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.

Apolipoprotein C-II: New findings related to genetics, biochemistry, and role in triglyceride metabolism

“…For example, in liver, the farnesoid X receptor (known as FXR or NR1H4), which binds bile acids and regulates genes involved in bile acid synthesis and transport, plays a major role in APOC2 gene transcription. In macrophages, however, key transcription factors for the APOC2 gene include the liver X receptor (LXR), whose role is to correct for cellular cholesterol 47, 48 and signal transducer and activator of transcription 1 (STAT1), which mediates cellular responses to interferons and certain cytokines and growth factors 49 . In intestine, ApoC2 gene expression increases with dietary lipids, as might be expected, but recent work in mice has also demonstrated a unique regulatory mechanism involving CD36 sensing of dietary fat 50 .…”

“…Moreover, ATP-binding cassette transporter A1 (ABCA1) is also upregulated by LXR in macrophages, and since apoC-II, as well as apoE, apoC-I, and apoC-IV are all able to act as acceptors for cholesterol efflux from macrophages 73 , the coordinate upregulation of ABCA1 and this gene cluster may enhance cholesterol efflux from macrophages, including foam cells in the arterial wall 55 . Finally, LXR is has been shown to have an anti-inflammatory role in macrophages 47 .…”

Oxysterols in intestinal immunity and inflammation

“…An LXR agonist had a protective effect in a mouse model of colitis . However, an unwanted side effect of current LXR agonists is the stimulation of fatty acid synthesis, causing hypertriglyceridaemia .…”

Selective LXR agonist, DMHCA, corrects the retina-bone marrow axis in type 2 diabetes

“…Mechanistically, DMHCA indirectly activates LXR through the inhibition of desmosterol reduction, the final step in the predominant cholesterol biosynthesis pathway, leading to the accumulation of the potent LXR agonist desmosterol (22). During endogenous LXR activation, fatty acid biosynthesis is stimulated through the transcriptional induction of SREBP1c, leading to elevated triglyceride levels (23). Intriguingly, DMHCA selectively activates the cholesterol efflux arm of the LXR pathway, through the induction of ATP-binding cassette transporter (ABCA1), with minimal effect on SREBP1c compared to other LXR agonists, T0901317 and GW3965 (21-25).…”

“…Intriguingly, DMHCA selectively activates the cholesterol efflux arm of the LXR pathway, through the induction of ATP-binding cassette transporter (ABCA1), with minimal effect on SREBP1c compared to other LXR agonists, T0901317 and GW3965 (21-25). Thus, DMHCA has superior clinical potential as a cholesterol lowering agent because it lacks the undesirable adverse effect profile that plagued the first generation of LXR modulators, while retaining the ability to lower circulating LDL and restore peripheral cholesterol homeostasis (21,23).…”