Human Metabolism E-Book

Keith N. Frayn

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 984

Veröffentlichungsjahr: 2019

Beschreibung

The updated bestselling guide to human metabolism and metabolic regulation

The revised and comprehensively updated new edition of Human Metabolism (formerly Metabolic Regulation – A Human Perspective) offers a current and integrated review of metabolism and metabolic regulation. The authors explain difficult concepts in clear and concise terms in order to provide an accessible and essential guide to the topic. This comprehensive text covers a wide range of topics such as energy balance, body weight regulation, exercise, and how the body copes with extreme situations, and illustrates how metabolic regulation allows the human body to adapt to many different conditions.

This fourth edition has been revised with a new full colour text design and helpful illustrations that illuminate the regulatory mechanisms by which all cells control the metabolic processes necessary for life. The text includes chapter summaries and additional explanatory text that help to clarify the information presented. In addition, the newly revised edition includes more content on metabolic pathways and metabolic diseases. This important resource:

• Is a valuable tool for scientists, practitioners and students across a broad range of health sciences including medicine, biochemistry, nutrition, dietetics, sports science and nursing
• Includes a full colour text filled with illustrations and additional diagrams to aid understanding
• Offers a companion website with additional learning and teaching resources.

Written for students of medicine, biochemistry, nutrition, dietetics, sports science and nursing, Human Metabolism has been revised and updated to provide a comprehensive review of metabolism and metabolic regulation.

Leseprobe

Human Metabolism

A Regulatory Perspective

Fourth Edition

Keith N. Frayn

Emeritus Professor of Human MetabolismRadcliffe Department of MedicineUniversity of OxfordOxford, UK

and

Rhys D. Evans

Reader in Metabolic BiochemistryDepartment of Physiology, Anatomy and GeneticsUniversity of OxfordOxford, UKand

Consultant in Anaesthetics and Intensive Care MedicineOxford University Hospitals NHS TrustJohn Radcliffe HospitalOxford, UK

This edition first published 2019 © 2019 Keith N. Frayn and Rhys D. Evans

Edition HistoryPortland Press (1e, 1996); Blackwell Science (2e, 2003); Wiley-Blackwell (3e, 2010).(Editions 1 to 3 published under the title of Metabolic Regulation: A Human Perspective.)

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of Keith N. Frayn and Rhys D. Evans to be identified as the authors of this work has been asserted in accordance with law.

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Library of Congress Cataloging-in-Publication Data Names: Frayn, K. N. (Keith N.), author. | Evans, Rhys D. (Rhys David), author. Title: Human metabolism : a regulatory perspective / Keith N. Frayn and Rhys D. Evans. Other titles: Metabolic regulation Description: Fourth edition. | Hoboken, NJ : Wiley-Blackwell, 2019. | Preceded by Metabolic regulation / Keith N. Frayn. 3rd ed. 2010. | Includes bibliographical references and index. | Identifiers: LCCN 2018039797 (print) | LCCN 2018041323 (ebook) | ISBN 9781119331445 (Adobe PDF) | ISBN 9781119331469 (ePub) | ISBN 9781119331438 (paperback) Subjects: | MESH: Metabolism—physiology | Metabolic Diseases—physiopathology | Metabolic Networks and Pathways—physiology Classification: LCC QP171 (ebook) | LCC QP171 (print) | NLM QU 120 | DDC 612.3/9—dc23 LC record available at https://lccn.loc.gov/2018039797

Cover images: courtesy of Keith Frayn and Rhys Evans, © John Wiley & Sons, Inc. Cover design by Wiley

CONTENTS

Cover

Preface

Abbreviations

About the companion website

CHAPTER 1 The underlying principles of human metabolism

1.1 Metabolism in perspective

1.2 The chemistry of food – and of bodies

1.3 General overview of metabolism

Note

CHAPTER 2 Cellular aspects of metabolic regulation

2.1 What is metabolic regulation?

2.2 What makes one tissue different from another?

2.3 Rapid changes in metabolic flux and how they are achieved

2.4 Longer-term control of metabolic pathways

Note

CHAPTER 3 Coordination of metabolism in the whole body

3.1 Metabolic regulation involves communication between tissues

3.2 What connects the tissues?

3.3 Hormones and their receptors

3.4 Hormones and short-term control of enzyme activity

3.5 Hormones and longer-term control of enzyme activity

CHAPTER 4 Digestion and intestinal absorption

4.1 The strategy of digestion

4.2 Stages of digestion

4.3 Absorption from the small intestine

4.4 The large intestine

Note

CHAPTER 5 Metabolic specialisation of organs and tissues

5.1 The liver

5.2 Adipose tissue

5.3 Skeletal muscle

5.4 The heart

5.5 The kidneys

5.6 The brain

5.7 The endothelium – a large organ distributed throughout the body

5.8 Enterocytes

5.9 Cells of the immune system

Notes

CHAPTER 6 Communication systems

6.1 Communication systems

6.2 Hormones important in metabolic regulation

6.3 The nervous system and metabolism

Note

CHAPTER 7 Integration of carbohydrate, fat and protein metabolism in normal daily life

7.1 The body’s fuel stores

7.2 Carbohydrate metabolism

7.3 Lipid metabolism

7.4 Amino acid and protein metabolism

7.5 Links between carbohydrate, lipid, and amino acid metabolism

7.6 Blood flow and the integration of metabolism

7.7 An integrated overview of metabolism: a metabolic diary

7.8 Metabolic control in a physiological setting

Notes

CHAPTER 8 Metabolic challenges: Coping with some extreme physiological situations

8.1 Situations in which metabolism is significantly altered from its normal pattern

8.2 Exercise

8.3 Growth and development

Notes

CHAPTER 9 Metabolic challenges: Coping with some pathological situations

Pathological challenges to metabolism

9.1 Starvation

9.2 The period of adapted starvation

9.3 Pathological stress: the metabolic response to tissue injury and the effects of inflammation, infection and trauma

9.4 Cancer metabolism

CHAPTER 10 Lipoprotein metabolism and atherosclerosis

10.1 Introduction to lipoprotein metabolism

10.2 Outline of the pathways of lipoprotein metabolism

10.3 Regulation of lipoprotein metabolism

10.4 Disturbances of lipoprotein metabolism

CHAPTER 11 Energy balance and body weight regulation

11.1 Energy balance and body weight

11.2 Energy balance

11.3 Conditions of low body weight

11.4 Treatment of obesity

Note

CHAPTER 12 Diabetes mellitus

12.1 Different types of diabetes

12.2 Clinical features of diabetes

12.3 Metabolic alterations in diabetes mellitus

12.4 Treatment of diabetes mellitus

12.5 The longer-term complications of diabetes

12.6 Prevention of diabetes

Note

Index

End User License Agreement

List of Tables

Chapter 1

Table 1.1

Table 1.2

Chapter 2

Table 2.2-1

Table 2.1

Table 2.2

Table 2.3

Table 2.4

Table 2.5

Table 2.6

Chapter 3

Table 3.1

Table 3.2

Chapter 4

Table 4.1

Table 4.2

Table 4.3

Chapter 5

Table 5.1

Table 5.2

Table 5.3

Chapter 6

Table 6.1

Table 6.2

Table 6.3

Chapter 7

Table 7.1

Table 7.2

Table 7.3

Chapter 8

Table 8.1

Table 8.2

Table 8.3

Table 8.4

Table 8.5

Chapter 9

Table 9.1

Table 9.2

Chapter 10

Table 10.1

Table 10.2

Chapter 11

Table 11.1

Table 11.2

Table 11.3

Table 11.4

Chapter 12

Table 12.1

Table 12.2

Table 12.3

List of Illustrations

Chapter 1

Figure 1.1 Rates of energy intake and output for a motor vehicle. The rate of intake (top ...

Figure 1.2 Rates of energy intake and output for a person during a typical day. The rate o...

Figure 1.3 (a) Three-dimensional structure of the methane molecule and (b) the molecular s...

Figure 1.4 Chemical structures of some lipids. A typical saturated fatty acid (palmitic ac...

Figure 1.5 Structure of biological membranes in mammalian cells. Cell membranes and intrac...

Figure 1.6 Cholesterol and a typical cholesteryl ester (cholesteryl oleate). In the struct...

Figure 1.7 Some simple sugars and disaccharides. Glucose and fructose are shown in their ‘...

Figure 1.8 Structure of glycogen. Left-hand side: each circle in the upper diagram represe...

Figure 1.9 Pictures of the molecular shapes of different fatty acids. (a) saturated fatty ...

Figure 1.10 Comparison of fat and carbohydrate as fuel sources. Raw potatoes (right) are hy...

Figure 1.11 Structure of an amino acid. At physiological pH (7.4) the carboxyl group is ion...

Figure 1.12 Catabolism and anabolism.

Figure 1.13 Overall metabolic energy flux. The three energy groups (fats, carbohydrates, pr...

Figure 1.14 Pathways of glucose metabolism inside the cell. The pathways of glucose (carboh...

Figure 1.15 Lactate and ethanol metabolism. Glycolysis produces NADH from NAD

+

. (a) In aero...

Figure 1.16 Pathways of lipid metabolism in the cell. Synthesis of fatty acids from acetyl-...

Figure 1.17 Lipid metabolism pathways. Importance of lipolysis and esterification pathways ...

Figure 1.18 Parallel between soap manufacture (saponification) and fat mobilisation. In sap...

Figure 1.19 Metabolism of amino acids. To be metabolised, amino acids must first be deamina...

Figure 1.20 Transamination reactions. Transamination involves the transfer of an amino grou...

Figure 1.21 Deamination of amino acids. By linking transamination reactions to oxidative de...

Figure 1.22 Urea cycle. One nitrogen atom enters the cycle as an ammonium ion from glutamat...

Figure 1.23 Metabolism of the carbon skeletons of amino acids following their deamination. ...

Chapter 2

Figure 2.2.1  

Figure 2.1 Sodium-linked active transport. By co-transport with Na

+

ions, substance X may ...

Figure 2.2 GLUT4 recruitment to the cell membrane. There is an intracellular pool of GLUT4...

Figure 2.3 Different methods for achieving changes in metabolic flux within a cell. A hypo...

Figure 2.5.1  

Figure 2.4 Different stages at which the amount of a protein present in a cell may be cont...

Figure 2.5 Operation of the circadian clock at a cellular level. The proteins CLOCK (circa...

Figure 2.6 Glucose control of expression of lipogenic genes. Glucose increases gene expres...

Figure 2.7 The PPAR system. The ligand for the PPAR (a fatty acid, or a fatty acid derivat...

Figure 2.8 The SREBP system. The full-length SREBP protein is located in the endoplasmic r...

Chapter 3

Figure 3.1 The circulatory system. Oxygenated blood from the lungs returns in the pulmonar...

Figure 3.2 Diffusion of chemical substances through the interstitial fluid. A typical tiss...

Figure 3.3.1 Synthesis and breakdown of cAMP

Figure 3.3.2 PI3K, phosphatidylinositol-3-kinase; PLC, phospholipase C....

Figure 3.4.1 Signal chain for regulation of many metabolic processes by insulin. Insulin bin...

Figure 3.4.2 Signal chain for stimulation of glycogen breakdown by adrenaline (or noradrenal...

Figure 3.4.3 Signal chain for control of hormone-sensitive lipase (HSL) in adipocytes. HSL i...

Chapter 4

Figure 4.1 Anatomy of the digestive tract and associated organs.

Figure 4.2 Control of gastric acid secretion. Plus signs indicate stimulation or activatio...

Figure 4.3 Structure of a villus of the small intestine. One of the absorptive cells (ente...

Figure 4.4 Vessels carrying the products of digestion away from the small intestine. Subst...

Figure 4.2.1

Figure 4.5 Lipid digestion and absorption in the small intestine. Fatty acids and choleste...

Figure 4.6 Hormonal regulation of the secretion of digestive juices. Gastrin stimulates hy...

Figure 4.7 Absorption of monosaccharides from the intestine. Monosaccharides enter the ent...

Figure 4.8 Esterification pathways for the formation of triacylglycerol. The monoacylglyce...

Figure 4.9 Cholesterol absorption. Niemann-Pick C1-like protein-1 (NPC1L1), expressed at t...

Chapter 5

Figure 5.1 Arrangement of hepatocytes in liver lobules. In a cross-section of the liver, t...

Figure 5.2 Outline of glucose metabolism and its hormonal regulation in the liver. Dashed ...

Figure 5.1.1

Figure 5.2.1

Figure 5.3.1 Pathways around pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase...

Figure 5.3 The pentose phosphate pathway and its links with lipogenesis. G 6-P, glucose 6-...

Figure 5.4 Overview of fatty acid metabolism in the liver. Fatty acids cross the hepatocyt...

Figure 5.5 The pathway of ketone body formation from acetyl-CoA (ketogenesis). This is loc...

Figure 5.4.1

Figure 5.6 Outline of amino acid metabolism in the liver. Liver contains the enzymes of gl...

Figure 5.7 Appearance of brown and white adipose tissue. Left, white adipose tissue under ...

Figure 5.8 Overview of fatty acid and glucose metabolism in white adipose tissue. The body...

Figure 5.9 The action of lipoprotein lipase in white adipose tissue. Top panel: Lipoprotei...

Figure 5.10 The intracellular pathway of lipolysis in adipocytes. Triacylglycerol (TAG) in ...

Figure 5.11 Suppression of fat mobilisation by insulin. Top panel: Insulin restrains fat mo...

Figure 5.12 Uncoupling of respiration in brown adipose tissue (and potentially other tissue...

Figure 5.13 Human brown adipose tissue depots. Brown adipose tissue (BAT) depots around the...

Figure 5.14 Structural organisation of skeletal muscle. One cell is a

muscle fibre

. The who...

Figure 5.15 The creatine kinase reaction in muscle. The reaction is referred to as the Lohm...

Figure 5.16 Fibre-type composition of leg muscles in athletes. Different types of muscle fi...

Figure 5.17 ATP generation in skeletal muscle. Only major pathways are shown: each arrow ma...

Figure 5.7.1

Figure 5.18 (a) Section of kidney and (b) schematic view of energy metabolism in different ...

Figure 5.19 The endothelium, a smooth single-celled lining of blood vessels.

Figure 5.20 Generation of nitric oxide (NO) from arginine in endothelial cells leads to rel...

Figure 5.21 Amino acid metabolism in enterocytes. In the fed state the enterocytes oxidise ...

Chapter 6

Figure 6.1 The location of endocrine glands involved in energy metabolism. The thymus is s...

Figure 6.2 Islets of Langerhans in the pancreas. The pancreatic tissue has been immunostai...

Figure 6.3 Synthesis of insulin. Insulin is first synthesised as one long polypeptide, pre...

Figure 6.4 Glucose stimulation of insulin secretion in the pancreatic β-cell. Glucose ente...

Figure 6.5 Dose–response curve for the effects of glucose concentration on the secretion o...

Figure 6.6 Pituitary hormones and their target organs.

Figure 6.7 The anatomy of the thyroid gland.

Figure 6.8 Biosynthesis of the thyroid hormones. Thyroxine (T

4

) and triiodothyronine (T

3

) ...

Figure 6.9 The anatomy of the adrenal glands.

Figure 6.10 Biosynthesis of the catecholamines. Noradrenaline is a neurotransmitter, releas...

Figure 6.11 Propranolol (a β-adrenergic blocker) inhibits lipolysis in response to exercise...

Figure 6.12 The leptin system and regulation of fat stores. Leptin is produced in, and secr...

Figure 6.13 The idea of ‘incretins’ (gut-derived hormones that augment insulin secretion). ...

Figure 6.14 Basic structure of a nerve cell (neurone).

Figure 6.15 The structures of two important neurotransmitters, acetylcholine, and noradrena...

Figure 6.1.1  

Figure 6.2.1  

Figure 6.16 The human brain and its main components.

Figure 6.17 The neuromuscular junction.

Figure 6.18 Types of neurotransmission in the central and peripheral nervous systems. ACh, ...

Figure 6.19 Plasma glucagon, adrenaline, and noradrenaline concentrations in response to ra...

Chapter 7

Figure 7.1 Relative constancy of blood glucose concentrations during a typical day, compar...

Figure 7.2 An analogy for metabolic regulation. The temperature in a thermostatically cont...

Figure 7.3 The pattern of glucose metabolism after an overnight fast. The numbers are appr...

Figure 7.4 Concentrations of insulin, glucose, and lactate in blood after an overnight fas...

Figure 7.5 Rates of glucose release from liver, from exogenous (dietary) and endogenous (g...

Figure 7.6 Increases in liver and skeletal muscle glycogen after a single meal in normal s...

Figure 7.7 The pattern of glucose metabolism after a carbohydrate breakfast. The direct pa...

Figure 7.8 Plasma non-esterified fatty acid (NEFA) concentrations after an overnight fast ...

Figure 7.9 The pattern of non-esterified fatty acid (NEFA) metabolism after an overnight f...

Figure 7.10 The milky appearance of blood plasma (right) after a fatty meal, compared with ...

Figure 7.11 Triacylglycerol concentrations in plasma after a meal. The figure shows concent...

Figure 7.12 The pattern of plasma triacylglycerol metabolism after a breakfast containing b...

Figure 7.13 Overview of protein and amino acid turnover in the body. We eat (very approxima...

Figure 7.14 The typical pattern of amino acid metabolism in different tissues. The diagram ...

Figure 7.15 The reactions that synthesise (glutamine synthetase) and break down (glutaminas...

Figure 7.16 Major amino acids interconversions in muscle. (Adipose tissue and brain may be ...

Figure 7.17 Major pathways for amino acid flow between tissues. The major sites of amino ac...

Figure 7.18 The intestinal-renal pathway. Enterocytes consume large amounts of glutamine (s...

Figure 7.19 Overall control of protein synthesis and breakdown in muscle (and other tissues...

Figure 7.3.1 Source: modified from Frayn, K. N. & Evans, R. D. (in press) Oxford Textbook of...

Figure 7.20 The glucose–alanine cycle operates in concert with the Cori (glucose–lactate) c...

Figure 7.21 Blood flow through adipose tissue and forearm muscle during a typical day with ...

Figure 7.22 Increasing fat storage with successive meals during a typical day with three me...

Chapter 8

Figure 8.1 Concentrations of ATP and of phosphocreatine (PCr) in Type II fibres in human m...

Figure 8.4.1  

Figure 8.2 Coordinated regulation of glycogenolysis and contraction by Ca

2+

ions in skelet...

Figure 8.5.1 Source: based on Newsholme, E. A., & Leech, A. R. (1983) Biochemistry for the M...

Figure 8.4 Relationship between initial glycogen concentration in the quadriceps muscle an...

Figure 8.5 Schematic drawing of the distribution of blood flow between various organs and ...

Figure 8.6 Plasma concentrations of cortisol (top panel) and growth hormone (bottom panel)...

Figure 8.7 Plasma glucose (top panel) and insulin (lower panel) concentrations during aero...

Figure 8.8 Coordination of metabolism by the nervous system during endurance exercise. Adr...

Figure 8.9 Glycogen concentrations in leg muscle after one-legged exercise (bicycling on a...

Figure 8.10 Plasma triacylglycerol (TAG) concentrations after a high-fat test meal on two o...

Figure 8.11 Offspring and maternal energy requirements in humans. Red circles represent foe...

Figure 8.12 Fuel disposition in the developing foetus. The foetus requires all three nutrit...

Chapter 9

Figure 9.1 The phases of starvation, assessed from the point of view of glucose metabolism...

Figure 9.2 Liver glycogen concentrations in normal human volunteers, after overnight fast,...

Figure 9.3 Rate of urinary nitrogen excretion in five obese subjects during starvation. So...

Figure 9.4 Serum concentrations of triiodothyronine (T

3

) and reverse triiodothyronine (rev...

Figure 9.5 Concentrations of non-esterified fatty acids (NEFAs) and ketone bodies (the sum...

Figure 9.6 Major fuel flows in prolonged starvation. Protein (especially that in muscle) a...

Figure 9.7 Urinary nitrogen, phosphorus and sulphur excretion following major trauma. Sour...

Figure 9.8 Phases of metabolic change following acute injury, such as trauma. The ‘ebb’ ph...

Figure 9.9 Pattern of alteration of net nitrogen excretion and resting energy expenditure ...

Figure 9.10 Metabolic response to severe burn injury. Skin as injured tissue is both the or...

Figure 9.11 Interconnection of hormonal (both endocrine and cytokine) changes with immune s...

Figure 9.12 Changes associated with severe injury-sepsis and critical illness. The vertical...

Figure 9.13 The Warburg effect. Normal cells, when provided with adequate oxygen, mostly ox...

Figure 9.14 Altered metabolic pathways in cancer cells. Metabolism in tumour cells is direc...

Figure 9.15 Cancer cachexia. Characteristic loss of muscle tissue mass, with weakness, but ...

Figure 9.16 Effects of cancer growth on host metabolism and the aetiology of cancer cachexi...

Chapter 10

Figure 10.1 A typical lipoprotein particle.

Figure 10.2 The exogenous pathway of lipoprotein metabolism. Apo, apolipoprotein; FA, fatty...

Figure 10.3 The endogenous pathway of lipoprotein metabolism. Particles may undergo several...

Figure 10.3.1

Figure 10.4 HDL metabolism. Pre-β HDL is apolipoprotein AI (APOAI) associated with some pho...

Figure 10.5 Forward and reverse cholesterol transport. Cholesterol is secreted by the liver...

Figure 10.6 Relationship between risk of death from cardiovascular disease (coronary heart ...

Figure 10.7 Lowering of cardiovascular disease with reduction in serum cholesterol. The dat...

Figure 10.6-1 CETP, cholesteryl ester transfer protein (Section 10.2.3.2); TAG, triacylglycer...

Figure 10.8 Impaired postprandial triacylglycerol metabolism in patients with coronary hear...

Chapter 11

Figure 11.1.1 Summary of central pathways regulating appetite.

Figure 11.1 Relationship between serum leptin concentration and percentage body fat in 179 ...

Figure 11.2 Growth of a child with leptin deficiency due to a mutation in the leptin gene. ...

Figure 11.3 Antoine Lavoisier measuring the O

2

consumption of his assistant, Séguin. The pi...

Figure 11.3.1 Data for the example are reproduced from Garrow, J. S. (1988) Obesity and Relat...

Figure 11.4 Components of energy expenditure. A typical 24-hour energy expenditure of 10 00...

Figure 11.5 Relationship between body fat content and body weight in a series of 104 women....

Figure 11.6 Relationship between metabolic rate and fat-free mass (FFM; a measure of lean b...

Figure 11.7 Insulin resistance in obese men. Plasma glucose and insulin concentrations are ...

Chapter 12

Figure 12.1 A sufferer from Type 1 diabetes mellitus in the early days of insulin therapy, ...

Figure 12.2 Typical plasma glucose and insulin responses to a carbohydrate load in Type 2 d...

Figure 12.1.1 Redrawn from Felber, J. -P., Acheson, K. J., & Tappy, L. (1993) From Obesity to...

Figure 12.3 The metabolic pattern in untreated Type 1 diabetes. Pathways accelerated by ins...

Figure 12.4 Twenty-four-hour profiles of plasma glucose concentration in non-diabetic subje...

Figure 12.5 Twenty-four-hour profiles of plasma non-esterified fatty acid (NEFA) concentrat...

Figure 12.6 Plasma insulin concentrations in non-diabetic subjects and people with Type 1 d...

Figure 12.7 Non-enzymatic glycation of proteins. A sugar molecule in its straight-chain, al...

Figure 12.8 The polyol pathway for production and further metabolism of sorbitol. The enzym...

Guide

Cover

Table of Contents

Preface

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E1

Preface

The first edition of Metabolic Regulation: A Human Perspective appeared in 1996. (It was pink.) When the second edition was published (in green) in 2003, it seemed that a revolution was taking place in metabolism. Tissues that we always thought were ‘doing metabolism’ turned out to be secreting hormones, adipose tissue and leptin being the prime example. By 2010, when the third (blue) edition was published, there were yet more changes in our understanding of metabolism and its regulation. The regulation of gene expression by nutrients (including, for instance, the carbohydrate-response element binding protein) was much better understood than previously. The techniques of genetic manipulation had also increased our understanding of metabolic pathways. In 1996, nobody could have guessed that a mouse without the adipose tissue enzyme hormone-sensitive lipase would be viable, let alone relatively normal: that finding led to the discovery of another enzyme of fat mobilisation, adipose triglyceride lipase. Similar studies made us revise our ideas about other ‘well-established’ enzymes such as phosphoenolpyruvate carboxykinase. Now, in 2018, we see more radical developments in the field. We always thought that hormones were hormones and metabolites were metabolites – now we know that the distinction is far from clear, with many compounds we regard as metabolites signalling through receptors as do ‘true hormones,’ thereby modulating metabolism. (We note in passing that the late Derek Williamson – colleague to both of us, and mentor to one [RDE], would not have been surprised: he had long predicted that the ketone bodies had a signalling role.)

We have always recognised that this textbook needed to be regarded as a complement to a more conventional biochemistry textbook, which would give details of pathways rather than just notes on their regulation. We have both taught metabolism to biochemistry and medical students in Oxford, and for this edition decided to combine our areas of expertise and to add material to the book that would enable it to be used more independently. Thus, in Chapter 1 of this new edition, we have provided overviews of metabolic pathways that will then be described in more detail in subsequent chapters. A particular emphasis of the later chapters, as in previous editions, is the tissue-specificity of these metabolic pathways. We are aware that this textbook is used by medical and nursing students and that has prompted us to include more material relevant to metabolism in clinical situations such as cancer, sepsis, and trauma. We hope this material will be of interest to all students, including those of nutrition and sports science, as it illustrates how metabolism may be perturbed. The small revision to the title of the book reflects these changes.

We thank Michael Goran, Fredrik Karpe, Denise Robertson and Garry Tan, who have helped us by reading, and commenting on, sections of the book. Any errors remaining are our responsibility. We are enormously grateful to Anne Clark, Mike Symonds and Roy Taylor for providing pictures and data. We give special thanks to Professor Rui Fontes of the University of Porto who translated edition 3 into Portuguese, and in so doing pointed out many errors, most of which had persisted through all the editions. Jenny Seward and James Watson, and their editorial team at Wiley, have been very helpful to us as we prepared this edition. Finally, we thank Theresa and Helen for putting up with us during the hours we spent at the computer producing this new edition.

About the companion website

This book is accompanied by a companion website:

www.wiley.com/go/frayn

The website includes:

PowerPoint slides of all the figures in the book for downloading

Multiple choice questions

Key learning points

Further reading

CHAPTER 1The underlying principles of human metabolism

Key learning points

We eat food. We expend energy doing exercise, sleeping, just being. What happens to the food between it entering our mouths and its being used for energy? That’s what metabolism (at least, so far as this book is concerned) is all about.

In order to cover the periods when we are not eating, we need to store metabolic fuels. We store fuel as fat (triacylglycerol) and as carbohydrate (glycogen). Fat provides considerably more energy per gram stored. Proteins are not stored specifically as energy reserves but they may be utilised as such under certain conditions. We must regulate both the storage and mobilisation of energy to match intake to expenditure. That is what we will refer to as metabolic regulation.

Molecules involved in metabolism differ in an important property: polarity. Polar molecules (those with some degree of electrical charge) mix with water (which is also polar); non-polar molecules, which include most lipids (fatty substances), usually don’t mix with water. This has profound implications for the way they are handled in the body. They also differ in the amount of energy they contain, affecting their efficiency as fuels.

Some molecules have both polar and non-polar aspects: they are said to be amphipathic. They can form a bridge between polar and non-polar regions. Amphipathic phospholipid molecules can group together to form membranes, such as cell membranes.

Energy is derived from metabolic substrates derived from food-stuffs principally by oxidation, a chemical process involving electron transfer from electron donor (reducing agent) to electron acceptor (oxidising agent), the final electron acceptor being oxygen.

The different organs in the body have their own characteristic patterns of metabolism. Substrates flow between them in the bloodstream (circulation). Larger blood vessels divide into fine vessels (capillaries) within the tissues, so that the distances that molecules have to diffuse to or from the cells are relatively small (more detail in

Chapter 3

).

The different classes of metabolic substrates have characteristic chemical properties; by utilising all three types of metabolic substrates derived from the three major food energy groups (carbohydrates, fats, and proteins) energy storage (anabolism) and release (catabolism) in many physiological conditions is achieved.

General features of metabolism include synthesis and breakdown of substrates, and complete breakdown to release energy by oxidation. The tricarboxylic acid cycle (TCA cycle) is the central cellular mechanism for substrate oxidation to H

2

O and CO

2

, with consumption of O

2

. It operates within mitochondria.

Carbohydrate metabolism centres around the sugar glucose. Carbohydrate metabolic pathways include conversion to glycogen and its reverse, glucose breakdown and oxidation, glucose conversion to lipid, and synthesis of glucose (gluconeogenesis).

Lipid metabolism for energy centres on the interconversion of fatty acids and triacylglycerol. Triacylglycerol synthesis involves esterification of fatty acids with glycerol; triacylglycerol breakdown (

lipolysis

) involves liberation of fatty acids and glycerol from stored triacylglycerol. The oxidation of fatty acids occurs through a pathway known as β-oxidation.

Amino acid metabolism involves incorporation of amino acids into protein, and its reverse (protein synthesis and breakdown), and further metabolism of the amino acids, either to convert them to other substrates (e.g. lipids) or final oxidation. The nitrogen component of amino acids is disposed of by conversion to urea in the liver.

1.1 Metabolism in perspective

To many students, metabolism sounds a dull subject. It involves learning pathways with intermediates with difficult names and even more difficult formulae. Metabolic regulation may sound even worse. It involves not just remembering the pathways, but remembering what the enzymes are called, what affects them and how. This book is not simply a repetition of the molecular details of metabolic pathways. Rather, it is an attempt to put metabolism and metabolic regulation together into a physiological context, to help the reader to see the relevance of these subjects. Once their relevance to everyday life becomes apparent, then the details will become easier, and more interesting, to grasp.

This book is written from a human perspective because, as humans, it is natural for us to find our own metabolism interesting – and very important for understanding human health and disease. Nevertheless, many aspects of metabolism and its regulation that are discussed are common to other mammals. Some mammals, such as ruminants, have rather specialised patterns of digestion and absorption of energy; such aspects will not be covered in this book.

Metabolism might be defined as the biochemical reactions involved in converting foodstuffs into fuel. (There are other aspects, but we will concentrate on this one.) As we shall shortly see, that is not a constant process: ‘flow’ through the metabolic pathways needs to change with time. An important aspect of these pathways is therefore the ability to direct metabolic products into storage, then retrieve them from storage as appropriate. In this chapter we shall give an overview of the major pathways involved in carbohydrate, lipid, and protein metabolism. In later chapters we shall see that these pathways operate within specific tissues – or sometimes between tissues – and not all cells carry out the same set of metabolic reactions. We intend to give enough detail of metabolic pathways that a student will be able to understand them, but inevitably a more detailed biochemistry textbook will provide more. We shall concentrate upon understanding how these pathways operate in human terms, and how they are regulated.

Now we have mentioned metabolic regulation, so we should ask: why is it necessary? An analogy here is with mechanical devices, which require an input of energy, and convert this energy to a different and more useful form. The waterwheel is a simple example. This device takes the potential energy of water in a reservoir – the mill-pond – and converts it into mechanical energy which can be used for turning machinery, for instance, to grind corn. As long as the water flows, its energy is extracted, and useful work is done. If the water stops, the wheel stops. A motor vehicle has a different pattern of energy intake and energy output (Figure 1.1). Energy is taken in very spasmodically – only when the driver stops at a filling station. Energy is converted into useful work (acceleration and motion) with an entirely different pattern. A long journey might be undertaken without any energy intake. Clearly, the difference from the waterwheel lies in the presence of a storage device – the fuel tank. But the fuel tank alone is not sufficient: there must also be a control mechanism to regulate the flow of energy from the store to the useful-work-producing device (i.e. the engine). In this case, the regulator is in part a human brain deciding when to move, and in part a mechanical system controlling the flow of fuel.

Figure 1.1Rates of energy intake and output for a motor vehicle. The rate of intake (top panel) is zero except for periods in a filling station, when it is suddenly very high. (Notice that the scales are different for intake and output.) The rate of output is zero while the car is parked with the engine off; it increases as the car is driven to the filling station, and is relatively high during a journey. When totalled up over a long period, the areas under the two curves must be equal (energy intake = energy output) – except for any difference in the amounts of fuel in the tank before and after.

What does this have to do with metabolism? The human body is also a device for taking in energy (chemical energy, in the form of food) and converting it to other forms. Most obviously, this is in the form of physical work, such as lifting heavy objects. However, it can also be in more subtle forms, such as producing and nurturing offspring. Any activity requires energy. Again, this is most obvious if we think about performing mechanical work: lifting a heavy object from the floor onto a shelf requires conversion of chemical energy (ultimately derived from food) into potential energy of the object. But even maintaining life involves work: the work of breathing, of pumping blood around the vascular system, of chewing food and digesting it. At a cellular level, there is constant work performed in the pumping of ions across membranes, and the synthesis and breakdown of the chemical constituents of cells.

What is your pattern of energy intake in relation to energy output? For most of us, the majority of energy intake occurs in three relatively short periods during each 24 hours, whereas energy expenditure is largely continuous (the resting metabolism) with occasional extra bursts of external work (Figure 1.2). It is clear that we, like the motor vehicle, must have some way of storing food energy and releasing it when required. As with the motor vehicle, the human brain may also be at the beginning of the regulatory mechanism, although it is not the conscious part of the brain: we do not have to think when we need to release some energy from our fat stores, for instance. Some of the important regulatory systems that will be covered in this book lie outside the brain, in organs which secrete hormones, particularly the pancreas. But whatever the internal means for achieving this regulation, we manage to store our excess food energy and to release it just as we need.

Figure 1.2Rates of energy intake and output for a person during a typical day. The rate of energy intake (top panel) is zero except when eating or drinking, when it may be very high. The rate of energy output (heat + physical work) (lower panel) is at its lowest during sleep; it increases on waking and even more during physical activity. As with the car, the pattern of energy intake may not resemble that of energy expenditure, but over a long period the areas under the curves will balance – except for any difference in the amounts of energy stored (mainly as body fat) before and after. Source: data for energy expenditure are for a person measured in a calorimetry chamber and were kindly supplied by Prof Susan Jebb of Nuffield Department of Primary Care Health Sciences, Oxford University.

This applies to the normal 24-hour period in which we eat meals and go about our daily life. But the body also has to cope with less well-organised situations. In many parts of the world, there are times when food is not that easily available, and yet people are able to continue relatively normal lives. Clearly, the body’s regulatory mechanisms must recognise that food is not coming in and allow an appropriate rate of release of energy from the internal stores. In other situations, the need for energy may be suddenly increased. Strenuous physical exercise may increase the total rate of metabolism in the body to 20 times its resting level. Something must recognise the fact that there is a sudden need to release energy at a high rate from the body’s stores. During severe illness, such as infections, the rate of metabolism may also be increased; this is manifested in part by the rise in body temperature. Often the sufferer will not feel like eating normally. Once again, the body must have a way of recognising the situation, and regulating the necessary release of stored energy.

What we are now discussing is, indeed, metabolic regulation. Metabolic regulation in human terms covers the means by which we take in nutrients in discrete meals, and deliver energy as required, varying from moment to moment and from tissue to tissue, in a pattern which may have no relationship at all to the pattern of intake. Metabolic regulation works ultimately at a molecular level, mainly by modulation of the activities of enzymes. But one should not lose sight of the fact that these molecular mechanisms are there to enable us to lead normal lives despite fluctuations in our intake and our expenditure of energy. In this book, the emphasis will be on the systems within the human body which sense the balance of energy coming in and energy required, particularly the endocrine (hormonal) and the nervous systems, and which regulate the distribution and storage of nutrients after meals, and their release from stores and delivery to individual tissues as required.

The intention of this preamble is to illustrate that, underlying our everyday lives, there are precise and beautifully coordinated regulatory systems controlling the flow of energy within our bodies. Metabolic regulation is not a dry, academic subject thought up just to make biochemistry examinations difficult; it is at the centre of human life and affects each one of us every moment of our daily lives.

1.2 The chemistry of food – and of bodies

Energy is taken into the body in the form of food. The components of food may be classified as macronutrients and micronutrients. Macronutrients are those components present in a typical serving in amounts of grams rather than milligrams or less. They are the well-known carbohydrate, fat, and protein. Water is another important component of many foods, although it is not usually considered a nutrient. Micronutrients are vitamins, minerals, and nucleic acids: they are not oxidised to provide energy, but rather they are used to facilitate biochemical mechanisms of the body. Although these micronutrients play vital roles in the metabolism of the macronutrients, they will not be discussed in any detail in this book, which is concerned with the broader aspects of what is often called energy metabolism.

The links between nutrition and energy metabolism are very close. We eat carbohydrates, fats, and proteins. Within the body these relatively large molecules are broken down to smaller components, rearranged, stored, released from stores, and further metabolised, but essentially whether we are discussing food or metabolism the same categories of carbohydrate, fat, and protein can be distinguished. This is not surprising since our food itself is of organic origin, whether plant or animal.

In order to understand metabolism and metabolic regulation, it is useful to have a clear idea of some of the major chemical properties of these components. This is not intended as a treatise in physical or organic chemistry but as a starting point for understanding some of the underlying principles of metabolism. The discussion assumes a basic understanding of the meaning of atoms and molecules, of chemical reactions and catalysis, and some understanding of chemical bonds (particularly the distinction between ionic and covalent bonding).

1.2.1 Some important chemical concepts

1.2.1.1 Polarity

Some aspects of metabolism are more easily understood through an appreciation of the nature of polarity of molecules. Polarity refers to the distribution of electrical charge over the molecule. A non-polar molecule has a very even distribution of electrical charge over its surface and is electrically neutral overall (the negative charge on the electrons is balanced by the positive charge of the nucleus). A polar molecule has an overall charge, or at least an uneven distribution of charge. The most polar small particles are ions – that is, atoms or molecules which have entirely lost or gained one or more electrons. However, even completely covalently bonded organic molecules may have a sufficiently uneven distribution of electrical charge to affect their behaviour. Polarity is not an all-or-none phenomenon; there are gradations, from the polar to the completely non-polar.

Polarity is not difficult to predict in the molecules which are important in biochemistry. We will contrast two simple molecules: water and methane. Their relative molecular masses are similar – 18 for water, 16 for methane – yet their physical properties are very different. Water is a liquid at room temperature, not boiling until 100 °C, whereas methane is a gas (‘natural gas’) which only liquifies when cooled to −161°C. We might imagine that similar molecules of similar size would have the same tendency to move from the liquid to the gas phase, and that they would have similar boiling points. The reason for their different behaviours lies in their relative polarity. The molecule of methane has the three-dimensional structure shown in Figure 1.3a. The outer electron ‘cloud’ has a very even distribution over the four hydrogen atoms, all of which have an equal tendency to pull electrons their way. The molecule has no distinct electrical poles – it is non-polar. Because of this very even distribution of electrons, molecules near each other have little tendency to interact. In contrast, in the water molecule (Figure 1.3b) the oxygen atom has a distinct tendency to pull electrons its way, shifting the distribution of the outer electron cloud so that it is more dense over the oxygen atom, and correspondingly less dense elsewhere. Therefore, the molecule has a rather negatively charged region around the central oxygen atom, and correspondingly positively charged regions around the hydrogen atoms. Thus, it has distinct electrical poles – it is a relatively polar molecule. It is easy to imagine that water molecules near to each other will interact. Like electrical charges repel each other, unlike charges attract. This gives water molecules a tendency to line up so that the positive regions of one attract the negative region of an adjacent molecule (Figure 1.3b). So, water molecules, unlike those of methane, tend to ‘stick together’: the energy needed to break them apart and form a gas is much greater than for methane, and hence water is a liquid while methane is a gas. The latent heat of evaporation of water is 2.5 kJ g−1, whereas that of methane is 0.6 kJ g−1. Note that the polarity of the water molecule is not as extreme as that of an ion – it is merely a rather uneven distribution of electrons, but enough to affect its properties considerably.

Figure 1.3(a) Three-dimensional structure of the methane molecule and (b) the molecular structure of water. (a) The hydrogen atoms of methane (CH4) are arranged symmetrically in space, at the corners of a tetrahedron. (b) The molecular structure of water. Top: view of the ‘electron cloud’ surrounding the molecule; bottom, interactions between water molecules. The molecule has a degree of polarity, and this leads to electrical interactions between neighbouring molecules by the formation of hydrogen bonds. These bonds are not strong compared with covalent bonds, and are constantly being formed and broken. Nevertheless, they provide sufficient attraction between the molecules to account for the fact that water is a liquid at room temperature whereas the non-polar methane is a gas.

The contrast between water and methane may be extended to larger molecules. Organic compounds composed solely of carbon and hydrogen – for instance, the alkanes or ‘paraffins’ – all have the property of extreme non-polarity: the chemical (covalent) bond between carbon and hydrogen atoms leads to a very even distribution of electrons, and the molecules have little interaction with each other. A result is that polar molecules, such as those of water, and non-polar molecules, such as those of alkanes, do not mix well: the water molecules tend to bond to each other and to exclude the non-polar molecules, which can themselves pack together very closely because of the lack of interaction between them. In fact, there is an additional form of direct attraction between non-polar molecules, the van der Waals forces. Random fluctuations in the density of the electron cloud surrounding a molecule lead to minor, transient degrees of polarity; these induce an opposite change in a neighbouring molecule, with the result that there is a transient attraction between them. These are very weak attractions, however, and the effect of the exclusion by water is considerably stronger. The non-polar molecules are said to be hydrophobic (water fearing or water hating).

A strong contrast is provided by an inorganic ionic compound such as sodium chloride. The sodium and chlorine atoms in sodium chloride are completely ionised under almost all conditions. They pack very regularly in crystals in a cubic form. The strength of their attraction for each other means that considerable energy is needed to disrupt this regular packing – sodium chloride does not melt until heated above 800 °C. And yet it dissolves very readily in water – that is, the individual ions become separated from their close packing arrangement rather as they would on melting. Why? Because the water molecules, by virtue of their polarity, are able to come between the ions and reduce their attraction for each other. In fact, each of the charged sodium and chloride ions will become surrounded by a ‘shell’ of water molecules, shielding it from the attraction or repulsion of other ions. Sodium chloride is said to be hydrophilic – water loving. The terms polar and hydrophilic are for the most part interchangeable. Similarly, the terms non-polar and hydrophobic are virtually synonymous.

Ionic compounds, the extreme examples of polarity, are not confined to inorganic chemistry. Organic molecules may include ionised groups. These may be almost entirely ionised under normal conditions – for instance, the esters of orthophosphoric acid (‘phosphate groups’), as in the compounds AMP, ADP, and ATP, in metabolites such as glucose 6-phosphate, and in phospholipids. Most of the organic acids involved in intermediary metabolism, such as lactic acid, pyruvic acid, and the long-chain carboxylic acids (fatty acids), are also largely ionised at physiological hydrogen ion concentrations (Box 1.1). Thus, generation of lactic acid during exercise raises the hydrogen ion concentration (the acidity) both within the cells where it is produced, and generally within the body, since it is released into the bloodstream.

Box 1.1 Ionisation state of some acids at normal hydrogen ion concentrations

The normal pH in blood plasma is around 7.4. (It may be somewhat lower within cells, down to about 6.8.) This corresponds to a hydrogen ion concentration of 3.98 × 10−8 mol l−1 (since – log10 of 3.98 × 10−8 is 7.4).

The equation for ionisation of an acid HA is:

this equilibrium is described by the equation:

where Ki is the dissociation or ionisation constant and is a measure of the strength of the acid: the higher the value of Ki the stronger (i.e. the more dissociated) the acid.

Ki in the equation above relates the concentrations expressed in molar terms (e.g. mol/l). (Strictly, it is not the concentrations but the ‘effective ion concentrations’ or ion activities