Molecular Aspects of Alcohol and Nutrition. A Volume in the Molecular Nutrition Series

365 Pages·2015·33.814 MB·English

by  Patel, Vinood B

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
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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