**8. Other therapeutics targeted to HDL**

Besides the traditional drugs (e.g., statins, niacin, and PPARs agonists), there are some emerging molecules targeted to regulating HDL metabolism [180].

#### **8.1 RVX-208 (apabetalone)**

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

**25**

*High-Density Lipoprotein: From Biological Functions to Clinical Perspectives*

levels, and decrease atherosclerosis in LDL-R knockout mice

management. However, we still need long-term phase III trial data to verify these

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

[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.

FXR is a bile acid-activated nuclear receptor that regulates cholesterol homeostasis and HDL metabolism [206]. Activation of FXR is reported to lead to both pro- and anti-atherosclerotic effects, because a major metabolic change caused by FXR agonists is a reduction of plasma HDL-C in LDL-R knockout mice [206, 207]. In addition, FXR agonists promote HDL-C excretion into feces in mice and monkeys [207]. Therefore, FXR agonists have received much attention as a potential therapeutic target, and different agonists (GW4064, 6ECDCA, FXR-450, and PX20606) have been generated as a strategy for regulating HDL metabolism [207, 208]. These observations will support further studies to investigate the potential roles of FXR

HDL is a major carrier of circulating miRNAs in plasma as mentioned above. Meanwhile, miRNAs have also emerged as the important regulators on HDL metabolism. Several studies demonstrated that miRNAs control the expression of a large number of genes associated with HDL metabolism, including ABCA1, ABCG1, and SR-BI [209, 210]. These findings strongly suggested that miRNAs regulate HDL biogenesis, cholesterol efflux, and uptake in the liver, thereby controlling the whole

miR-33 could repress the expression of ABCA1/ABCG1 proteins; however, knockout of miR-33 upregulates ABCA1/ABCG1 expression, promotes HDLmediated cholesterol efflux, increases plasma HDL-C levels, and prevents the progression of atherosclerosis [213–215]. Besides raising HDL-C levels, inhibition of

*DOI: http://dx.doi.org/10.5772/intechopen.91136*

effects on real-world CVD patients.

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

**8.3 Farnesoid X receptor (FXR) agonists**

activation on HDL regulation.

**8.4 miRNA inhibitors**

RCT process [211, 212].

management. However, we still need long-term phase III trial data to verify these effects on real-world CVD patients.
