**1. Introduction**

172 Dyslipidemia - From Prevention to Treatment

Weisberg, S.P.; Hunter, D.; Huber, R.; Lemieux, J.; Slaymaker, S.; Vaddi, K.; Charo, I.; Leibel,

Willcox, B.J.; Willcox, D.C.; Todoriki, H.; Fujiyoshi, A.; Yano, K.; He, Q.; Curb, J.D. & Suzuki,

life span, *Ann N Y Acad Sci,* vol.1114, pp. 434-455, issn 0077-8923 (Print) Yamauchi, T.; Kamon, J.; Waki, H.; Terauchi, Y.; Kubota, N.; Hara, K.; Mori, Y.; Ide, T.;

vol.115, No.5, pp. 1111-1119, issn 0021-9738 (Print)

R.L. & Ferrante, A.W., Jr. (2006). Ccr2 modulates inflammatory and metabolic effects of high-fat feeding, *J Clin Invest,* vol.116, No.1, pp. 115-124, issn 0021-9738 Wellen, K.E. & Hotamisligil, G.S. (2005). Inflammation, stress, and diabetes, *J Clin Invest,*

M. (2007). Caloric restriction, the traditional okinawan diet, and healthy aging: The diet of the world's longest-lived people and its potential impact on morbidity and

Murakami, K.; Tsuboyama-Kasaoka, N.; Ezaki, O.; Akanuma, Y.; Gavrilova, O.; Vinson, C.; Reitman, M.L.; Kagechika, H.; Shudo, K.; Yoda, M.; Nakano, Y.; Tobe, K.; Nagai, R.; Kimura, S.; Tomita, M.; Froguel, P. & Kadowaki, T. (2001). The fatderived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity, *Nat Med,* vol.7, No.8, pp. 941-946, issn 1078-8956 (Print) Yun, Z.; Maecker, H.L.; Johnson, R.S. & Giaccia, A.J. (2002). Inhibition of ppar gamma 2 gene

expression by the hif-1-regulated gene dec1/stra13: A mechanism for regulation of adipogenesis by hypoxia, *Dev Cell,* vol.2, No.3, pp. 331-341, issn 1534-5807 (Print) Zehetner, J.; Danzer, C.; Collins, S.; Eckhardt, K.; Gerber, P.A.; Ballschmieter, P.;

Galvanovskis, J.; Shimomura, K.; Ashcroft, F.M.; Thorens, B.; Rorsman, P. & Krek, W. (2008). Pvhl is a regulator of glucose metabolism and insulin secretion in pancreatic beta cells, *Genes Dev,* vol.22, No.22, pp. 3135-3146, issn 0890-9369 (Print)

& Cinti, S. (2009). The presence of ucp1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue,

Zingaretti, M.C.; Crosta, F.; Vitali, A.; Guerrieri, M.; Frontini, A.; Cannon, B.; Nedergaard, J.

*FASEB J,* vol.23, No.9, pp. 3113-3120, issn 1530-6860 (Electronic)

High density lipoprotein (HDL) is a macromolecular complex of proteins and lipids that is produced primarily by the liver through a complex pathway that requires initially the functions of apolipoprotein A-I (apoA-I), ATP binding cassette transporter A1 (ABCA1) and lecithin:cholesterol acetyl transferase (LCAT) (Zannis et al., 2006b). Following synthesis, HDL affects the functions of the arterial wall cells through signaling mechanisms mediated by scavenger receptor class B type-I (SR-BI) and other cell surface proteins. The impetus for studying HDL has been the inverse correlation that exists between plasma HDL levels and the risk for coronary artery disease (CAD) (Gordon et al., 1989). HDL promotes cholesterol efflux (Gu et al., 2000; Nakamura et al., 2004), prevents oxidation of low density lipoprotein (LDL) (Navab et al., 2000a; Navab et al., 2000b), inhibits expression of proinflammatory cytokines by macrophages (Okura et al., 2010) as well as expression of adhesion molecules by endothelial cells (Cockerill et al., 1995; Nicholls et al,. 2005b). HDL inhibits cell apoptosis (Nofer et al., 2001) and promotes endothelial cell proliferation and migration (Seetharam et al., 2006). HDL stimulates release of nitric oxide (NO) from endothelial cells thus promoting vasodilation (Mineo et al., 2003). HDL also inhibits platelet aggregation and thrombosis (Dole et al., 2008) and has antibacterial, antiparasitic and antiviral activities (Parker et al., 1995; Singh et al., 1999; Vanhollebeke and Pays, 2010). Due to these properties HDL is thought to protect the endothelium and inhibit several steps in the cascade of events that lead to the pathogenesis of atherosclerosis and various other human diseases.

This review focuses on two important aspects of contemporary HDL research. The first part considers briefly the structure of apoA-I and HDL and the key proteins that participate in the pathway of the biogenesis of HDL as well as clinical phenotypes associated with HDL abnormalities. The second part considers various physiological functions of HDL and apoA-I and the protective role of HDL against atherosclerosis and other diseases.

Pleiotropic Functions of HDL Lead to Protection from Atherosclerosis and Other Diseases 175

amino acid repeats which are organized in amphipathic a-helices (Nolte and Atkinson, 1992). Based on the crystal structure of apoA-I in solution (Borhani et al., 1997) a belt model was proposed to explain the structure of apoA-I on discoidal HDL particles. In this model, two antiparallel molecules of apoA-I are wrapped like a belt around a discoidal bilayer containing 160 phospholipid molecules and shields the hydrophobic fatty acid chains of the phospholipids. Analysis of the 93 Å spherical HDL in solution by small angle neutron scattering (SANS) showed that three molecules of apoA-I fold around a central lipid core that has 88.4 Å x 62.8 Å dimensions to form a spheroidal HDL (sHDL) particle (Wu et al., 2011).

**3.2 Interactions of ApoA-I with ABCA1 are the first step in the biogenesis of HDL**  ABCA1 is a ubiquitous protein that belongs to the ABC family of transporters and is expressed abundantly in the liver, macrophages, brain and various other tissues (Kielar et al., 2001). ABCA1 was shown to promote the efflux of cellular phospholipids and cholesterol to lipid free or minimally lipidated apoA-I and other apolipoproteins and amphipathic peptides, but it does not promote efflux to spherical HDL particles (Remaley et al., 2001; Wang et al., 2000). The functional interactions between apoA-I and ABCA-1 are important for the biogenesis of HDL. In the abscence of either apoA-I (Matsunaga et al., 1991) or ABCA-1 (Brunham et al., 2006) HDL is not formed. Adenovirus mediated gene transfer of apoA-I mutants in apoA-I-/- mice showed that deletion of the C-terminal region of apoA-I prevented the formation of HDL (Chroni et al., 2007). The ability of ABCA1 to promote cholesterol efflux from macrophages is very important for the prevention of formation of foam cells in the atherosclerotic lesions (Van Eck et al., 2002). Mutations resulting in inactivation of ABCA1 are present in patients with Tangier disease (Brunham et al., 2006). The deficiency is associated with very low levels of total plasma and HDL cholesterol and abnormal lipid deposition in various tissues (Christiansen-Weber et al., 2000; McNeish et al., 2000). The ABCA1 deficiency in humans or experimental animals may contribute to accelerated atherosclerosis (Joyce et al., 2002; Singaraja et al., 2003). Inactivation of the ABCA1 gene in macrophages increases the susceptibility to atherosclerosis (Van Eck et al., 2002; Van Eck et al., 2006). Specific amino acid substitutions found in the Danish general population were predictors of ischemic heart disease and reduced life expectancy (Frikke-

**3.3 Interactions of lipid-bound ApoA-I with LCAT stabilize the nascent HDL** 

Plasma LCAT is a 416 amino acid long enzyme that is synthesized and secreted by the liver and esterifies the free cholesterol of HDL and LDL. ApoA-I is a potent activator of LCAT (Fielding et al., 1972). Following esterification, the cholesteryl esters formed become part of the lipid core and the discoidal HDL is converted to mature spherical HDL (Chroni et al.,

Mutations in LCAT are associated with two phenotypes in humans. The familiar LCAT deficiency (FLD) is characterized by the inability of the mutant LCAT to esterify cholesterol on HDL and LDL and causes accumulation of discoidal HDL in the plasma. The fish eye disease (FED) is characterized by the inability of mutant LCAT to esterify cholesterol on HDL only. Both diseases are characterized by low HDL levels due to the inability of LCAT to convert the nascent immature pre-β and discoidal particles to mature spherical HDL

Schmidt et al., 2008).

(Santamarina-Fojo et al., 2001).

2005a).
