MOLECULAR ASPECTS OF ALCOHOL AND NUTRITION A VOLUME IN THE MOLECULAR NUTRITION SERIES Edited by Vinood B. Patel, Phd Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125, London Wall, EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright © 2016 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. 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Neither the publisher nor the authors assume any liability for any injury and/or damage to persons or property arising from this publication. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-800773-0 For information on all Academic Press publications visit our website at http://store.elsevier.com/ Publisher: Mica Haley Senior Acquisitions Editor: Tari K. Broderick Editorial Project Manager: Jeff Rossetti Production Project Manager: Chris Wortley Designer: Victoria Pearson Typeset by Thomson Digital Printed and bound in the United States of America List of Contributors Jill K. Badin, BS Department of Cellular & Integrative Elhaseen E. Elamin, MD, MSc, PhD Division of Physiology, Stark Neuroscience Research Institute, Indiana Gastroenterology-Hepatology, School for Nutrition, University-Purdue University at Indianapolis, Indianapolis, Toxicology and Metabolism, Maastricht University Medical IN, USA Center, Maastricht, the Netherlands Shashi Bala, PhD Department of Medicine, University of Caleb T. Epps, MS Department of Medicine, Division of Massachusetts Medical School, Worcester, MA, USA Preventive Medicine & Nutrition, Columbia University, William S. Blaner, PhD Department of Medicine, Division New York, NY, USA of Preventive Medicine & Nutrition, Columbia University, Sebastien Farnaud, MSc, PhD Department of Life Sciences, New York, NY, USA University of Bedfordshire, Luton, Bedfordshire, UK Larysa B. Bondarenko, PhD, DSc General Toxicology Reem Ghazali, MSc Department of Clinical Biochemistry, Department, Institute of Pharmacology and Toxicology of King Abdul Aziz University, Jeddah, Saudi Arabia; National Academy of Medical Sciences of Ukraine, Kyiv, Department of Biomedical Sciences, Faculty of Science & Ukraine Technology, University of Westminster, London, UK Patrick Burke, MS Department of Neuroscience & Physiology, William J. Giardino, PhD Department of Psychiatry & SUNY Upstate Medical University, Syracuse, NY, USA Behavioral Sciences, Stanford University, Stanford, CA, USA Ute Burkhardt, PhD Department of Pharmacology, Goethe Helen G. Gika, PhD Department of Chemical Engineering, University Frankfurt, Frankfurt, Hessen, Germany Aristotle University of Thessaloniki, Thessaloniki, Greece Maria Camargo Moreno, MPH Department of Biochemistry Emilio González-Reimers, PhD Servicio de Medicina & Molecular Biology, SUNY Upstate Medical University, Interna, Hospital Universitario de Canarias, Universidad de Syracuse, NY, USA; Department of Neuroscience & La Laguna, Tenerife, Canary Islands, Spain Physiology, SUNY Upstate Medical University, Syracuse, Ewa Gruszewska Department of Biochemical Diagnostics, NY, USA; Developmental Exposure Alcohol Research Medical University of Bialystok, Bialystok, Poland Center, Binghamton University, Binghamton, NY, USA Daniel Gyamfi, MSc, PhD Department of Medical Olimpia Carreras, PhD Department of Physiology, Faculty Laboratory Technology, College of Health Sciences, Kwame of Pharmacy, Seville University, Seville, Spain Nkrumah University of Science & Technology, Kumasi, Ya-Jen Chiu, BS Department of Anatomy and Cell Biology, Ghana Indiana University-Purdue University at Indianapolis, Charles H. Halsted, MD University of California Davis, The Indianapolis, IN, USA; Department of Life Science, Genome and Biomedical Sciences Facility, Davis, California, National Taiwan Normal University, Taipei, Taiwan USA Lech Chrostek, PhD Department of Biochemical Diagnostics, Li-Shin Huang, PhD Department of Medicine, Columbia Medical University of Bialystok, Bialystok, Poland University, New York, NY, USA; Department of Medicine, Robin D. Clugston, PhD Department of Medicine, Division Division of Preventive Medicine & Nutrition, Columbia of Preventive Medicine & Nutrition, Columbia University, University, New York, NY, USA New York, NY, USA Cherry Ignacio, PhD Department of Biochemistry & Jason D. Coombes, PhD Regeneration and Repair Group, The Molecular Biology, SUNY Upstate Medical University, Institute of Hepatology, London, UK; Transplant Immunology Syracuse, NY, USA; Department of Neuroscience & and Mucosal Biology, Kings College London, UK Physiology, SUNY Upstate Medical University, Syracuse, Bogdan Cylwik, MD Department of Paediatric Laboratory NY, USA; Developmental Exposure Alcohol Research Center, Binghamton University, Binghamton, NY, USA Diagnostics, Medical University of Bialystok, Bialystok, Poland Daisy M. Jonkers, PhD Division of Gastroenterology- Claudio D’Addario, PhD Faculty of Bioscience and Hepatology, School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Technology for Food, Agriculture and Environment, Maastricht, the Netherlands University of Teramo, Teramo, Italy; Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Shosuke Kawanishi, PhD Department of Environmental Institutet, Stockholm, Sweden and Molecular Medicine, Mie University Graduate School Kwabena Owusu Danquah, MSc, PhD Department of of Medicine, Tsu, Japan; Laboratory of Public Health, Department of Health Sciences, Faculty of Pharmaceutical Medical Laboratory Technology, College of Health Sciences, Sciences, Suzuka University of Medical Science, Suzuka, Kwame Nkrumah University of Science & Technology, Japan Kumasi, Ghana ix x List of Contributors Jochen Klein, PhD Department of Pharmacology, Goethe Kwame Nkrumah University of Science & Technology, University Frankfurt, Frankfurt, Hessen, Germany Kumasi, Ghana Sherry Chiao-Ling Lo, PhD Department of Anatomy Vinood B. Patel, PhD Department of Biomedical and Cell Biology, Indiana University-Purdue University Sciences, Faculty of Science & Technology, University of at Indianapolis, Indianapolis, IN, USA; Indiana Alcohol Westminster, London, UK Research Center, Indiana University-Purdue University at Guilherme V. Portari, PhD Department of Nutrition, Indianapolis, Indianapolis, IN, USA Federal University of Triângulo Mineiro, Uberaba, MG, Mauro Maccarrone, MS, PhD School of Medicine and Brazil Center of Integrated Research, Campus Bio-Medico Geraldine Quintero-Platt, MD Servicio de Medicina University of Rome, Rome, Italy; European Center Interna, Hospital Universitario de Canarias, Universidad for Brain Research (CERC)/Santa Lucia Foundation, de La Laguna, Tenerife, Canary Islands, Spain Rome, Italy Marisol Resendiz, BA, BS Department of Cellular & Ann M. Manzardo, PhD Department of Psychiatry and Integrative Physiology, Stark Neuroscience Research Behavioral Sciences, University of Kansas Medical Center, Institute, Indiana University-Purdue University at Kansas City, Kansas, USA Indianapolis, Indianapolis, IN, USA Antonio Martínez-Riera, MD Servicio de Medicina Interna, Andrey E. Ryabinin, PhD Department of Behavioral Hospital Universitario de Canarias, Universidad de La Neuroscience, Oregon Health and Science University, Laguna, Tenerife, Canary Islands, Spain Portland, OR, USA Ad A. Masclee, MD, PhD Division of Gastroenterology- Amit Saha, BA Department of Medicine, Division of Hepatology, School for Nutrition, Toxicology and Preventive Medicine & Nutrition, Columbia University, Metabolism, Maastricht University Medical Center, New York, NY, USA Maastricht, the Netherlands Francisco Santolaria-Fernández, MD Servicio de Medicina Valentina Medici, MD Division of Gastroenterology and Interna, Hospital Universitario de Canarias, Universidad de Hepatology, University of California Davis, Sacramento, La Laguna, Tenerife, Canary Islands, Spain California, USA Helmut K. Seitz, MD, PhD Centre of Alcohol Research, Kosha Mehta, MSc, PhD Department of Biomedical University of Heidelberg, Heidelberg, Baden-Württemberg, Sciences, Faculty of Science and Technology, University of Germany; Department of Medicine (Gastroenterology and Westminster, London, UK Hepatology), Salem Medical Centre, Heidelberg, Baden - Frank A. Middleton, PhD Department of Biochemistry Württemberg, Germany & Molecular Biology, SUNY Upstate Medical University, Ganna M. Shayakhmetova, PhD General Toxicology Syracuse, NY, USA; Department of Neuroscience & Department, Institute of Pharmacology and Toxicology of Physiology, SUNY Upstate Medical University, Syracuse, National Academy of Medical Sciences of Ukraine, Kyiv, NY, USA; Department of Psychiatry & Behavioral Sciences, Ukraine SUNY Upstate Medical University, Syracuse, NY, USA; Camila S. Silva, PhD Division of Biochemical Toxicology, Developmental Exposure Alcohol Research Center, National Center for Toxicological Research, US Food and Binghamton University, Binghamton, NY, USA Drug Administration, Jefferson, AR, USA Kaoru Midorikawa, PhD Department of Environmental Qian Sun, PhD Center for Translational Biomedical and Molecular Medicine, Mie University Graduate School Research, University of North Carolina at Greensboro, of Medicine, Tsu, Japan Kannapolis, NC, USA Fatemeh Momen-Heravi, DDS, MPH Department of Wing-Kin Syn, MBChB Regeneration and Repair Group, Medicine, University of Massachusetts Medical School, The Institute of Hepatology, London, UK; Liver Unit, Worcester, MA, USA Barts Health NHS Trust, London, UK; Department of Sebastian Mueller, MD, PhD Centre of Alcohol Research, Physiology, University of the Basque Country, Leioa, Spain; University of Heidelberg, Heidelberg, Baden-Württemberg, Department of Surgery, Loyola University, Chicago, IL, Germany; Department of Medicine (Gastroenterology and USA; Transplant Immunology and Mucosal Biology, Kings Hepatology), Salem Medical Centre, Heidelberg, Baden - College London, UK Württemberg, Germany Balasubramaniyan Vairappan, PhD Department of Mariko Murata, MD, PhD Department of Environmental Biochemistry, Jawaharlal Institute of Postgraduate Medical and Molecular Medicine, Mie University Graduate School Education and Research (JIPMER), Dhanvantari Nagar, of Medicine, Tsu, Japan Pondicherry, India Fátima Nogales, MD Department of Physiology, Faculty of Helio Vannucchi, MD, PhD Department of Internal Pharmacy, Seville University, Seville, Spain Medicine, Division of Nutrition, University of São Paulo, María Luisa Ojeda, PhD Department of Physiology, Faculty Ribeirão Preto, Brazil of Pharmacy, Seville University, Seville, Spain Kesheng Wang, PhD Department of Biostatistics and Kwabena Owusu Danquah, MSc, PhD Department of Epidemiology, College of Public Health, East Tennessee Medical Laboratory Technology, College of Health Sciences, State University, Johnson City, USA List of Contributors xi Liang Wang, MD, PhD, MPH Department of Biostatistics Feng C. Zhou, PhD Department of Cellular & Integrative and Epidemiology, College of Public Health, East Tennessee Physiology, Stark Neuroscience Research Institute, Indiana State University, Johnson City, USA University-Purdue University at Indianapolis, Indianapolis, IN, USA; Department of Anatomy and Cell Biology, Indiana Ian D. Wilson, DSc Department of Surgery & Cancer, University-Purdue University at Indianapolis, Indianapolis, Imperial College, London, UK IN, USA; Indiana Alcohol Research Center, Indiana Ke-Qin Xie, PhD Institute of Toxicology, School of Public University-Purdue University at Indianapolis, Indianapolis, Health, Shandong University, Jinan City, China IN, USA; Indiana University School of Medicine, and Tao Zeng, PhD Institute of Toxicology, School of Public Department of Psychology, Indiana University-Purdue Health, Shandong University, Jinan City, China University at Indianapolis, Indianapolis, IN, USA Wei Zhong, DVM, PhD Center for Translational Biomedical Zhanxiang Zhou, PhD Center for Translational Biomedical Research, University of North Carolina at Greensboro, Research, University of North Carolina at Greensboro, Kannapolis, NC, USA Kannapolis, NC, USA Series Preface In this series on Molecular Nutrition, the editors of alike. It embraces traditional and nontraditional formats each book aim to disseminate important material per- of nutritional sciences in different ways. Each book in taining to molecular nutrition in its broadest sense. The the series has both overviews and detailed and focused coverage ranges from molecular aspects to whole organs, chapters. and the impact of nutrition or malnutrition on individu- Molecular Nutrition is designed for nutritionists, di- als and whole communities. It includes concepts, policy, eticians, educationalists, health experts, epidemiologists, preclinical studies, and clinical investigations relating to and health-related professionals such as chemists. It is molecular nutrition. The subject areas include molecu- also suitable for students, graduates, postgraduates, re- lar mechanisms, polymorphisms, SNPs, genomic wide searchers, lecturers, teachers, and professors. Contribu- analysis, genotypes, gene expression, genetic modifica- tors are national or international experts, many of whom tions, and many other aspects. Information given in the are from world-renowned institutions or universities. It Molecular Nutrition series relates to national, interna- is intended to be an authoritative text covering nutrition tional, and global issues. at the molecular level. A major feature of the series that sets it apart from other texts is the initiative to bridge the transintellec- V.R. Preedy tual divide so that it is suitable for novices and experts Series Editor xiii Preface Molecular Nutrition is designed for nutritionists, dieti- and protein metabolic processes occurring in the liver, as tians, educationalists, health experts, and epidemiolo- well as other parts of the body. An example of this dis- gists, as well as for health-related professionals such as turbance is the disorder, alcoholic liver disease (ALD), in chemists. It is also suitable for students, graduates, post- which fat deposition occurs. Alcohol is also a major con- graduates, researchers, lecturers, teachers, and profes- tributing factor to diabetes and the metabolic syndrome. sors. Contributors are national or international experts, In the United States alone there are 18 million people with many of whom are from world-renowned institutions or alcoholism and 26 million people who have diabetes; universities. It is intended to be a one-stop-shop of every- nondiabetic alcoholics are at risk of hypoglycemia. Alco- thing to do with nutrition at the molecular level. hol also affects nutrient absorption in the gastrointestinal In this book, Molecular Aspects of Alcohol and Nutrition, tract, which can lead to anemia and reduced amounts of we focus on alcohol. Readers must be mindful that, for fat-soluble vitamins. Secondary consequences of alcohol many, alcohol is an important part of the diet. For ex- consumption are reduced levels of minerals such as mag- ample, in the USA, the NIAAA has reported that in the nesium and calcium and trace elements such as zinc. last year, 60% of women and 72% of men are drinkers. Alcohol also affects many extrahepatic organs and Approximately 20–35% of women and men drink daily. tissues. For example, thiamine deficiency can cause the Thus, alcohol is an important nutrient in its own right memory loss seen in Wernicke/Korsakoff syndrome; and contributes significantly to overall dietary intake. acute and chronic pancreatitis can lead to disruption in In some individuals, however, ethanol may comprise fat and glucose regulation; fetal alcohol syndrome itself about three quarters of total energy intake. Therefore, in is a serious consequence of maternal alcohol consump- this book, alcohol is considered a component in the diet tion, which is also a major contributing factor to the lack rather than a mood-altering psychoactive agent. of nutrients consumed by the alcoholic mother. In terms Alcohol is an important field to study within Mo- of the treatment of alcoholics, an area of continued re- lecular Nutrition as both alcohol and its toxic metabolite search important for nutritionists is studying the effect acetaldehyde disrupts and impairs normal macro- and of parenteral nutrition, high-protein diets, and antioxi- micronutrient regulation at the molecular level. For ex- dant therapy. ample, alcohol affects many gene pathways involved in Molecular Aspects of Alcohol and Nutrition is divided fat and glucose metabolism such as fatty acid oxidation into three sections. Section I covers nutrition and alcohol and synthesis, the SREBP pathway, the ketogenic path- in terms of general aspects and contribution to the diet. way, pathways involved in the regulation of methionine In Section II, there are chapters on alcohol and aldehyde and glutathione synthesis, Vitamin A regulation, and mi- dehydrogenases, metabolic profiling, apoptosis, CRF1 tochondrial genes involved in energy production. Alco- receptor signaling, nutrient pathways, choline supple- hol also disrupts iron homeostatic control from intestinal mentation, and Vitamins B and D. Section III includes iron absorption to iron response genes in the liver. Al- discussion of enzymes, gene expression, microRNAs, cohol also affects and interferes with cell signaling, cell epigenetic modulations, DNA damage, repair proteins, death pathways, calcium homeostasis leading to osteo- DNA methylation, sweet preference genes, ALDH2, iron porosis, and oxygen balance. regulation, carcinogenesis, and DNA adducts. This book is relevant to nutritionists and nutrition re- searchers as alcohol disrupts normal fat, carbohydrate, Vinood B. Patel xv C H A P T E R 1 Nutrients and Liver Metabolism Daniel Gyamfi, MSc, PhD, Kwabena Owusu Danquah, MSc, PhD Department of Medical Laboratory Technology, College of Health Sciences, Kwame Nkrumah University of Science & Technology, Kumasi, Ghana INTRODUCTION (PPARs), and sterol-regulatory-element-binding protein 1c (SREBP-1c). The liver, considered to be the largest and heaviest organ (1.0–1.5 kg) in the human body, consists of two HEPATIC CARBOHYDRATE METABOLISM lobes: a larger right lobe, and a smaller left lobe. It is located beneath the diaphragm, and in the upper right quadrant of the abdominal cavity. The role of the liver Carbohydrate is one of the major sources of energy in nutrients’ metabolism cannot be overlooked, since for the human body. Glucose (a monosaccharide) is con- the liver is positioned strategically in the human body, sidered as the central molecule in carbohydrate metab- such that almost all absorbed nutrients, after digestion olism, since the metabolism of other important mono- in the gastrointestinal tract, pass through the liver via the saccharides (such as fructose, galactose, etc.), which are hepatic portal vein, before they are distributed to other commonly found in diet, is linked virtually to glucose tissues; though some nutrients can also get to the liver metabolic pathways. The liver plays an essential role in via the systemic circulation from other tissues, such as the carbohydrate metabolism, by monitoring and sta- skeletal muscles (lactate, amino acids, etc.) and adipose bilizing blood glucose levels in two major conditions: tissues (fatty acids). absorptive (feeding) state when the liver stores glucose The liver is involved in metabolism of the major nu- as glycogen (via glycogenesis); and postabsorptive (fast- trients: carbohydrate, lipid, and protein (Figure 1.1). It ing) state when the liver releases glucose (via glycoge- can take up glucose (after a meal), and oxidizes it (via nolysis), or synthesizes glucose from noncarbohydrate glycolysis), to produce energy, and at high blood glu- sources (via gluconeogenesis). cose concentration, the liver stores glucose as glycogen (glycogenesis), and converts glucose into fat (lipogen- Glycogenesis and Glycogenolysis esis). When blood glucose concentration is low (dur- Absorptive State ing fasting), the liver releases glucose via glycogenoly- sis, and can synthesize glucose (gluconeogenesis) from Intestinal glucose that is absorbed after the digestion noncarbohydrate precursors (lactate, pyruvate, glycerol, of a carbohydrate-containing meal is carried by hepatic and certain amino acids). Formerly, regulation of these portal vein to the liver. Within the liver, glucose crosses pathways particularly at the molecular level was mainly the membrane of hepatocytes by way of facilitated dif- assigned to hormones, such as insulin and glucagon, fusion, using principally GLUT 2 glucose transporters, but recent advances indicate that nutrients themselves that are membrane bound transporters with very high play an important role in the transcriptional regulation K , ranging from 15 mmol/L to 20 mmol/L, and their m of most of these pathways, independent of hormones. expression, and activities are independent of insulin sig- This chapter describes the major pathways involved in naling. As a result, the rate at which glucose is taken up hepatic energy metabolism, and seeks to tackle some by the hepatocytes is proportional to the concentration of the current advances made in biochemical and, es- of glucose in the blood. pecially, transcriptional regulations of these pathways Once taken up by the hepatocytes, the enzyme by carbohydrate responsive element binding protein glucokinase (GK) (the rate-limiting enzyme for he- (ChREBP), peroxisomal proliferator-activated receptors patic glucose utilization) phosphorylates glucose to Molecular Aspects of Alcohol and Nutrition. http://dx.doi.org/10.1016/B978-0-12-800773-0.00001-X Copyright © 2016 Elsevier Inc. All rights reserved. 3 4 1. NUTRIENTS AND LIvER METAbOLISM FIGURE 1.1 The main functions of the liver in categories. glucose-6-phosphate. Glucokinase (hexokinase IV) molecule, to increase nonreducing ends for chain exten- belongs to the hexokinase family with a high K for sion or degradation, is catalyzed by branching enzyme. m glucose (10 mmol/L), and under physiological con- However, recent research indicates that glycogen forma- ditions, it is not affected by its product, glucose- tion after meals is not only from the pathway that di- 6-phosphate, which allows for postprandial glycogen rectly synthesizes glycogen from glucose, but also from storage within the hepatocytes (Figure 1.2). Glucoki- an indirect pathway, where glycogen can be synthesized nase (inactive in the fasting state, since it is bound to using three-carbon gluconeogenic substrates such as glucokinase regulatory protein (GKR) within the nu- glycerol, lactate, etc.3,4 cleus), is active in postprandial state, since abundance On the other hand, through glycolysis (a 10-step pro- of glucose, and insulin-action synergistically cause its cess that occurs in the cytoplasm with or without the rapid dissociation from GKR with subsequent trans- presence of oxygen), glucose-6-phosphate synthesized is location into the cytoplasm.1,2 All these characteristic converted to pyruvate with a net gain of two ATP and features exhibited by the liver help in the rapid up- two nAdH molecules per glucose molecule. Pyruvate is take, and phosphorylation of glucose during high further either converted to lactate (in the absence of oxy- blood glucose concentration. gen) or decarboxylated to acetyl-CoA that can either be depending on the systemic metabolic state, the processed in the tricarboxylic acid (TCA) cycle (to pro- glucose-6-phosphate synthesized within the hepato- duce energy, reducing equivalents (nAdH and FAdH ) 2 cytes may either be further processed in glycolysis, or and carbon dioxide) in the mitochondria (in the presence be utilized for glycogen synthesis (glycogenesis). Liver of oxygen), or be utilized for de novo lipogenesis (dnL) glycogen formation is catalyzed by glycogen synthase in the cytosol. The reducing equivalents generated in the (GS) after conversion of glucose-6-phosphate to uri- TCA cycle (nAdH and FAdH ), and glycolysis (nAdH) 2 dine diphospate-glucose (UdP-glucose) via glucose- enter the mitochondrial electron transport chain to syn- 1-phosphate. GS is activated allosterically by glucose- thesize ATP via oxidative phosphorylation. Glycolysis is 6-phosphate, but inactive when phosphorylated. Protein regulated by GK, phosphofructokinase 1 (inhibited by its kinases such as, AMP-activated protein kinase (AMPK), product fructose-1,6-bisphosphate), AMP, and pyruvate protein kinase A (PKA), and glycogen synthase kinase kinase (that catalyzes the final reaction, phosphoenolpyr- 3 (GSK3) phosphorylate GS. Insulin suppresses PKA uvate to pyruvate). Insulin, epinephrine, and glucagon leading to dephosphorylation of GS, and activation of also regulate pyruvate kinase via the phosphoinositide glycogen synthesis. The creation of branches in glycogen 3-kinase (PI3K) pathway. Another alternative pathway I. GEnERAL And InTROdUCTORy ASPECTS HEPATIC CARbOHYDRATE METAbOLISM 5 FIGURE 1.2 Overview of hepatic carbohydrate metabolism. After a meal, glucose is taken up by hepatocytes via glucose transporter 2 (GLUT2), and oxidizes via glycolysis in the cytosol to form pyruvate that produces more ATP through tricarboxylic acid (TCA) cycle, and mi- tochondrial oxidative phosphorylation pathway. The glucose 6-phosphate (G6P) formed in glycolysis can also be utilized to synthesize glyco- gen by glycogen synthase (GS), or can enter pentose phosphate pathway. In the excess intake of dietary carbohydrate, glucose is converted to fatty acids (triacylglycerol) through lipogenesis where pyruvate is converted to acetyl-CoA, and then citrate that exits the mitochondria via citrate carrier (CC) into the cytosol. during low cellular energy condition (e.g., fasting), the stored liver glycogen is broken down by the enzyme glycogen phosphorylase (GP) to G6P that can join the glycolytic and pentose phosphate pathways, or be converted by the enzyme glucose 6-phosphatase (G6Pase) to glucose. When glycogen becomes depleted (e.g., in starvation), hepatocyte synthesize glucose via gluconeogenesis using pyruvate, glycerol, certain amino acids and the intermediates of TCA cycle. These processes are regulated by hormones, such as, insu- lin and glucagon. dashed arrows indicate multiple enzymatic steps. The blue portions represent gluconeogenesis. ACC, acetyl-CoA carboxyl- ase; FAS, fatty acid synthase; G1P, glucose 1-phosphate; PPM, phosphoglucomutase; GK, glucokinase; F6P, fructose 6-phosphate; F1,6P, fruc- tose 1,6-bisphosphate; FBPase, fructose 1,6-bisphosphatase; Glyc 3-P, glyceraldehydes 3-phosphate; G6Pd, glucose 6-phosphate dehydrogenase; 6PG, 6-phosphogluconate; Ribose 5P, ribose 5-phosphate; OAA, oxaloacetate; PK, pyruvate kinase; PEP, phosphoenolpyruvate; PC, pyruvate carboxylase; PEPCK, phosphoenolpyruvate carboxykinase; PdH, pyruvate dehydrogenase; 2PG, 2-phosphoglycerate; dHAP, dihydroxyacetone phosphate; PFK1, phosphofructokinase 1; PFK2, phosphofructokinase 2; F2,6P, fructose 2,6-bisphosphate; FBPase2, fructose 2,6-bisphosphatase. for degradation of glucose-6-phosphate in hepatocytes of glycogen polymer to produce glucose-1-phosphate, is the pentose phosphate pathway that provides the cell which is converted to glucose-6-phosphate by phospho- with nAdPH, an important antioxidant and cosubstrate glucomutase. Glycogen phosphorylase action stops at for dnL, and cholesterol synthesis.5 four glucose monomers to a branched point, and deb- ranching enzyme cleaves the last four glucose mono- Postabsorptive State mers. The glucose-6-phosphate synthesized is trans- When the concentration of glucose in the blood falls ported finally into the endoplasmic reticulum (ER), and (for instance, between meals, or during starvation/ dephosphorylated by glucose-6-phosphatase, mainly fasting), the glycogen stored in the liver is broken down synthesized in the liver, to produce glucose (Figure 1.2) to release glucose (glycogenolysis) to restore the blood that is released into the circulation. glucose concentration. The breakdown of glycogen is The regulation of glycogenolysis is the reverse of catalyzed by glycogen phosphorylase (GP) that cleaves glycogenesis, thus glycogen phosphorylase is acti- glucose via phosphorolysis from the nonreducing ends vated, while glycogen synthase is inhibited.4 Glycogen I. GEnERAL And InTROdUCTORy ASPECTS