**6. Conclusion**

186 Dyslipidemia - From Prevention to Treatment

were modulated through a Ca2+ dependent pathway. Subsequent in vitro and in vivo studies showed that rHDL inhibited lipolysis in 3T3-L1 adipocytes partially via activation of AMPK pathway (Drew et al., 2011). Infusion of rHDL also inhibited fasting induced lipolysis and fatty acid oxidation but increased the circulating non essential fatty acids possibly due to the action of phospholipase on the rHDL phospholipids (Drew et al., 2011). The HDL dependent glucose uptake by the skeletal muscle cells was abrogated by inhibition of ABCA1 with a blocking antibody suggesting that ABCA1 functions not related to cholesterol efflux, may contribute to the increased glucose uptake and β-oxidation by skeletal muscle cells obtained from patients with type 2 diabetic mellitus (Drew et al., 2011). The effect of apoA-I on glucose metabolism was also studied in C2C12 myocytes and apoA-I deficient mice. Consistent with the studies with primary human skeletal muscle cultures, apoA-I stimulated AMPK and acetyl-CoA carboxylase (ACC) phosphorylation and glucose uptake and endocytosis into C2C12 cells. The apoA-I deficient mice had increased fat content decreased glucose tolerance and increased expression of gluconeogenic enzymes in the liver and decreased AMPK-dependent

Atherosclerosis is associated with lipid and lipoprotein abnormalities (Zannis et al., 2004b). Low HDL levels (Gordon et al., 1989) and decreased concentration of the largest size HDL subpopulations (Asztalos et al., 2004) are associated with increased risk of CAD. The antiatherogenic functions of HDL and apoA-I have been, to a large extent, attributed to the beneficial effects that HDL exerts on cells of the arterial wall as well as their ability to promote efflux from macrophages and other cells of the arterial wall via ABCA1, ABCG1 and SR-BI (Wang et al., 2007). Hepatic overexpression of apoA-I gene in the background of apoE or LDLr deficient mice reduced the atherosclerosis burden of these mice following an atherogenic diet (Tangirala et al., 1999). These findings demonstrate the importance of apoA-I and HDL for atheroprotection. In contrast, double deficient mice for apoA-I and the LDLr fed an atherogenic diet developed atherosclerosis and had increased concentration of circulating auto-anibodies, increased population of T, B, dendritic cells and macrophages, as well as increased T cell proliferation and activation. The abnormal phenotype was corrected by adenovirus mediated gene expression of apoA-I (Wilhelm et al., 2010). Similarly apoA-I transgenic rabbits were resistant to diet induced atherosclerosis (Duverger et al., 1996). Two clinical trials showed that intravenous administration of 15 mg/kg of apoA-IMILANO/phospholipid complexes in five weekly doses in patients with acute coronary syndrome resulted in significant regression of atherosclerosis as it was shown by intravascular ultrasound (Nicholls et al., 2006; Nissen et al., 2003). The epidemiological studies (Gordon et al., 1989), combined with studies of experimental animals (Duverger et al., 1996; Tangirala et al., 1999) and clinical intervention studies (Barter et al., 2007; Sorrentino et al., 2010) highlight the importance of increased HDL levels for atheroprotection. However, human subjects have been identified with high HDL levels and CAD (Ansell et al., 2003). In addition, increased HDL levels in humans treated with the CETP inhibitor torcetrapib, increased cardiovascular, and non-cardiovascular deaths (Barter et al., 2007). These findings suggest that high HDL levels are not always synonymous with atheroprotection. The concept that emerges from all the studies is that the most important factor for atheroprotection is the functionality of HDL. Understanding of the structure-function and the cell signaling associated with HDL and apoA-I will provide molecular explanations for their beneficial effects for atherosclerosis and other

phosphorylation in skeletal muscle and the liver (Han et al., 2007).

**5.7 Role of apoA-I and HDL in atheroprotection** 

human diseases and apoA-I.

Numerous prospective epidemiological studies have established an inverse correlation between HDL cholesterol levels and the risk for CAD. However, the discovery of human subjects with high HDL cholesterol levels and CAD, combined with clinical intervention studies designed to raise HDL levels and studies of animal models, led to the realization that high levels of HDL cholesterol alone are not sufficient to prevent atherosclerosis. HDL via its protein and/or lipid components participates in numerous interactions with the endothelium, other cells of the vascular wall, as well as with β pancreatic cells, and has a protective effect against atherothrombosis and other diseases. The key proteins that participate in the biogenesis, remodeling and signaling of HDL are of great importance for the functionality of HDL. Mutations in apoA-I, ABCA1 and LCAT affect the biogenesis of HDL and either prevent formation of HDL or generate aberrant HDL subpopulations which may have altered functions. The ability of HDL to inhibit the oxidation of LDL, prevents the induction of pro-inflammatory and pro-apoptotic pathways that are detrimental to the endothelium. HDL interacts directly with the endothelial cells via SR-BI and the ABCG1. These interactions lead to NO release and vasodilatation, promote reendothelialization and suppress expression of adhesion molecules on endothelial cells in response to proinflammatory cytokines. As a result of these and other interactions of the sphingolipid components of HDL with S1P receptors, HDL protects from apoptosis and inflammation and promotes endothelial cell growth and migration. Understanding the complexity and the functions of HDL may facilitate in the near future the development of new HDL-based therapies to prevent or treat atherosclerosis and other human diseases.
