Structural analysis identifies an escape route from the adverse lipogenic effects of liver X receptor ligands

Abstract

Liver X receptors (LXRs) are attractive drug targets for cardiovascular disease treatment due to their role in regulating cholesterol homeostasis and immunity. The anti-atherogenic properties of LXRs have prompted development of synthetic ligands, but these cause major adverse effects—such as increased lipogenesis—which are challenging to dissect from their beneficial activities. Here we show that LXR compounds displaying diverse functional responses in animal models induce distinct receptor conformations. Combination of hydrogen/deuterium exchange mass spectrometry and multivariate analysis allowed identification of LXR regions differentially correlating with anti-atherogenic and lipogenic activities of ligands. We show that lipogenic compounds stabilize active states of LXRα and LXRβ while the anti-atherogenic expression of the cholesterol transporter ABCA1 is associated with the ligand-induced stabilization of LXRα helix 3. Our data indicates that avoiding ligand interaction with the activation helix 12 while engaging helix 3 may provide directions for development of ligands with improved therapeutic profiles.

Lipid metabolism in cancer progression and therapeutic strategies

“…The LXR transcriptional factor is critical in control of cholesterol homeostasis. When intracellular cholesterol content is increased, LXRs are activated to help drive cholesterol efflux by inducing the transcription of genes linked to the efflux of cholesterol, such as ATP binding cassette subfamily A member 1 (ABCA1) and ATP binding cassette subfamily G member 1 (ABCG1) 91 . LXR can also bind to SREBP to reduce its transcriptional activity, thus reducing de novo synthesis of cholesterol 92 …”

Screening for liver X receptor modulators: Where are we and for what use?

“…On the other hand, this ligand-dependent interaction on LXRβ-LBD causes a selective dissociation of the transcriptional co-repressor NCOR1, which in turn affects target gene expression. Curiously, this phenomenon was not observed for LXRα (Belorusova et al, 2019). From these results, it is clear that important differences exist in the structural dynamics of LXRα, relative to those of LXRβ.…”

“…Recently, using hydrogen/deuterium exchange mass spectrometry coupled to functional assays, Belorusova et al (2019) have revealed that LXRα-β LBD are differently stabilized depending on the ligand nature. They identified only in LXRα that the H3/H5 regions are preferentially stabilized by the different ligands (Belorusova et al, 2019).…”

“…Recently, using hydrogen/deuterium exchange mass spectrometry coupled to functional assays, Belorusova et al (2019) have revealed that LXRα-β LBD are differently stabilized depending on the ligand nature. They identified only in LXRα that the H3/H5 regions are preferentially stabilized by the different ligands (Belorusova et al, 2019). Interestingly, the selective oestrogen receptor modulators (SERMs) also induced ligand-dependent dynamics in the structure of helix 3 that differs between the oestrogen receptor isoforms, ERα/β (Dai et al, 2009).…”

Comprehensive profiling of liver x receptor splicing in triple negative breast cancer reveals existence of novel splice variants that are prognostic for survival

“…Belorusova et al reported peptides of LXRα comprising the H3 and partial part of H5 correlated to high ABCA1 expression [30]. In addition, the differential relationship between target genes and LXRa isoforms in different patient groups also points to an oncogenic role for LXRa and a tumour suppressor role for LXRβ in TNBC tumours.…”