Preface

Lipids are water insoluble in nature and need to be transported in body fluids in the form of lipid:protein complexes, i.e. lipoproteins. Lipoproteins consist of a lipid core of triglycerides and cholesteryl esters, and an amphiphilic surface of free cholesterol and phospholipids. Apolipoproteins (apo-Lp) are interchelated into surface lipids of the lipid droplet forming the mature plasma lipoproteins (Fig.1).

#### **Figure 1.**

Nascent lipoproteins on the other hand lack the lipid core and have a disc like structure. There are four main lipoprotein density classes - chylomicrons, very low density lipoproteins, low density lipoproteins (LDL) and high density lipoproteins (HDL) - and yet each of them may be divided into numerous subfractions. The major function of lipoproteins is the delivery of nutrient lipids, i.e. triglycerides (TG), phospholipids (PL) and cholesterol, to various organs and tissues. Whereas dietary TG and PL may be absorbed up to almost 100%, the absorption rate of cholesterol ranges from 30 – 60% only and is influenced by genes and other nutritional factors. There exist some 15 or more proteins associated with lipids in the form of apo-Lp that function as "structural proteins", co-factors and inhibitors of enzymes, ligands for specific cell surface receptors and possibly others. Although unsaturated and polyunsaturated fat is considered to be beneficial, these lipids are prone to oxidation and degradation. These products contribute significantly to common diseases found in civilized countries such as atherosclerosis, coronary heart disease, Type-2 diabetes mellitus, stroke, Alzheimer disease but also auto-immune diseases and cancer. A major trigger for these diseases is LDL whose mass consist to approx. 50% of cholesterol. Oxidized and modified LDL are taken up by scavenger receptors of macrophages and transform them into foam cells. Foam cells in turn synthesize inflammatory cytokines and enzymes hat lead to a vicious cycle of self-perpetuation that triggers smooth muscle cell proliferation, lipid deposition and plaque formation in the arterial intima (Fig.2).

#### **Figure 2.**

Similar pathways appear to be also involved in Alzheimer disease and cancer. HDL on the other hand have anti-atherogenic, anti-thrombotic anti-oxidative effects and therefore are considered to be beneficial (Fig.3).

#### **Figure 3.**

XII Preface

in the arterial intima (Fig.2).

**Figure 2.**

phospholipids (PL) and cholesterol, to various organs and tissues. Whereas dietary TG and PL may be absorbed up to almost 100%, the absorption rate of cholesterol ranges from 30 – 60% only and is influenced by genes and other nutritional factors. There exist some 15 or more proteins associated with lipids in the form of apo-Lp that function as "structural proteins", co-factors and inhibitors of enzymes, ligands for specific cell surface receptors and possibly others. Although unsaturated and polyunsaturated fat is considered to be beneficial, these lipids are prone to oxidation and degradation. These products contribute significantly to common diseases found in civilized countries such as atherosclerosis, coronary heart disease, Type-2 diabetes mellitus, stroke, Alzheimer disease but also auto-immune diseases and cancer. A major trigger for these diseases is LDL whose mass consist to approx. 50% of cholesterol. Oxidized and modified LDL are taken up by scavenger receptors of macrophages and transform them into foam cells. Foam cells in turn synthesize inflammatory cytokines and enzymes hat lead to a vicious cycle of self-perpetuation that triggers smooth muscle cell proliferation, lipid deposition and plaque formation

Similar pathways appear to be also involved in Alzheimer disease and cancer. HDL on the other hand have anti-atherogenic, anti-thrombotic anti-oxidative effects and

therefore are considered to be beneficial (Fig.3).

As we know there exist so called "LDL" creatures such as primates or rabbits that easily develop atherosclerosis and myocardial infarction upon overfeeding with lipid rich diet. On the other hand, "HDL" creatures such as rats, mice and dogs hardly develop atherosclerosis by feeding them an atherogenic Western-type diet. Thus numerous attempts are made to interfere with elevated LDL and low HDL concentrations therapeutically in individuals at increased risk for myocardial infarction and stroke.

By typing into databases such as Medline or PubMed the word "lipoprotein" one gets more than 100.000 hits that highlights the common interest in this topic. It is actually impossible to cover all aspects of lipoprotein structure, function, metabolism and pathophysiology in one issue like the present volume, but attempts have been made to concentrate on topics that are in focus of current lipoprotein research. These topics have been divided into 10 sections.

**Section 1** deals with important issues of lipoprotein structure, the assembly and kinetics of apoB containing lipoproteins, and the role of Lp(a) in kidney patients.

**Section 2** reviews clinical chemical methods for diagnosing patients at increased risk for atherosclerotic diseases, myocardial infarction and stroke. In addition, hints are given how to approach biological databases and how to interprete complex data sets.

#### XVI Preface

In **Section 3**, the characterization of dys- and hyperlipoproteinemias is described in detail and their impact on caedivascular disease and mortality is presented.

In **Section 4**, the impact of lipid lowering drugs, of long chain polyunsaturated fatty acids and of endoscopic treatments on lipoprotein metabolism and atherogenesis is described.

**Section 5** highlights the important issue of lipid oxidation and prevention by antioxidants. There is no doubt that the oxidative stress per se and the supply of antioxidative vitamins and plant compound such as polyphenols play a eminent role in atherogenesis, yet also other factors mainly genes and environment influence the development of atherosclerosis , cardiovascular diseases and stroke.

**Section 6**: It is obvious that without animal models it would have been impossible to study the function and metabolism of lipoproteins in detail. Thus in this chapter, models for dys-and hyperlipoproteinemia are described in addition to the influence of diet on obesity and atherosclerosis. Finally, genetically modified animals and animals with inborn errors of lipoprotein metabolism such as the WHHL rabbit are described for studying the role of lipoproteins in the development of atherosclerotic diseases.

Neurodegenerative diseases are a burden for the civilized world and still in progress. **Section 7** highlights different forms of brain diseases with major emphasis to stroke and Alzheimer disease that without doubt are causally related to lipid rich diet, lipid oxidation and derangements in lipoprotein metabolism.

**Section 8** summarized the most important theories of the involvement of lipids and lipoproteins in the development of cancer.

Adipose tissue has been recognized as an important organ for hormone and cytokine production. One of the best studied adipokinine, adiponectin is characterized in **Section 9**. In addition hyperlipoproteinemias associated with chronic virus hepatitis is outlined in that chapter.

Last but not least, lipids and lipoproteins play an eminent role in platelet and leucocyte function, and hemostasis. This is the topic of **Section 10** that also focuses on one of the most atherogenic lipoprotein, Lp(a). Lp(a) has been studied for more than 50 years and we still do not know the physiological function of that particle that is found only in primates, and in a somewhat different structure in hedgehogs.

Intense investigations in all these areas are still going one and we wait for exciting new developments mediated by "omics" methods and translational research. This volume will help new investigators in the field to get acquainted with the general topic of lipoprotein research and guides scientists interested in this area to emerging new fields.

> **Saša Frank and Gerhard Kostner** Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria

**Lipoprotein Structure and Assembly** 
