Liver X Receptor Signaling in Lipid Metabolism and Inflammation

Liver X receptors (LXRs) are ligand‐activated nuclear receptors that serve as key sensors and regulators of cellular lipid homeostasis and inflammatory programmes. Two isoforms, LXRα and LXRβ, respond to endogenous oxysterols to orchestrate transcriptional networks governing cholesterol efflux, fatty acid synthesis and the balance between lipogenesis and lipid export. By inducing transporters such as ABCA1 and ABCG1, LXRs promote reverse cholesterol transport and dampen pro‐inflammatory signalling in macrophages and hepatocytes. Conversely, activation of lipogenic genes including SREBP-1c and fatty acid synthase underlies an adaptive increase in triglyceride synthesis. Cross‐talk between LXR‐driven lipid pathways and inflammatory mediators, notably via modulation of NF-κB and interferon networks, positions LXRs at the interface of metabolic regulation and immune response. Dysregulation of LXR signalling is implicated in atherosclerosis, non‐alcoholic fatty liver disease and other chronic inflammatory disorders, while fine‐tuning of LXR activity holds promise for therapies that restore lipid balance and restrain inflammation without provoking adverse lipogenic side effects.

Research from Nature Portfolio

Recent studies in mammalian systems have illuminated the essential role of LXRα in maintaining hepatic cholesterol homeostasis and preventing inflammation. Analysis of naturally occurring loss-of-function mutations in LXRα revealed that impaired receptor activity leads to hepatocellular cholesterol crystal accumulation, diffuse inflammatory responses and progression to hepatitis and fibrosis in mice fed a Western-style diet. Intriguingly, despite reduced hepatic triglyceride content, these models developed severe inflammatory pathology, an effect alleviated by hepatocyte-specific overexpression of functional LXRα. Observations of an inverse relationship between steatosis and cholesterol crystallisation further suggest that controlled lipogenesis may serve a protective role by buffering excess free sterols. These findings underscore the necessity of balanced LXRα activity to coordinate lipid storage and export, thereby safeguarding liver health.

Liver X Receptor Signaling in Lipid Metabolism and Inflammation publication trend

The graph below shows the total number of articles in liver x receptor signaling in lipid metabolism and inflammation across all publications each year (not limited to Nature Index journals).

Technical terms

Liver X receptor (LXR): A class of oxysterol-activated nuclear receptors (LXRα and LXRβ) that regulate genes controlling cholesterol, fatty acid and glucose metabolism, as well as inflammatory responses.

Cholesterol efflux: The process by which excess intracellular cholesterol is transported to acceptor molecules (e.g. HDL) via transporters such as ABCA1 and ABCG1, facilitating reverse cholesterol transport.

Efferocytosis: The clearance of apoptotic cells by phagocytes, a process promoted by LXR-driven gene programmes that maintain tissue homeostasis and resolve inflammation.

Macrophage foam cells: Lipid-laden macrophages found in atherosclerotic plaques, characterised by accumulation of cholesterol esters and associated with chronic inflammation.

References

1. Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health. Nature Metabolism (2024).
2. Reprogramming of the LXRα Transcriptome Sustains Macrophage Secondary Inflammatory Responses. Advanced Science (2024).
3. Therapeutic biomaterials with liver X receptor agonists based on the horizon of material biology to regulate atherosclerotic plaque regression in situ for devices surface engineering. Regenerative Biomaterials (2024).
4. Liver X Receptors: Regulators of Cholesterol Metabolism, Inflammation, Autoimmunity, and Cancer. Frontiers in Immunology (2020).