Liver X Receptor Assays
Overview of Liver X Receptors (LXRs)
LXR is defined as a nuclear receptor that normally binds to the retinoid X receptor (RXR) to assemble heterodimers for multiple roles. Activation of LXR-RXR induces the expression of multiple genes implicated in multiple metabolic activities. There are two distinct isoforms, LXRα and LXRβ. LXRα is mainly present in the liver and is also discovered at lower levels in the gut, macrophages, kidney, lung, and adrenal gland, whereas LXRβ is widely present in a variety of tissues.
Functions of LXRs
LXRs are well known to be nuclear oxysterol receptors and are also thought to be physiological regulators of lipid modulation as well as cholesterol homeostasis. In addition to the essential metabolic functions, they are closely related to immune response and inflammation regulation. These results position LXR at the crossroads between metabolism and immunity. What's more, accumulating evidence declares that LXRs are attractive targets for the treatment of diverse malignancies, providing a new and attractive perspective for tumor therapy.
Fig.1. LXRs may be related to various pathological conditions. (Komati, 2017)
Mechanisms of LXRs
The relevant information for several LXRs-like receptors is summarized in the table below.
| Receptor | Gene | Mechanism | Agonists | Antagonists |
| LXRα | NR1H3 |
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| LXRβ | NR1H2 | |||
| FXRα | NR1H4 |
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| FXRβ | NR1H5P |
Published Data
| Paper Title | Liver X receptor activation impairs neutrophil functions and aggravates sepsis |
| Journal | The Journal of infectious diseases |
| Published | 2020 |
| Abstract | LXRs are nuclear receptors that are closely associated with varied metabolic developmental and inflammatory diseases. Although neutrophils express LXR-α and LXR-β, the relationship of their activation to sepsis remains unclear. This article validated that activation of LXR reduces neutrophil chemotaxis and killing ability in vitro. It is worth noting that mice treated with LXR agonists developed higher mortality from sepsis, which may involve decreased neutrophil infiltration of infected foci as well as multiple organ failure. In contrast, treatment with LXR antagonists resulted in increased numbers of neutrophils, decreased bacterial load, and multiple organ dysfunction in the abdominal cavity of septic mice. Furthermore, neutrophils from septic individuals disclosed increased ABCA1 mRNA levels and attenuated chemotactic response to CXCL8. |
| Result |
The data reported here revealed a complex role in the activation of LXR on neutrophils in sepsis. The researchers demonstrated that murine and human neutrophils express LXR-α and LXR-β mRNA and that the encoded proteins are activated during sepsis, inducing ABCA1 mRNA synthesis. Furthermore, severe sepsis mice had higher levels of LXR agonists compared to non-severe sepsis mice, demonstrating the close link between LXR activation and sepsis outcomes. Indeed, treatment of septic mice with LXR antagonists was accompanied by increased neutrophil migration to infected foci and increased bactericidal capacity, thereby reducing systemic inflammation and multiple organ dysfunction. Taken together, the data from the present study show that LXR activation can have an impact on neutrophil function, leading to poor outcomes during sepsis. Therefore, the development of novel LXR antagonists may represent a promising strategy for improving sepsis outcomes.
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Fig.2. LXR activation in mouse neutrophils affects chemotactic and microbicidal abilities. (Souto, 2020)
References
- Komati, R.; et al. Ligands of therapeutic utility for the liver X receptors. Molecules. 2017; 22(1): 88.
- Souto, F.O.; et al. Liver X receptor activation impairs neutrophil functions and aggravates sepsis. The Journal of infectious diseases. 2020; 221(9): 1542-1553.
