Mutations in LXRα lead to liver cholesterol buildup, hepatitis, and fibrosis in individuals on a Western diet, highlighting the receptor's role in maintaining liver health. In a recent study published in Nature Metabolism , researchers from the United Kingdom (UK) investigated the effects of functionally impaired mutations in liver X receptor-α (LXRα) in humans and mice, focusing on cholesterol regulation, liver dysfunction, and diet influences. They found that mutated LXRα leads to elevated liver cholesterol, cholesterol crystal accumulation, severe hepatitis, and fibrosis, with reduced triglycerides but no steatosis.
This suggests the protective role of LXRα in maintaining liver health. Background LXRs, particularly LXRα receptors in hepatocytes, play a crucial role in cholesterol homeostasis by regulating cholesterol synthesis, uptake, and excretion. Activation of LXRα also induces hepatic lipogenesis, increasing liver and serum triglycerides.
While early research aimed to use LXR agonists to enhance reverse cholesterol transport and combat atherosclerosis, the challenge of separating cholesterol benefits from harmful lipid accumulation hindered the progress of this approach. Attention has now shifted to using LXR inhibitors to reduce triglyceride buildup and treat metabolic dysfunction-associated steatotic liver disease (MASLD). While LXR-inverse agonists show promise in reducing inflammation, steatosis, and fibrosis in rodent models, there remain concerns about in.