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Hyperlipidemia is thought of as an important contributor to coronary disease, diabetes, and fatty liver. Liver X receptor β (LXRβ) was considered as a validated target for hyperlipidemia therapy due to its role in regulating cholesterol homeostasis and immunity. However, many current drugs applied in clinics are not selectively targeting LXRβ, and they can also activate LXRα which activates SREBP-1c that worked as an activator of lipogenic genes. Therefore, exploiting agonists selectively targeting LXRβ is urgent. Here, computational tools were used to screen potential agonists selectively targeting LXRβ from 112 terpenes of alismatis rhizoma. Firstly, a structural analysis between selective and nonselective agonists was used to explore key residues of selective binding with LXRβ. Our data indicated that Phe 271 , Ser 278 , Met 312 , His 435 , and Trp 457 were important to compounds binding with LXRβ, suggesting that engaging ligand interaction with these residues may provide directions for the development of ligands with improved selective profiles. Then, ADMET analysis, molecular docking, MD simulations, and calculation of binding free energy and its decomposition were executed to screen the agonists whose bioactivity was favorable from 112 terpenes of alismatis rhizoma. We found that two triterpenes 16-hydroxy-alisol B 23-acetate and alisol M 23-acetate showed favorable ADMET properties and high binding affinity against LXRβ. These compounds could be considered as promising selective agonists targeting LXRβ. Our work provides an alternative strategy for screening agonists selectively targeting LXRβ from alismatis rhizoma for hyperlipidemia disease treatment.

Reverse cholesterol transport (RCT) and transintestinal cholesterol efflux (TICE) are two important pathways for body cholesterol elimination. We studied these pathways in an animal model of diabetes and obesity (ob/ob) where HDL function is compromised as a result of hyperglycemia, low-grade inflammation and oxidative stress. Co-treatment of ob/ob mice with PPAR-α (fenofibrate) and LXR (T0901317) agonists increased fecal cholesterol by 12-fold; PPAR-α and LXR agonists individually showed 2.6- and 4.0-fold fecal cholesterol excretion, respectively. We investigated the mechanism of synergistic efficacy of PPAR-α and LXR agonists in fecal cholesterol excretion. LXR agonist and the combination of PPAR-α and LXR agonists had greater HDL-C elevation. Ex vivo cholesterol efflux showed correlation with the fecal cholesterol excretion but was not sufficient to explain 12-fold increases in the fecal cholesterol in the co-treated mice. Therefore, we examined TICE to explain the 12-fold increases in the fecal cholesterol. A strong positive correlation of fecal cholesterol with ATP binding cassette transporter G5 (ABCG5) and G8 and a negative correlation with NPC1L1 was observed. ABCG5, G8 and NPC1L1 are involved in intestinal cholesterol absorption. The extent of influence of PPAR-α and LXR agonists on RCT and TICE was distinctly different. PPAR-α agonist increased fecal cholesterol primarily by influencing TICE, while LXR agonist influenced fecal cholesterol excretion via both RCT and TICE mechanisms. Synergistic efficacy on fecal cholesterol excretion following co-treatment with PPAR-α and LXR agonists occurred through a combination of RCT, TICE, and the key enzyme in bile synthesis, cholesterol 7-α hydroxylase (cyp7a1). These results suggest that cholesterol efflux, biliary cholesterol excretion, and TICE collectively contributed to the 12-fold increases in the fecal cholesterol excretion in ob/ob mice co-treated with PPAR-α and LXR agonists.

The balance of major excitatory (glutamate, Glu) and inhibitory (γ-aminobutyric acid, GABA), named as E/I neurotransmission, is critical for proper information processing. Anxiety-like responses upon stress are accompanied by abnormal alterations in the formation and function of synapses, resulting in the imbalance of E/I neurotransmission in the amygdala. Liver X receptors (LXRs), including LXRα and LXRβ isoforms, are nuclear receptors responsible for regulating central nervous system (CNS) functions besides maintaining metabolic homeostasis. However, little is known about the contribution of LXRs in E/I balance in regulating anxiety-related behaviors induced by stress. In this study, we found stress-induced anxiety led to the expression reduction of LXRβ not LXRα in mice amygdala. GW3965, a dual agonist for both LXRα and LXRβ, alleviated anxiety-like behaviors of stressed mice through activation of LXRβ, confirmed by the knockdown of LXRβ mediated by lentiviral shRNAs in the basolateral amygdala (BLA). This was paralleled by correcting the disequilibrium of E/I neurotransmission in the stressed BLA. Importantly, GW3965 exerted anxiolytic effects by correcting the promoted amplitude and frequency of miniature excitatory postsynaptic current (mEPSC), and augmenting the decreased that of miniature inhibitory postsynaptic current (mIPSC) in the stressed BLA. This suggests that stress-induced anxiety-like behaviors can largely be ascribed to the deficit of LXRβ signaling in E/I neurotransmission in BLA. These findings highlight the deficiency of LXRβ signaling in the amygdala linked to anxiety disorder, and LXRβ activation may represent a potential novel target for anxiety treatment with an alteration in synaptic transmission in the amygdala.

Retinoid X receptor (RXR) ligands have a wide range of beneficial effects in mouse models of Alzheimer's disease (AD). Recently accumulated evidence suggests that early neuroinflammation may be a therapeutic target for AD treatment. We therefore investigated the anti-inflammatory effects of the prenylated flavanoids SPF1 and SPF2, which were previously isolated from root of Sophora tonkinensis and identified as potent ligands for RXR, and potential mechanisms involved. SPF1 and SPF2 efficiently reduced interleukin (IL)-1β messenger RNA (mRNA) and IL-6 mRNA levels in lipopolysaccharide-stimulated and tumor necrosis factor-α-stimulated RAW264.7 cells, whereas SPF3-which has a structure similar to SPF1 and SPF2 but no RXR ligand activity-did not exhibit such effects. Intriguingly, the liver X receptor (LXR) ligand T0901317 reduced proinflammatory cytokine mRNA levels, and these effects were potentiated by SPF1. With regard to the mechanism underlying the anti-inflammatory effects, SPF1 induced significant amounts of activating transcription factor 3 (ATF3) mRNA and protein, and this effect was potentiated by T0901317. SPF1 also reduced translocation of nuclear factor κB (NF-κB) into nuclei. The production of proinflammatory cytokines was significantly inhibited by SPF1, and this effect was primarily exerted via RXR/LXR heterodimers. The effects of SPF1 may partly depend on the induction of ATF3, which may bind to the p65 subunit of NF-κB, resulting in reduced translocation of NF-κB into nuclei and reduced NF-κB transcription. Although inflammatory effects mediated by RXR/LXR heterodimers have not been thoroughly investigated, the above-described results shed light on the mechanism of the anti-inflammatory effect via RXR/LXR heterodimer.

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by beta-amyloid (Aβ) accumulation and neurofibrillary tangles formation in the brain which are associated to synaptic deficits and dementia. Liver X receptor (LXR) agonists have been demonstrated to revert of pathologic and cognitive defects in murine models of AD through the regulation of Apolipoprotein E, ATP-Binding Cassette A1 (ABCA1), by dampening neuroinflammation and also by reducing the levels of amyloid-β (Aβ) accumulation in the brain. However, the role of LXR with regard to the regulation of synaptic function remains relatively understudied. In the present paper, we analyzed the in-vitro effect of the LXR agonist GW3965 on synaptic function upon exposure of primary hippocampal cultures to oligomeric amyloid-β (oAβ(1-42)). We showed that oAβ(1-42) exposure significantly decreased the density of mature (mushroom shaped) dendritic spines density and synaptic contacts number. oAβ(1-42) also modulates the expression of pre- (VGlut1, SYT1, SV2A) and post-synaptic (SHANK2, NMDA) proteins, it decreases the expression of PINK1, and increases ROCKII, and activates of caspase-3; these changes were prevented by the pre-treating neuronal cultures with GW3965. These results show further support the role of the LXR agonist GW3965 in synaptic physiology and highlight its potential as an alternative pharmacological strategy for AD.

Liver X receptor (LXR), a member of the nuclear receptor superfamily, mainly serves as a reverse cholesterol transporter in lipid metabolism. It has been demonstrated that LXR is a promising target for the treatment of cardiovascular diseases. LXR is also involved in cancer metabolism, glucose homeostasis, immunity, and various physiological processes. The antitumor function of LXR has become of great interest to researchers in recent years. However, while it is believed that activating LXR with small molecules could be a promising approach to cancer treatment, effective drugs that target LXR are yet to be reported. To find compounds that are potentially capable of activating LXR, we utilized a high-throughput screening method to search the MolMall database for suitable compounds. Seven candidates with lower GB/SA Hawkins scores than the reference ligand T0901317 were identified. Based on the results of molecular dynamics (MD) simulations, binding free energy analysis, and an analysis of the agonism mechanism, ZINC90512020 and ZINC3845032 were predicted to have high affinities for LXR and high relative stabilization, and were therefore selected as potential LXR agonists. Both of these compounds will undergo further development with a view to utilizing them for the treatment of LXR-related cardiovascular diseases or cancers.