fed muscles use glucose from glycogenàglycolysis (faster than using fat) Anaerobic metabolism under high exertion (what’s this?) 30% of resting O2 consumption is muscle o may increase 25x under high exertion but… o ATP production may increase much more than that! phosphocreatine + ADP ⇋ creatine + ATP (4 seconds) (20 seconds) o Followed by anaerobic fermentation o Then fatigue (lowered pH from lactate accumulation) Special case: Heart muscle o Completely aerobic (40% of cytoplasm is mitochondria) o Oxidation of F.A. (resting), ketones, glucose, pyruvate, lactate o No oxygen—tissue dies (myocardial infarction) Copyright © 2019 John Wiley & Sons, Inc. The Muscle: Creatine Kinase § Muscles have versatile fuel sources Anaerobic metabolism under high exertion o Phosphocreatine buffers ATP concentration during exercise burst o Reaction catalyzed by creatine kinase: phosphocreatine + ADP ⇋ creatine + ATP Followed by anaerobic fermentation (20 seconds) o Then fatigue (lowered pH from lactate accumulation) o Later, phosphocreatine replenished by creatine kinase Copyright © 2019 John Wiley & Sons, Inc. Phosphocreatine buffers ATP concentration during exercise burst Increasing Intensity of Effort ATP Source During Exercise The Muscle Figure 12.4 Overview of where metabolism occurs in the body. Copyright © 2019 John Wiley & Sons, Inc. Adipocytes Defined § Adipocytes are fat-storing cells of adipose tissue that acquire fatty acids from either chylomicrons or VLDL § These lipids are stored in triacylglycerols in a single large lipid storage droplet § Release free fatty acids and glycerol upon stimulation Copyright © 2019 John Wiley & Sons, Inc. Adipose Tissue § Both a metabolically active tissue and an endocrine tissue that secretes several molecules that regulate appetite and metabolism. § Provides long-term energy for future use 70 kg adult male is ~15 kg fat o 141,000 kCal (590,000 kJ) o Enough energy for 12 weeks! Stored as triacylglycerol o Fatty acids from import o Glycerol from DHAP (glycolysis) § Stores and regulates the release of free fatty acids and glycerol from triacylglycerols Copyright © 2019 John Wiley & Sons, Inc. Adipose Tissue Figure 12.4 Overview of where metabolism occurs in the body. Copyright © 2019 John Wiley & Sons, Inc. The Kidney § Excretes toxic metabolites from the body § Consumes 10% of the body’s energetic need § Uses gluconeogenesis § Oxidatively deaminates glutamine Copyright © 2019 John Wiley & Sons, Inc. The Kidney Figure 12.4 Overview of where metabolism occurs in the body. Copyright © 2019 John Wiley & Sons, Inc. iClicker Question Section 12.2 Learning Objective § Compare the functions of the organs of the body in different metabolic states. § Which is the most selfish organ? A. Liver B. Muscle C. Brain D. Kidneys E. Other tissues Copyright © 2019 John Wiley & Sons, Inc. States of Metabolism Figure 12.5 States of metabolism. Copyright © 2019 John Wiley & Sons, Inc. Nutrition and Metabolism Figure 12.6 Compositions of different diets. Copyright © 2019 John Wiley & Sons, Inc. Ketosis Defined § Ketosis is the process in which excessive ketone bodies are in the blood § Occurs during periods of starvation (or other perturbances of metabolism) § Can be lethal! Copyright © 2019 John Wiley & Sons, Inc. Metabolic States State Fuel Fed Mixed from diet Postprandial Fatty acids made in the liver from dietary sources; glucose Postabsorptive Fatty acids from adipose tissue; glucose from glycogen stores Re-fed Mixed from diet; use of liver gluconeogenesis to replenish glycogen Fasted Carbohydrates depleted, fatty acids, ketone bodies, gluconeogenesis Starved Ketone bodies and fatty acids, limited gluconeogenesis Copyright © 2019 John Wiley & Sons, Inc. Fed and Postprandial States § Fed state Organism has just finished eating Lipids are transported through the circulation on chylomicrons Overlaps with the postprandial state § Postprandial state Period where metabolites are absorbed from the small intestine § Glucose levels are elevated Excess may be stored as glycogen or fatty acids Pancreas secretes insulin Copyright © 2019 John Wiley & Sons, Inc. Postabsorptive State § Follows digestion but precedes hunger § Glucagon signals for glucose levels to be maintained § Catecholamines signal adipose tissue to mobilize fatty acids from triacylglycerols for fuel § Gluconeogenesis occurs in the liver § Insulin levels are low, and epinephrine is high Copyright © 2019 John Wiley & Sons, Inc. Re-fed State § Consuming a meal while in postabsorptive state § Levels of glucose, amino acids, and dietary fats in chylomicrons increase § Liver remains resistant to the effects of glucose and insulin. Copyright © 2019 John Wiley & Sons, Inc. Fasted State § 12–48 hours after consuming a meal § Lack of dietary lipids in circulation § Free fatty acids from adipose tissue increase in the blood. § Levels of fatty acids and triacylglycerols increase in the liver § Liver glycogen stores are depleted Copyright © 2019 John Wiley & Sons, Inc. Starved State § 24–48 hours after consuming a meal § Metabolism is altered to spare protein in muscle and use ketone bodies as the predominant fuel for the brain. § Upregulation of mitochondrial hydroxymethylglutarylCoA synthase (HMG-CoA synthase) § Brain switches from glucose to ketone bodies as its main source of fuel. Copyright © 2019 John Wiley & Sons, Inc. States of Metabolism - Review This Next Time: we take a more detailed look at endocrine (hormone) regulation of metabolism, and things that can go wrong (i.e. metabolic diseases)! Figure 12.5 States of metabolism. Copyright © 2019 John Wiley & Sons, Inc. (Image: “Unhealthy diet killing millions around the world: Lancet study” usatoday.com) Section 12.3 Learning Objective § Illustrate how organs can communicate with one another to regulate complex processes such as metabolism. § What are some different signaling systems? Autocrine Paracrine Endocrine Copyright © 2019 John Wiley & Sons, Inc. Endocrinology Defined § Endocrinology is the study of chemical signaling and its effects in the body § Endocrine organs produce hormones (signaling molecules) § Hormones are secreted in the bloodstream We will focus on hormones related to fuel metabolism, especially o Insulin o Glucagon o Epinephrine Copyright © 2019 John Wiley & Sons, Inc. Examples of Hormones Copyright © 2019 John Wiley & Sons, Inc. Copyright © 2019 John Wiley & Sons, Inc. Peptide Hormones § Peptide hormones are hormones made from short chains of amino acids. § Examples include insulin glucagon Ghrelin (“I’m hungry!”) Leptin (“I’m full…”) PYY (pancreatic peptide YY—appetite supressant) Copyright © 2019 John Wiley & Sons, Inc. Biosynthesis of Catecholamines – Tyrosine-derived hormones Figure 12.8 Biosynthesis of catecholamines. Copyright © 2019 John Wiley & Sons, Inc. Thyroid Hormones – Tyrosine-based with iodine substituents Copyright © 2019 John Wiley & Sons, Inc. Hypothalamus Defined § The hypothalamus is a region of the brain that integrates neuronal and hormonal signals § Hormones are small enough to pass through the blood– brain barrier § Contains two important regions Arcuate nucleus (controls appetite) Paraventricular nucleus Copyright © 2019 John Wiley & Sons, Inc. Thyroid and Steroid Hormones Figure 12.9 Action of thyroid and steroid hormones. Copyright © 2019 John Wiley & Sons, Inc. Hormonal Regulation of Gene Expression § Nuclear hormone receptors § Small proteins found in the cytosol or nucleus of the cell § Upon ligand binding, they become active and translocate to specific DNA sequences § Activate gene transcription § Resident nuclear transcription factors § Binding of the transcription factor complex initiates binding of other proteins § All of which act to alter levels of gene expression § Ex. CREB (cAMP response elementbinding protein) Copyright © 2019 John Wiley & Sons, Inc. Figure 12.11 Copyright © 2019 John Wiley & Sons, Inc. All rights reserved. Sirtuins Defined § Sirtuins are a group of seven proteins that can act as deacetylases § They regulate genes by modifying histones and may directly affect metabolic pathways by deacetylating enzymes § NAD+ dependent Catalyze: Lys + NAD+ à nicotinamide + O-acetyl-ADP-ribose + deacetylated lysine § Sirtuins are inhibited by nicotinamide Copyright © 2019 John Wiley & Sons, Inc. Sirtuins Reactions Figure 12.12 Sirtuins reactions. Copyright © 2019 John Wiley & Sons, Inc. Key Hormonal Effects on Fuel Metabolism § Tissue Insulin Glucagon Epinephrine Muscle (+) GLC uptake No effect Inc glycogen synth (+) glycogenolysis Adipose (+) GLC uptake (+) lipogenesis (-) lipolysis (+) lipolysis Liver* (+) glycogen synth (-) glycogen synth (+) lipogenesis (+) glycogenolysis (-) gluconeogenesis (+) lipolysis (-) glycogen synth (+) glycogenolysis (+) gluconeogenesis *what about glucose uptake? (+) = increase; (-) = decrease Think of important fuel metabolism processes in these organs! Section 12.4 Learning Objective § Describe how metabolic diseases function at the chemical level. Copyright © 2019 John Wiley & Sons, Inc. Body Mass Index Defined § Body mass index (BMI) is used as an indicator of how overweight an individual is. § A measure to determine obesity (BMI > 30) § An optimal BMI is in the range of 18.5 to 24.9 § BMI is a flawed metric, but it is commonly used BMI = kg/m2 where: kg is body mass (in kilograms) m2 = height (in meters) squared Copyright © 2019 John Wiley & Sons, Inc. Body Mass Index: a Biased Metric § 2023 Annual Meeting of the American Medical Association (AMA) House of Delegates § AMA Council on Science and Public Health report outlined the harms and benefits of using BMI BMI is an imperfect way to measure body fat in multiple groups does not account for differences across race/ethnic groups, sexes, genders, and age-span § Recommend using alternative measures for diagnosing obesity Body Mass Index: a Biased Metric § BMI based primarily on data collected from previous generations of non-Hispanic white populations § Example: even at the same BMI, a Black woman may carry more weight in the hip and thigh area while a white woman may accumulate more weight around the middle, putting her at higher risk for heart disease and Type 2 diabetes. § BMI should be used in conjunction with other health measures such as a patient’s genetics, blood pressure, cholesterol, visceral fat, and waist circumference Obesity: An Epidemic Figure 12.14 Obesity is epidemic in the United States. Copyright © 2019 John Wiley & Sons, Inc. Obesity: An Epidemic Obesity rates in several countries Image: www.oecd.org Obesity: An Epidemic Obesity among adults (2015). Copyright © 2019 John Wiley & Sons, Inc. www.oecd.org/health/health-data.htm Obesity: An Epidemic Obesity in Canada 2011-2012. Image: www.150.statcan.gc.ca Obesity: An Epidemic Obesity rates in Canadian provinces, 2004. ◼ Percent of population obese ◼ Percent of population obese or overweight Obesity in Canada 2004. Image: Health Reports. Statistics Canada. 17 (3): 61–7. PMID 16981487 Copyright © 2019 John Wiley & Sons, Inc. Medications That Treat Obesity Figure 12.15 Drugs that target obesity. Copyright © 2019 John Wiley & Sons, Inc. Medications That Treat Obesity One of these drugs is a lipase inhibitor, and three act on hormone receptors (serotonin; endocannabinoid). Which is the lipase inhibitor? Figure 12.15 Drugs that target obesity. Copyright © 2019 John Wiley & Sons, Inc. Medications That Treat Obesity Semaglutide (Ozempic) Ozempic is an antidiabetic and anti-obesity medication. Inhibits glucagon production and gluconeogenesis Lowers appetite and slows digestion in the stomach May enhance growth of pancreatic β cells à increased insulin Diabetes: An Insulin Signaling Disease § Diabetes mellitus § Type I Pancreatic β cells are destroyed No insulin production § Type II Cells cannot respond to insulin Linked to obesity § Gestational A result of elevated levels of pregnancy hormones, which influence insulin signaling Copyright © 2019 John Wiley & Sons, Inc. Drugs Used to Treat Diabetes inhibit gluconeogenesis in liver stimulate insulin release in pancreas Copyright © 2019 John Wiley & Sons, Inc. increase in the storage of fatty acids in adipocytes Other Hormonal Disorders Disease Hormone affected Symptoms Diabetes insipidus Vasopressin Mutation of vasopressin receptor leads to less sodium reabsorbtion in the kidney and excessive urination. Diabetes mellitus Insulin Signaling defect results in inability to properly take glucose into cells. Addison’s disease Corticosteroids Low levels of corticosteroids leads to mineral imbalance and hypoglycemia. Cushing’s disease Adrenocorticotropic hormone (ACTH) Increased levels of ACTH leads to elevated corticosteroids and weight gain. Hashimoto’s disease Thyroid hormones Autoimmune attack on thyroid protein(s) results in depressed thyroid hormone levels and weight gain. Graves’ disease Thyroid hormones Elevated thyroid hormones result in weight loss and increase in metabolic rate. Copyright © 2019 John Wiley & Sons, Inc. Metabolic Syndrome Defined § Metabolic syndrome is a group of 10 related pathophysiologies related to obesity and diabetes. Figure 12.16 United States Mortality rates in 2014. Copyright © 2019 John Wiley & Sons, Inc. Diseases of Absence § These are disorders where wasting away (cachexia) occurs. § These include malnutrition and starvation (Kwashiorkor and marasmus) cancer Copyright © 2019 John Wiley & Sons, Inc. Kwashiorkor and Marasmus Figure 12.17 Kwashiorkor and marasmus. Copyright © 2019 John Wiley & Sons, Inc. Diseases of Indulgence: Alcohol Overconsumption § Ethanol can be found in small amounts in foods § It is metabolized by the liver § The enzymes involved are NAD+ dependent. § The acetate produced may be used by the brain as fuel when alcohol is consumed in excess Figure 12.18 Ethanol metabolism. Copyright © 2019 John Wiley & Sons, Inc. Diseases of Indulgence: Alcohol Overconsumption § Disulfiram used as a treatment for chronic alcoholism § Acetaldehyde dehydrogenase inhibitor § Why would this be effective? Ethanol metabolism. Copyright © 2019 John Wiley & Sons, Inc. Copyright Copyright © 2019 John Wiley & Sons, Inc. All rights reserved. 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