Preface

Chapter 8 **Quantitative Proteomic Analysis of Skeletal Muscle Detergent-Resistant Membranes in a Smith-Lemli-Opitz**

> Maria Luís Cardoso, Rui Vitorino, Henrique Reguengo, Susana Casal, Rui Fernandes, Isabel Duarte, Sofia Lamas, Renato Alves, Francisco

**Syndrome Mouse 125**

**VI** Contents

Amado and Franklim Marques

In the food, the diet, and the body, one often hears the term "cholesterol" and asks "what is this cholesterol?" In this book entitled *Cholesterol - Good, Bad, and the Heart*," now you got the answers given by the experts in the field. Moreover, you can explore more by reading the references/citations given in the articles of each chapter. It is still an emerging field and lot more is being discovered. You will be amazed how much knowledge is already there in this book on cholesterol.

The book contains eight chapters. The first section covers the structural and functional fea‐ tures of cholesterol in Chapters 1 to 5.

In Chapter 1, Zhiwei Y. et al. describe cholesterol in various forms, as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and cholesteryl ester trans‐ fer protein (*CETP*), the molecules that play central roles in the transport of cholesterol. HDL-C has been well known as antiatherogenic (good cholesterol), whereas LDL-C (bad cholesterol) is considered to be a major cause of atherosclerotic cardiovascular diseases. In Chapter 2, Zhang Weizhan describes cholesterol balance regulation by endocrine hormones and regula‐ tion of lipid metabolism in humans and rats and its linkage with genetic differences. In Chap‐ ter 3, Hissa B. and Pontes B. explore the role of cholesterol in cellular processes, such as modulating actin architecture and cellular contractility, lipid rafts, and membrane heteroge‐ neity. In Chapter 4, Gungor Banu focusses on biosensors as analytical tools to measure choles‐ terol with very high precision, sensitivity, and speed and thus overcomes the disadvantages of the earlier procedures. In Chapter 5, Bikram H.A. shows that cholesterol is an important and useful parameter for distinguishing between pleural fluid exudates and transudates.

The second section includes Chapters 6 to 8 on cholesterol and the heart. In Chapter 6, Eyup A. et al. give a comprehensive review of cholesterol hypothesis and epidemiology of atherosclero‐ sis. In Chapter 7, Yuan Y. et al. discuss the role of dietary cholesterol as a risk factor in the pathogenesis of nonalcoholic fatty liver disease. In Chapter 8, , Cardoso ML. et al. describe biochemical, phenotypic, and neurophysiological characteristics of the mouse model of Smith-Lemli-Opitz syndrome (SLOS), an inborn error of metabolism in cholesterol biosynthesis.

You will realize that cholesterol is an essential and extremely important building block of cell membranes and thus serves vital functions in the body. It is also a precursor for the synthesis of steroid hormones, bile acids, and vitamin D. What makes it good or bad is the type of lipo‐ protein that binds to it. One is high-density lipoprotein, or HDL, and the cholesterol bound to it is the HDL-cholesterol, and it is the good cholesterol (antiatherogenic), whereas the lowdensity lipoprotein, or LDL-bound cholesterol, LDL-cholesterol, is the bad cholesterol (athe‐ rogenic). LDL-cholesterol contributes to fatty buildups and narrows blood vessels and raises the risk for heart attack and stroke. HDL-cholesterol protects against heart attack and stroke.

I convey my appreciation to all the contributing authors and to the IntechOpen team, partic‐ ularly, Romina Rovan, the Publishing Process Manager, for her generous help, guidance, and support in the preparation of this book.

I believe this book will be incredibly powerful and useful in teaching to give new perspec‐ tives on cholesterol.

> **Madan L. Nagpal, PhD, FLS** University of South Carolina, USA

**Section 1**

**Cholesterol Features: Structural and Functional**

**Cholesterol Features: Structural and Functional**

I convey my appreciation to all the contributing authors and to the IntechOpen team, partic‐ ularly, Romina Rovan, the Publishing Process Manager, for her generous help, guidance,

I believe this book will be incredibly powerful and useful in teaching to give new perspec‐

**Madan L. Nagpal, PhD, FLS** University of South Carolina, USA

and support in the preparation of this book.

tives on cholesterol.

VIII Preface

**Chapter 1**

**Provisional chapter**

**Structural Basis and Functional Mechanism of**

**Structural Basis and Functional Mechanism of** 

DOI: 10.5772/intechopen.76015

Lipoprotein transports lipids in circulation and is primary driver/modulator of atherosclerosis. Highly dynamics of lipoprotein conformations are crucial to lipid transport along the cholesterol transport pathway, where high-density lipoprotein (HDL), lowdensity lipoprotein (LDL) and cholesteryl ester transfer protein (CETP) are major players in lipid digestion & transport and the plasma cholesterol metabolism. This chapter covered how do HDL, LDL and CETP induce the metabolisms during cholesterol transport, and summarized recent process in the spatial information of the three lipoproteins, especially the elevations of plasma HDL and LDL, and shine a light on the assembly processes of lipoprotein particles and the substrates dynamics exchanges, for an in-depth understanding on the correlation between various lipoprotein classes and cardiovascular risk. **Keywords:** lipoproteins, structure–function relationship, cholesterol transport, reverse

Cardiovascular disease (CVD), a leading cause of mortality in many developed and developing countries [1], roots in the evolvement of atherosclerosis which is associated with profound disturbances of cholesterol metabolism. To some degree, these metabolism disturbances attribute to the net movement of cholesterol among blood and peripheral tissues. For instance, cellular cholesterol uptake is increased in atherosclerosis, while cholesterol efflux is downregulated [2]. Lipoproteins (consists of apolipoproteins, phospholipid and cholesterol) play an

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

**Lipoprotein in Cholesterol Transport**

Zhiwei Yang, Dongxiao Hao, Yizhuo Che, Lei Zhang

cholesterol transport (RCT), lipoprotein particle metabolism

**Lipoprotein in Cholesterol Transport**

Zhiwei Yang, Dongxiao Hao, Yizhuo Che,

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Lei Zhang and Shengli Zhang

and Shengli Zhang

**Abstract**

**1. Introduction**

http://dx.doi.org/10.5772/intechopen.76015

#### **Chapter 1 Provisional chapter**

#### **Structural Basis and Functional Mechanism of Lipoprotein in Cholesterol Transport Structural Basis and Functional Mechanism of Lipoprotein in Cholesterol Transport**

DOI: 10.5772/intechopen.76015

Zhiwei Yang, Dongxiao Hao, Yizhuo Che, Lei Zhang and Shengli Zhang Zhiwei Yang, Dongxiao Hao, Yizhuo Che, Lei Zhang and Shengli Zhang

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.76015

#### **Abstract**

Lipoprotein transports lipids in circulation and is primary driver/modulator of atherosclerosis. Highly dynamics of lipoprotein conformations are crucial to lipid transport along the cholesterol transport pathway, where high-density lipoprotein (HDL), lowdensity lipoprotein (LDL) and cholesteryl ester transfer protein (CETP) are major players in lipid digestion & transport and the plasma cholesterol metabolism. This chapter covered how do HDL, LDL and CETP induce the metabolisms during cholesterol transport, and summarized recent process in the spatial information of the three lipoproteins, especially the elevations of plasma HDL and LDL, and shine a light on the assembly processes of lipoprotein particles and the substrates dynamics exchanges, for an in-depth understanding on the correlation between various lipoprotein classes and cardiovascular risk.

**Keywords:** lipoproteins, structure–function relationship, cholesterol transport, reverse cholesterol transport (RCT), lipoprotein particle metabolism

### **1. Introduction**

Cardiovascular disease (CVD), a leading cause of mortality in many developed and developing countries [1], roots in the evolvement of atherosclerosis which is associated with profound disturbances of cholesterol metabolism. To some degree, these metabolism disturbances attribute to the net movement of cholesterol among blood and peripheral tissues. For instance, cellular cholesterol uptake is increased in atherosclerosis, while cholesterol efflux is downregulated [2]. Lipoproteins (consists of apolipoproteins, phospholipid and cholesterol) play an

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

important role in the transport of cholesterol [3]. Based on density and size, lipoproteins can be classified as ultra-low- (chylomicrons), very low- (VLDL), intermediate- (IDL), low- (LDL), and high- density lipoproteins (HDL) [4]. The last two might be the significant sections of cholesterol transport and metabolism: (1) LDL could transfer lipids into the blood vessel walls, and contribute to the atherosclerosis, which causally be associated with CVD and all-cause mortality; (2) HDL could remove the lipids and carry them back to the liver, being regarded as "good" one [5, 6]. Hence, the lipoprotein-mediated cholesterol metabolism (cholesterol transport) has aroused great attention and showed the benefit for the in-depth understanding of CVDs, as well as the prevention and treatment of CVDs.

To best of our knowledge, there are scant reviews elaborating the structure–function relationship of lipoproteins albeit the schematic illustrating is oncoming clear. A comprehensive understanding in this regard was endeavored, and then bioavailability that is closely related with cholesterol transport was discussed. In this chapter, we will summarize the recent achievements towards the structural basis and functional mechanism of lipoproteins in cholesterol transport, mainly focusing on functions of HDL, LDL and CETP, conformation

Structural Basis and Functional Mechanism of Lipoprotein in Cholesterol Transport

http://dx.doi.org/10.5772/intechopen.76015

5

HDL, a plasma lipoprotein, plays an important role in cholesterol metabolism [21–23], with several potentially anti-atherogenic properties (remove cholesterol from macrophages) [24–26]. Knowing the assembly mechanism and spatial information is of great importance to mediate cholesterol transport. HDLs exit three main steadier state during the cholesterol transport process: lipid-free apoA-I (apoA-I, the major protein component of HDL particles), discoidal and spherical HDL, with highly heterogeneous and differences of density, size, shape, as well as

Structure of full-length lipid-free apoA-I (28-kD, 243 residues) at native states still remains unclear due to its high flexibility. The initial X-ray crystal structure revealed that N-terminal truncated (Δ(1–43)) lipid-free apoA-I features "horseshoe-shape" antiparallel helical dimers [27], being regarded as a vital initial model ("double-belt" model) for comprehending the structure of apoA-I on HDL subclasses (**Figure 2b**) [28]. Subsequent crystal organization of lipid-free Δ(1–43)apoA-I accommodated a four-helix bundle [29–31]. However, the structural information is out of step with some physical biochemical measurements, hinting the conformation dynamics of lipid-free apoA-I. The crystal structures of the N- and C-terminally truncated

**Figure 2.** Three structures of lipid-free apoA-I: (a) full-length lipid-free apoA-I, [36] (b) N-terminal truncated Δ(1–43)

apoA-I dimer, [27] and (c) C-terminal truncated Δ[185–243] apoA-I dimer [32].

dynamics of lipoprotein particles, and substrates dynamics exchanges.

**2. Structure and function of HDL**

composition of lipid and protein.

**2.1. Lipid-free apoA-I**

As shown in **Figure 1**, the lipoprotein-mediated cholesterol metabolism can be divided into exogenous and endogenous pathways [7]. Exogenous pathway is one of crucial ways to transport cholesterol to the body tissues (chylomicrons → VLDL → IDL → LDL) [8, 9], under the co-action of lipoprotein lipase (LPL) and hepatic lipase (HL) [10, 11]. While the higher plasma LDL level might drive the process of atherosclerosis [12]. Endogenous pathway delivers cholesteryl esters back to the liver, working cooperatively in a concurrent manner with ATPbinding cassette transporter A1 (ABCA1) [13], enzyme lecithin-cholesteryl acyltransferase (LCAT) [14], as well as HDL receptors scavenger receptor B1 (SR-BI) [15] or other unidentified HDL receptor (HDLR) [16]. It is widely accepted that HDL protein particles alleviate atherosclerosis with better cardiovascular health (reverse cholesterol transport, RCT) [6, 17, 18]. Besides, cholesteryl ester transfer protein (CETP) does a heteroexchange of triglycerides and cholesteryl esters between VLDL/ LDL and HDL, with the lessen of cholesterol eliminations [19, 20]. Therefore, the functions of HDL, LDL and CETP play the important roles during the cholesterol transport (lipoprotein particle metabolism), and pharmacological inhibition of CETP is being regarded as a way to prevent CVDs [19, 20].

**Figure 1.** Lipoprotein-mediated cholesterol metabolism in human body.

To best of our knowledge, there are scant reviews elaborating the structure–function relationship of lipoproteins albeit the schematic illustrating is oncoming clear. A comprehensive understanding in this regard was endeavored, and then bioavailability that is closely related with cholesterol transport was discussed. In this chapter, we will summarize the recent achievements towards the structural basis and functional mechanism of lipoproteins in cholesterol transport, mainly focusing on functions of HDL, LDL and CETP, conformation dynamics of lipoprotein particles, and substrates dynamics exchanges.
