**2.4 Cholesterol ester transfer protein (CETP)**

CETP plays a key role in the exchange of CE and triglycerides (TG) between HDL and apoB-containing lipoproteins (VLDL, IDL, and LDL). As a result of CETP activation, HDL becomes smaller and TG-enriched. It is estimated that 66% of CE in HDL returns to the liver through CETP, indicating an important role of CETP in RCT process and HDL remodeling [21]. Some studies found that deficiency of CETP in human is associated with increased plasma HDL-C levels but inversely displays a relatively increased CVD incidence [22]. Small HDL particles are not increased in CETP-deficient subjects, suggesting that ABCA1-mediated cholesterol efflux might not represent the predominant pathway of cellular cholesterol efflux. Earlier studies also demonstrated that HDL from CETP-deficient subjects is defective to mediate cholesterol efflux from cholesterol-loaded macrophages, leading to the hypothesis that enrichment of CE in HDL in homozygous subjects might not be favorable for the antiatherogenic activities of these particles [23]. However, HDL from CETP-deficient subjects has been shown to possess an increased capacity to mediate cholesterol efflux through ABCG1 [24].

Additionally, inhibition of CETP successfully elevates HDL-C levels and decreases LDL-C levels but unexpectedly does not show atheroprotections and even increases cardiovascular mortality [25–27]. Until now, almost all CETP inhibitors, including torcetrapib (Pfizer), dalcetrapib (RO4607381, Roche; JTT-705, JT), anacetrapib (MK-0859, Merck), and evacetrapib (LY2484595, Eli Lilly), were announced to be failed to reduce CVD accidence although significantly elevating plasma HDL-C levels.

#### **2.5 Scavenger receptor class B type I (SR-BI)**

As the last step in RCT, SR-BI has been shown to function as another HDL receptor that mediates selective cholesterol uptake in the liver. SR-BI knockout mice remarkably elevate HDL-C levels but paradoxically increase atherosclerosis [28]. Some studies also reported that variant of SR-BI in which leucine replaces proline 376 (P376L) abrogates its ability to uptake HDL from plasma to the liver. Consequently, these patients have a profound HDL-related phenotype and an increased CVD risk [29].
