**2.3 Lecithin: cholesterol acyltransferase (LCAT)**

*Apolipoproteins, Triglycerides and Cholesterol*

**2. HDL-C levels and CVD**

cholesterol" becomes more bewildering to be answered.

these patients, which challenge the traditional ideas.

rescue mechanism for atherosclerotic plaque regression.

be more valuable to predict CVD incidence than HDL-C levels [11].

**2.2 ATP-binding cassette transporter A1/G1 (ABCA1/G1)**

**2.1 Reverse cholesterol transport (RCT)**

protective effects and even becomes a pro-inflammatory, pro-oxidative, and proapoptotic factor [9]. Consequently, the question whether HDL-C is still the "good

For a half century, Framingham study has supported the concept that HDL-C was thought to be a "good" lipoprotein and a negative risk factor against atherosclerosis and a decreased HDL-C level emerged as an independent risk for CVD, owing to a strong inverse correlation between plasma HDL-C levels and CVD [1]. The basis of this concept mainly came from the role of HDL in RCT [10]. However, the understanding of HDL-C and its relationship to CVD has changed dramatically. Deficiency and inhibition of CEPT or mutation of scavenger receptor class B type I (SR-BI) increase plasma HDL-C levels but do not accordingly reduce CVD events in

An excess of cholesterol production or absorption is deleterious by contributing to cholesterol accumulation in vessel wall and subsequent atherosclerosis initiation. Thus, there is a physiological need to move the excessive cholesterol from peripheral tissues; this process is called reverse cholesterol transport (RCT) [10]. RCT represents the primary mechanism by which HDL delivers cholesterol from peripheral cells to the liver. This pathway of recycling and eliminating cholesterol is the antiatherogenic basis of high HDL-C levels against CVD and also represents a

The first step of RCT is cellular cholesterol efflux to apolipoprotein A-I (apoA-I) mediated by ATP-binding cassette transporter A1 (ABCA1). Cholesterol efflux also occurs toward mature HDL through ATP-binding cassette transporter G1 (ABCG1) and SR-BI. Cholesteryl esters (CE) of HDL can be transferred to apolipoprotein B (apoB)-containing lipoproteins through the action of CETP, with ultimate uptake by low-density lipoprotein (LDL) receptor (LDL-R) in the liver. Each step in this process may influence the plasma levels of HDL-C. Because of the failure of reducing CVD risk by elevating HDL-C, the cholesterol efflux capacity of HDL seems to

A major breakthrough in understanding the mechanisms of RCT came from the discovery of Tangier disease, which is characterized by low HDL-C levels and high CVD risk because of the molecular defect in ABCA1 [12]. Low HDL-C level in these patients is caused by decreased cellular cholesterol efflux owing to ABCA1 mutation as well as increased catabolism of lipid-poor apoA-I [13]. ABCA1 knockout mice have an extremely low HDL-C phenotype similar to that of Tangier disease patients [14]. Thus, ABCA1 is essential for HDL maturation. In addition, it is also worth noting that the interaction between apoA-I and ABCA1 in macrophages also displays significant anti-inflammatory effects through activating JAK2/STAT3 pathway [15]. These effects reduce the attraction of macrophages into the vessel wall and ultimately result in the decreased plaque formation. These findings implicated that ABCA1 is a direct molecular link between the cardio-protective effects of cholesterol export and the inhibition of inflammatory responses

**14**

in macrophages.

LCAT is responsible for the esterification of free cholesterol and thus for the maturation of HDL by transferring fatty acids from lecithin (phosphatidyl choline) to cholesterol [18]. Once esterified, cholesterol moves from the surface to the hydrophobic core of HDL. In the presence of LCAT, the bidirectional movement of cholesterol between cells and HDL results in cholesterol efflux. Therefore, LCAT plays a central role in the initial step of RCT.

As a result of cholesterol esterification, LCAT also maintains a gradient of free cholesterol between cell membranes and lipoproteins. The activity of LCAT is essential to maintain the normal HDL metabolism and the optimal functional properties of HDL particles. In human, LCAT deficiency is responsible for low HDL-C levels, which changes HDL distribution and composition [19]. HDL from transgenic mice overexpressing human LCAT is prior to accepting free cholesterol from fibroblast compared to control HDL. It is likely that LCAT-mediated changes in HDL composition favor cholesterol accommodation within the particles. The flux of CE to the liver is increased in human LCAT-transgenic mice as a result of increased CE content in HDL but not an increased catabolic rate of HDL [20]. Although it is clear that LCAT deficiency in human and mice is associated with reduced HDL-C levels, it is still not defined whether LCAT overexpression or deficiency is pro- or anti-atherogenesis.
