**8.2 Liver X receptor (LXR) agonists**

*Apolipoproteins, Triglycerides and Cholesterol*

partially ABCA1-dependent fashion [176].

terol levels, including lowering VLDL and LDL levels [177].

**8. Other therapeutics targeted to HDL**

**8.1 RVX-208 (apabetalone)**

**7.3 Dual-domain peptides**

complexed with phospholipids, it is still capable of promoting cholesterol efflux in a

The rationale for constructing the dual-domain peptide (Ac-hE18A-NH2) is that 18A promotes the association of lipid-free apoE ligand-binding sequence with lipoproteins. The peptide Ac-hE18A-NH2 lowers plasma cholesterol levels in hyperlipidemic mice [177, 178]. *In vitro* studies, Ac-hE18A-NH2 also decreases monocyte adhesion to endothelial cells, attenuates LPS-induced inflammatory responses in HUVECs, and reduces lipid hydroperoxides in LDL [178]. Compared to 4F, Ac-hE18A-NH2 peptide was also shown to promote cholesterol efflux, improve endothelial dysfunctions, and lower plasma lipid hydroperoxides [179]. 4F binds oxidized lipid with high affinity, and Ac-hE18A-NH2 rapidly reduces plasma choles-

Besides the traditional drugs (e.g., statins, niacin, and PPARs agonists), there

RVX-208 is a selective antagonist of the bromodomain of bromodomain and extra-terminal (BET), which induces apoA-I mRNA and protein expression through an epigenetic mechanism in hepatocytes *in vitro*, leading to elevated levels of plasma apoA-I and HDL-C *in vivo* [181–183]. RVX-208 selectively binds to BET bromodomains, competing for a site bound by the endogenous ligand (acetylated lysine) [184]. RVX-208 also increases HDL-C levels, decreases LDL-C contents, and reduces atherosclerotic plaque formation in hyperlipidemic apoE knockout mice [185]. Thus, RVX-208 might be a promising new approach for CVD treatment. Microarray analysis found that RVX-208 upregulates many antiatherogenic gene expression and downregulates lots of pro-atherogenic gene expression *in vivo* [186]. RVX-208 reduces the vascular inflammation *in vitro* and in CVD patients by a BETdependent epigenetic mechanism [187]. RVX-208 remarkably represses the expression of pro-inflammatory cytokines (VCAM-1, MCP-1, and IL-6) *in vitro* and *in vivo* [185]. RVX-208 also increases 10 lipid classes in plasma HDL fractions, delays oral glucose absorption and endogenous glucose production, and reduces peripheral glucose disposal, which may protect against T2DM development [188]. RVX-208 reduces the expression of complement factors either *in vitro* or in mice and in CVD patients [189]. RVX-208 counters the trans-differentiation and calcification of VSMCs [190]. RVX-208 lowers serum alkaline phosphatase levels and improves CVD risk [191]. RVX-208 favorably modulates the vulnerability of carotid artery plaque through ultrasonic measurement, which is related to an increase of HDL-P levels [192]. These results demonstrated that the antiatherogenic functions of RVX-208 occur via a combination of lipid profile changes, anti-inflammatory activities, as well as many other protective properties. Recently, phase II trials showed that RVX-208 reduces MACE in treated patients, over and above that of apoA-I/HDL increasing action. This MACE reducing actions of RVX-208 is largely due to its novel anti-inflammatory actions [193, 194]. Currently, a phase III trial, BETonMACE, is ongoing to look for the effects of RVX-208 in CVD patients. Therefore, RVX-208 might act in multiple ways to inhibit atherosclerosis and would be an emerging option for CVD

are some emerging molecules targeted to regulating HDL metabolism [180].

**24**

LXR agonists, as the key regulators of ABCA1/ABCG1 expression in macrophages, have been shown to promote cholesterol efflux in macrophages *in vitro*, raise HDL-C levels, and decrease atherosclerosis in LDL-R knockout mice [195, 196]. Studies have highlighted the primary antiatherogenic activity of LXR agonists on macrophages [197]. Unfortunately, the first generation of LXR compounds has been hampered by their capacity to promote the expression of lipogenic genes in the liver, which elevate TG levels and increase hepatic steatosis [198]. LXR activator, T091317, induces gene expression of Niemann-Pick C1/2 (NPC1/2) in macrophages, increases cholesterol content in the outer layer of macrophage membranes, and decreases atherosclerosis in mice [199]. A novel LXR agonist, ATI-111, also prevents atherosclotic plaque formation in mice [200]. LXR agonist (LXR-623) is associated with increased expression of ABCA1 and ABCG1, but adverse central nervous system-related effects are noted in more than half of patients, leading to termination of the study [201, 202]. Other agonists (AZ876 and GW3965) were also shown to reduce the progression of atherosclerotic lesions [203]. Interestingly, restricting LXR activation to the intestine might also result in an increase in intestinal HDL formation via ABCA1, without developing fatty liver [204]. An intestinal-specific LXR agonist, GW6340, promotes cholesterol efflux in macrophages and increases intestinal excretion of HDL-C [205]. Thus, LXR agonists may be a highly plausible and conceptually attractive target for the treatment of dyslipidemia and atherosclerosis, particularly if it can be accomplished with selective targeting to macrophage or the intestine.
