Membrane Lipidomics for Personalized Health

By Carla Ferreri and Chryssostomos Chatgilialoglu

Lipidomics is an important aspect of personalized medicine in relation to nutrition and metabolism. This approach has become important due to the substantial presence of nutraceuticals in the market, since it gives personalized criteria on how to choose the right nutraceutical strategy for both prevention and for quality of life.

This multi-disciplinary textbook uses a simple and practical approach to provide a comprehensive overview of lipidomics and their connection with health and nutrition. The text is divided into two parts:
   -  Part 1 outlines the basics of lipidomics and focuses on the biochemical and nutritional aspects with descriptions of the analytical methods employed for the examination of cell membrane fatty acid composition.
   - Part 2 familiarizes the reader with the use of membrane lipidomic diagnostics in practical health care, using health conditions as examples to introduce the concept of lipidomic profiles in different physiological and pathological situations including prevention.
Through the various properties of membrane lipidomics, readers will be able to combine the molecular status of the cell membrane with the evaluation of the subject for personalized nutritional and nutraceutical strategies.

Membrane Lipidomics for Personalized Health will be beneficial to biologists, biochemists and medical researchers, as well as health care professionals, pharmacists, and nutritionists seeking in-depth information on the topic.

• Language: English
• Publisher: Wiley
• Release date: Jul 2, 2015
• ISBN: 9781118682753

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CONTENTS

Cover

Title page

About the Authors

Preface

Acknowledgments

Abbreviations

Part I: Molecular and Nutritional Basis of Cell Membranes and Lipidomics

1 Membranes for Life and Life for Membranes

1.1 CELL MEMBRANES: THE ROLE OF FATTY ACIDS AND THE EXCLUSION OF TRANS ISOMERS

1.2 ORGANIZATION AND HOMEOSTASIS

2 Fatty Acid Families

2.1 SATURATED FATTY ACIDS: BIOSYNTHESIS AND DIETARY REGULATION

2.2 MONOUNSATURATED FATTY ACIDS: THE IMPORTANCE TO BE Cis

2.3 POLYUNSATURATED FATTY ACIDS: THE ESSENTIALITY FOR HUMAN CELLS

3 Essential Fatty Acids

3.1 THE OMEGA-6 AND OMEGA-3 FAMILIES: CASCADES AND REGULATION

3.2 THE BALANCE BETWEEN OMEGA-6 AND OMEGA-3 PATHWAYS: NUTRITIONAL AND METABOLIC CONSIDERATIONS

3.3 FOOD AND MEMBRANES: A VIRTUOUS CYCLE

4 Free Radicals and Lipids

4.1 TRANS FATTY ACIDS FOR HUMANS: THE NUTRITIONAL INTAKE

4.2 ENDOGENOUS SOURCES OF TRANS FATTY ACIDS BY FREE RADICAL STRESS

4.3 FREE RADICALS AND LIPID OXIDATION: THE THRESHOLD FOR HEALTH

4.4 LIPOPROTEINS AND DEVELOPMENT OF MARKERS FOR LIPID REACTIVITY

Part II: Membrane Lipidomics for Personalized Health

5 What Is Lipidomics for Health

5.1 THE BIRTH OF THE POSTGENOMICS ERA

5.2 LIPIDOMICS IN THE POSTGENOMIC ERA

5.3 FATTY ACIDS INVOLVED IN MEMBRANE AND MEDIATOR LIPIDOMICS

5.4 MEMBRANE LIPIDOMICS: CELLULAR STRESS, TURNOVER, AND OPPORTUNITIES

5.5 PHOSPHOLIPIDS FROM DIETARY INTAKES TO BIOLOGICAL FUNCTIONS

6 Lipidomics of Erythrocyte Membranes

6.1 ERYTHROCYTE AS A COMPREHENSIVE HEALTH BIOMARKER

6.2 THE OPTIMAL VALUE INTERVALS AND THE MEMBRANE UNBALANCE INDEX

6.3 LIPID BIOSYNTHESIS AND RELATED INDICES

6.4 THE INDIVIDUATION OF MOLECULAR INDICATORS

7 Nutrilipidomics

7.1 WHEN FATTY ACIDS BECOME NUTRACEUTICALS: MEMBRANE THERAPY WITH NUTRILIPIDOMICS

7.2 FATTY ACID–BASED MEMBRANE LIPIDOMICS AND NUTRILIPIDOMICS: THE PERSONALIZED APPROACH FOR NUTRITION AND NUTRACEUTICALS IN HEALTH AND DISEASES

8 Lipidomic Profiles and Intervention Strategies in Prevention and Diseases

8.1 LIPIDOMICS AND SPORT

8.2 LIPIDOMICS AND PREGNANCY

8.3 LIPIDOMICS AND AGING

8.4 LIPIDOMICS AND CARDIOVASCULAR HEALTH

8.5 LIPIDOMICS AND OVERWEIGHT

8.6 LIPIDOMICS AND DERMATOLOGY

8.7 LIPIDOMICS AND NEUROLOGY

8.8 LIPIDOMICS AND OPHTALMOLOGY

8.9 CONCLUSIVE REMARKS

9 Lipidomics and Tutorials

9.1 FIRST STEPS FOR THE LIPIDOMIC ANALYSIS

9.2 LEARNING VERIFICATION

ANSWERS

References and Notes

Index

End User License Agreement

List of Tables

Chapter 02

Table 2.1 Percentages of fatty acids and families present in various human tissues

Chapter 03

Table 3.1 Omega-6/omega-3 ratios in different population and historical context

Table 3.2 Mean life span of human cells in the body

Chapter 05

Table 5.1 Mean fatty acid percentages

Chapter 06

Table 6.1 Mature Erythrocyte membrane fatty acid interval values of the Italian population composing the reference fatty acid cluster for lipidomic analysis

Table 6.2 The seven indices of lipid biosynthesis

Table 6.3 The output of molecular indicators for preventive panels of membrane lipidomics

List of Illustrations

Chapter 01

Figure 1.1 The membrane structure made of a double layer of phospholipids, and the fatty acid chains that form the hydrophobic layer

Figure 1.2 Details of the phospholipid molecule with variation of fatty acid tails and polar heads. In the box the structure of sphyngomielin is displayed

Figure 1.3 List of main saturated and unsaturated fatty acids, with their melting points, trivial nomenclature, and numerical annotation (number of C atoms : number of double bonds)

Figure 1.4 A representative region of the carbon atom chain in the saturated fatty acids (left, –CH2–CH2– groups), in the cis unsaturated fatty acids (center, with the cis >CH=CH< functionality), and in the trans unsaturated fatty acids

Figure 1.5 Free radical attack (X•) in the membrane bilayer and formation of trans phospholipids

Figure 1.6 Model of the distribution of the structure of phospholipid chain within the membrane bilayer; P= position, D= distance, GLYC= glycerol, COO= ester group, Cn= various position of the fatty acid chain, PO4= phosphate group, CHOL= cholesterol, W= water

Figure 1.7 A representative phospholipid, with the polar head of phosphatidylcholine and the two fatty acid hydrophobic tails attached to l-glycerol

Figure 1.8 Duplication of membranes during cell replication

Figure 1.9 Aggregation process of the phospholipid into a double layer, with folding and creation of the proto-cell or a liposome

Figure 1.10 Cholesterol and its position in membranes

Chapter 02

Figure 2.1 The food pyramid evolution in the turn of the twenty-first century

Figure 2.2 The linear structure of SFA (18 carbon atom, 18:0, stearic acid): top, the molecular space-filling model; bottom, the molecular structure displaying the atoms and bonds.

Figure 2.3 The main steps of the SFA–MUFA enzymatic interplay between elongase and desaturase

Figure 2.4 The two desaturase pathways on palmitic acid to give the two geometrical hexadecenoic isomers (9cis-16 : 1, palmitoleic acid and 6cis-16 : 1, sapienic acid) combined with other competitive pathways involving vaccenic acid (11cis-18 : 1) and linoleic acid (9cis,12cis-18 : 2)

Figure 2.5 Structure of coenzyme A and reaction with the acyl group of a fatty acid

Figure 2.6 Transformation of acyl-CoA into acyl carnitine to pass into the mitochondria

Figure 2.7 Main transformations involved in phospholipid synthesis

Figure 2.8 Formation of linoleic acid (omega-6) and alpha-linolenic acid (omega-3) from oleic acid occurring in plants

Chapter 03

Figure 3.1 The enzymatic pathways of the omega-6 family evidencing the fatty acids that can also be provided by dietary intake

Figure 3.2 The enzymatic pathways of the omega-3 family evidencing the fatty acids with dietary intakes and the genes involved in enzyme formation

Figure 3.3 Evidence of the enzymatic competition between the members of omega-6, and omega-3 families noted also as n-6 and n-3.

Figure 3.4 Transformation of EPA (omega-3) into the corresponding hydroperoxy derivatives by aspirin-triggered COX2 activity in the biosynthesis of resolvins of the E series

Figure 3.5 Some of the mediators produced omega-6 and omega-3 fatty acids and the main food sources where these EFA can be found

Figure 3.6 The cell membrane remodeling (Land’s cycle) starting from the phospholipase A2 activation and the intervention of the fatty acid pool.

Figure 3.7 Detachment of a fatty acid tail by the action of phospholipase A2 to obtain a lysophospholipid

Figure 3.8 Fate of arachidonic acid after detachment from membrane phospholipids by PLA2 partitioned between acyl-CoA synthesis and eicosanoid synthesis

Figure 3.9 The role of stimulation of macrophage proliferation by DGLA.

Figure 3.10 Examples of fatty acids contained in foods

Figure 3.11 Cell replication phases and membrane formation

Chapter 04

Figure 4.1 Examples of positional and geometrical isomers of monounsaturated fatty acids

Figure 4.2 Conjugated linoleic acid (CLA) isomers and comparison with linoleic acid

Figure 4.3 Isomerisation of fatty acids (a) shown for oleic acid and addition-elimination mechanism (b) shown for S-centered radicals.

Figure 4.4 Biosynthesis of arachidonic acid and the importance of the position 5 and 8 of the double bonds, for indicating the trans isomers of arachidonic acid as marker of endogenous isomerization

Figure 4.5 Mono-trans isomers of arachidonic acid

Figure 4.6 Enzymatic and nonenzymatic pathways of transformation of arachidonic acid into oxidation products such as aldehydes (4-HNE), isoprostanes, prostaglandins, and others.

Figure 4.7 Hydroperoxides formed from linoleic acid by the peroxidation process, starting from the reactivity of the bisallylic position

Figure 4.8 The main products from the peroxidation process: conjugated hydroperoxides (LOOH), 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA)

Figure 4.9 The interconnections between the different pathways of fatty acid–containing lipids, and the formation of lipoproteins as lipid assembly (PC = phosphatidylcholine, PS = phosphatidylserine, PE = phosphatidylethanolamine)

Figure 4.10 The two structures of oleic acid (MUFA) and linoleic acid (PUFA, omega-6). Reactive sites can be distinguished: linoleic acid shows the bisallylic groups, two allylic groups, and two double bonds (C9–C10 and C12–C13), whereas oleic acid has two allylic groups and one double bond (C9–C10)

Figure 4.11 The structures of the geometrical isomers expected from oleic and linoleic acids

Figure 4.12 Different locations of enzymatic and molecular antioxidant systems

Chapter 05

Figure 5.1 The cycle of stress, adaptation and the passage from injury to cell death.

Figure 5.2 The TLR family at work

Figure 5.3 The fate of lipids from nutrition to digestion and absorption

Figure 5.4 Hydrolysis from triglycerides to free fatty acids and glycerol and reversal triglyceride formation

Figure 5.5 Mitochondria and the structure of cardiolipin containing linoleic acid as fatty acid moieties

Chapter 06

Figure 6.1 Graphic representation of the lipidomic profile, compared to the optimal values (green area), and of the Membrane Unbalance Index coloured scale

Chapter 07

Figure 7.1 Science innovation in the center of the development of nutraceutical or food formulations oriented by the human molecular profiles

Chapter 08

Figure 8.1 Percentages of individuals having arachidonic acid percentage greater than 17% in their erythrocyte membranes, under different pathological conditions including healthy controls. Data by courtesy of Lipinutragen srl from the data base of 10000 analyses available in the company.

Chapter 09

Figure 9.1 Combined clinical–lipidomic observation for a personalized strategy

Membrane Lipidomics for Personalized Health

Carla Ferreri

Consiglio Nazionale delle Ricerche, Institute of Organic Synthesis and Photoreactivity, Italy

Chryssostomos Chatgilialoglu

National Center of Scientific Research Demokritos, Institute of Nanoscience and Nanotechnology, Greece

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This edition first published 2015

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Library of Congress Cataloging-in-Publication Data:

Ferreri, Carla, author.

  Membrane lipidomics for personalized health / Carla Ferreri and Chryssostomos Chatgilialoglu.

     p. ; cm.

  Includes bibliographical references and index.

  ISBN 978-1-118-54041-1 (cloth) – ISBN 978-1-118-54032-9 (pbk.)

  I. Chatgilialoglu, Chryssostomos, author.  II. Title.

[DNLM:   1. Fatty Acids–metabolism.   2. Membrane Lipids–metabolism.   3. Individualized Medicine.   4. Metabolomics–methods.   5. Nutritional Physiological Phenomena.   QU 85.6]     

    QP752.F35

    612.3′97–dc23

        2015016361

Dedicated to our sons Alexandros and Raffaella, who made our lives complete with love

About the Authors

Carla Ferreri was born in Napoli, graduated in Pharmacy in 1979 and postgraduated in Hospital Pharmacy in 1981. She started her studies in organic synthesis and medicinal chemistry as permanent research fellow at the University of Napoli. From 1990 she was involved in free radical research, and in 2001 she moved to the Consiglio Nazionale delle Ricerche, where she is now Senior Researcher, responsible for the project Biomarkers of Free Radical Stress at the Research Area of Bologna. She is interested in multidisciplinary research, involving free radicals, chemical transformations under biomimetic conditions (liposomes), biomarker discovery related to free radical stress, and lipid remodeling caused to cell membranes by various stress types. She is also consultant to companies for lipidomic profiles and nutraceutical formulations. Her activity is described in more than 160 scientific contributions. From this research the innovation project Lipidomic Profile of Cell Membranes: A Molecular Approach Applied to Human Health started, with a wide applicability to medicine, prevention, and quality of life. For this project Carla Ferreri was awarded in 2010 with the ITWIIN award as the Best Innovator Woman in Italy and received a special mention at the EUWIIN award 2011. Carla Ferreri is cofounder and R&D director of the company Lipinutragen, a spin-off officially recognized by CNR, and is cofounder of Lipinutramed, a newborn spin-off of the NCSR Demokritos in Athens (Greece).

Chryssostomos Chatgilialoglu was appointed Director of the Institute of Nanoscience and Nanotechnology (INN) in the NCSR Demokritos, Athens, in March 2014. He is also the Honorary President and Cofounder of spin-off companies Lipinutragen (Italy) and Lipinutramed (Greece). He chaired the COST Action CM0603 on Free Radicals in Chemical Biology, from 2007 to 2011, and is now the Chairman of the COST Action CM1201 on Biomimetic Radical Chemistry, running from 2012 to 2016.

In 1976, he received his doctorate degree in Industrial Chemistry from the University of Bologna and completed his postdoctoral studies at York University (UK) and National Research Council of Canada, Ottawa. From 1983, he worked for the Consiglio Nazionale delle Ricerche (Bologna), and was Research Director from 1991 to 2014. He has received many honors and awards including the Fluka Prize Reagent of the Year 1990, and is a world expert on free radicals. His research interests lie in free radical reactions increasingly addressing in the last decade applications in biomimetic chemistry and biomarker discovery, with fundamental acquisitions in DNA, lipid, and protein transformations.

He has published over 240 papers in peer-reviewed international journals, 33 book chapters, 6 patents, and 6 books (2 as author and 4 edited); he is Coeditor of the Encyclopedia of Radical in Chemistry, Biology and Materials (4 volumes), 2012 John Wiley & Sons, Ltd. Over 100 invited lectures at international conferences and over 120 invited research seminars at institutions.

Preface

The idea of this textbook is to offer a multi- and interdisciplinary treatment on lipidomics, which lies at the interface of several life science disciplines, from chemistry, biochemistry, biology, pharmacology, to medicine and health care as the final application. In particular, for health applications lipidomics must be treated in a functional way, building connections of lipid structures with their metabolic and nutritional origins, and with biological, pharmacological, and medical functions.

The book focuses on cell membrane lipidomics for the important structural and functional roles played by lipid molecules, in particular phospholipids, whose influence goes beyond the membrane compartment itself, expanding from the start of cell signaling to the regulation of gene expression. Nowadays, the central role played by the structure and functionality of the cell membrane has been recognized in many processes, such as the start of cascades for lipid-mediated signaling, having strong influence on the quality and sustainability of life. Phospholipids are evaluated in detail for their composition made of fatty acids, the hydrophobic part that forms the interior of the membrane bilayer. We will describe why and how the fatty acid residues of membrane phospholipids represent the result of a precise and successful balance between biosynthesis and diet, which can be realized in each individual. This is an important topic of molecular medicine.

In fact, considering that cell membranes display characteristic fatty acid compositions for each type of tissue, these compositions represent the lipid code necessary for the tissue functioning and to realize a normal tissue metabolism. Any change in the tissue fatty acid composition corresponds not only to a molecular change, but also to the start of possible tissue malfunction or degeneration. Stress, such as an increased oxidative status or a decrease in protective elements for metabolism, can cause an initial change in the fatty acid composition and its consequent healthy balance. In this book, membrane lipidomics will be focused as a powerful diagnostic tool of molecular health, starting from cell membranes.

The importance of the concept of unbalanced membrane fatty acid composition for the application in molecular medicine will be treated, which cannot be in principle a pathological status in itself, but can indicate an initial failure of the healthy status when present under physiological conditions. At this stage, lipidomics will also be shown as an important preventive and problem-solving tool, by which molecular unbalances can be addressed in a personalized way, applying the most appropriate strategy for the subject. It also contributes to the choice of diet, nutritional supplements, or functional foods for the restoration of the individual optimal balance.

In this context, lipidomic analysis can be part of the decisional activity of health operators for the formulation of the most adequate therapeutic strategy also based on nutritional lipid elements.

In fact, health operators cannot disregard the molecular aspect of the membrane since the lipid composition derives not only from the biosynthetic abilities of the body, but also from the dietary habits. As nutrition affords essential fatty acid, vitamins, and micronutrients strictly related with the enzyme and metabolic functioning to generate cells and cell membranes, the membrane status can be taken as a global health biomarker, interpreting the resulting balance among different fatty acid families.

From the patients’ point of view, a strategy suggested by health operators, which includes attention to