The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease

Abstract

The Liver X Receptors (LXRs) are oxysterol-activated transcription factors that upregulate a suite of genes that together promote coordinated mobilization of excess cholesterol from cells and from the body. The LXRs, like other nuclear receptors, are anti-inflammatory, inhibiting signal-dependent induction of pro-inflammatory genes by nuclear factor-κB, activating protein-1, and other transcription factors. Synthetic LXR agonists have been shown to ameliorate atherosclerosis and a wide range of inflammatory disorders in preclinical animal models. Although this has suggested potential for application to human disease, systemic LXR activation is complicated by hepatic steatosis and hypertriglyceridemia, consequences of lipogenic gene induction in the liver by LXRα. The past several years have seen the development of multiple advanced LXR therapeutics aiming to avoid hepatic lipogenesis, including LXRβ-selective agonists, tissue-selective agonists, and transrepression-selective agonists. Although several synthetic LXR agonists have made it to phase I clinical trials, none have progressed due to unforeseen adverse reactions or undisclosed reasons. Nonetheless, several sophisticated pharmacologic strategies, including structure-guided drug design, cell-specific drug targeting, as well as non-systemic drug routes have been initiated and remain to be comprehensively explored. In addition, recent studies have identified potential utility for targeting the LXRs during therapy with other agents, such as glucocorticoids and rexinoids. Despite the pitfalls encountered to date in translation of LXR agonists to human disease, it appears likely that this accelerating field will ultimately yield effective and safe applications for LXR targeting in humans.

Introduction

First identified in the mid-1990s as orphan members of the nuclear receptor (NR) superfamily, the Liver X Receptors (LXRα and LXRβ) were soon recognized to be activated by endogenous oxysterols (i.e., oxidized cholesterol), and to induce a suite of target genes that correct sterol overload by promoting cholesterol disposal from the cell and from the body (Fessler, 2008, Peet et al., 1998). The identification of LXRs as master regulators of cholesterol sensing and handling has led to sustained efforts to develop synthetic LXR agonists that might ultimately prove therapeutic against human atherosclerosis. Interest in the LXRs as drug targets has been further elevated by the discovery that they, like other NRs (e.g., the glucocorticoid receptor), have potent anti-inflammatory effects (Steffensen et al., 2013, Zelcer and Tontonoz, 2006). Indeed, pharmacological activation of LXR has now been shown not only to reduce atherosclerosis in rodent models but also to ameliorate pathology in a wide range of preclinical inflammatory disease models, ranging from atopic dermatitis, to acute lung injury, autoimmune disease, and neurodegenerative disorders (A-Gonzalez et al., 2009, Cui et al., 2012, Fowler et al., 2003, Smoak et al., 2008). Remarkably, LXR agonists also show early promise in models of cancer and viral infection, two disorders in which disrupted cellular cholesterol homeostasis has been shown to drive pathogenesis (Fessler, 2016, Lin et al., 2016, Ramezani et al., 2015).

Development of LXR agonists as therapeutics has proven quite challenging due to their precipitation of hepatic steatosis and hypertriglyceridemia, effects generally thought to arise from activation of LXRα in the liver. This has led the field to a range of innovative strategies, including LXRβ-selective agonists, tissue-selective LXR agonists, and LXR transrepression-selective agents. Further hurdles have arisen in the form of known differences between rodent and human physiology as well as unforeseen differences between non-human primates and humans. To date, the four LXR-targeted drugs that have made it to phase I clinical trials have unfortunately not advanced further. Nonetheless, it appears likely that with further refinement of advanced LXR therapeutics and evolving insights into the role of the LXRs in specialized cell types, opportunities for successful targeting of the LXRs in human disease will ultimately be realized.