Liver X Receptors and their Agonists: Targeting

Liver X receptors α (LXRα) and β (LXRβ) are essential for protection against cardiovascular diseases. LXRs are members of the nuclear receptor superfamily of DNA-binding transcription factors and act as sensors of cholesterol homeostasis. In this review, we introduce LXRs and briefly describe the roles of LXRs in reverse cholesterol transport and trans-intestinal cholesterol efflux. We discuss LXR agonists and the downstream genes of LXRs that are involved in the regulation of cholesterol transport. In addition, we describe the cardioprotective effects of LXRs against atherosclerosis, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, and myocardial hypertrophy. Finally, we expand our discussion to the actions of LXRs in atherosclerosis and suggest several potential research avenues that may be of interest to clinicians and basic scientists. The information included herein may be useful for the design of future experimental research studies and may advance the investigation of LXRs as therapeutic targets. Introduction Liver X receptors (LXRs) are members of the nuclear receptor superfamily of DNA-binding transcription factors and are sensors of cholesterol homeostasis. The LXR subfamily contains two isoforms, α and β (Ulven et al., 2005), which are regulated by the binding of physiological ligands (e.g., oxysterols and desmosterol) (Peet et al., 1998a; Yang et al., 2006), and synthetic LXR agonists (e.g., GW3965 and T0901317) (Harasiuk et al., 2015; Kappus et al., 2014). Cardiovascular diseases are the most common causes of mortality and morbidity worldwide, and emerging evidence shows that LXRs play cardioprotective roles in maintaining cholesterol homeostasis (Hong and Tontonoz, 2014), suppressing inflammation (Kappus et al., 2014), decreasing oxidation and apoptosis (He et al., 2014a), and suppressing insulin resistance (He et al., 2014b) and hypertrophy (Kuipers et al., 2010a). The focus of this review is to summarize the latest progress regarding the protective effects of LXRs in cho les tero l homeostas is and cardiovascular diseases. First, we briefly discuss the background information of LXRs and their roles in cholesterol transport. Then, we provide !41 Curr. Issues Mol. Biol. (2017) 22: 41-64. horizonpress.com/cimb Liver X Receptors and their Agonists: Targeting for Cholesterol Homeostasis and Cardiovascular Diseases Liver X Receptors Ma et al. in-depth descriptions of the downstream genes of LXRs in the regulation of cholesterol transport and LXR agonists that are involved in antiatherogenic activities. Next, we summarize the cardioprotect ive roles of LXRs against myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, and myocardial hypertrophy. Finally, we discuss several novel potential directions for future research on LXRs. The presented information is potentially useful for the design of future studies and the advancement of LXRs as therapeutic targets for cardiovascular diseases. General background on LXRs and their roles in cholesterol transport