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.
Study: Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health. Image Credit: Peakstock/Shutterstock.com
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 increased hepatic cholesterol, which is linked to inflammation and fibrosis. Mouse models with disrupted cholesterol regulation showed liver damage, and high dietary cholesterol exacerbates liver fibrosis in conjunction with high-fat diets.
Human genetics could potentially guide drug development by validating LXR as a therapeutic target and predicting potential side effects. Ongoing research aims to balance the benefits of inhibiting lipogenesis with the risks of cholesterol accumulation in treating MASLD.
In the present study, researchers investigated the impact of damaging mutations in LXRα, the main liver isoform, on human cardiometabolic health.
About the study
The study aimed to classify rare variants in the ligand-binding domain of the LXRα gene (NR1H3) using both experimental and statistical methods. Researchers analyzed exome data from 454,756 participants in the UK Biobank, focusing on missense variants with a minor allele frequency of less than 0.001 and specific scores. A few protein truncating variants in the C-terminus were also included due to their potential dominant negative (DN) effects.
Transactivation and yeast two-hybrid assays were performed to assess variant function. Luciferase-based assays were used to measure ligand-induced transcriptional activity of wild-type and mutant LXRα. The statistical analysis included a two-way ANOVA and mixed-effects models to evaluate loss-of-function (LOF), gain-of-function (GOF), and DN mutations.
Mouse models, including LXRα knockout and LXRαW441R mutants, were used to assess further the physiological effects of these variants under normal and Western diet conditions. The study also included ribonucleic acid sequencing (RNA-seq) and Western blot analysis to investigate the molecular mechanisms underlying the observed phenotypes.
Results and discussion
A total of 23 DN-related mutations were identified in LXRα, along with 20 LOF mutations and four GOF mutations. DN mutations were less common than LOF mutations and showed modest effects. Carriers of LOF mutations showed elevated serum high-density lipoprotein (HDL) cholesterol, apolipoprotein A1 levels, and liver enzymes, with similar trends for DN mutations.
Damaging LXRα variants were associated with increased HDL cholesterol, decreased triglycerides, and higher liver enzyme levels, confirming the loss of LXRα's lipogenic effects. Analysis indicated changes in HDL particle composition and reduced very low-density lipoprotein (VLDL) triglyceride content, consistent with LXRα's hepatic roles.
Carriers faced a 32% increased risk of significant elevation in alanine aminotransferase (ALT), although caution is warranted due to the small sample size for alcohol-related liver disease. The polygenic risk score correlated with liver fat and ALT levels but did not interact with LXRα carrier status, suggesting the effects of damaging variants are independent of liver fat predisposition.
Further, LXRα W441R mice on a low-fat diet showed a modest increase in serum levels of liver enzymes and reduced triglycerides. However, when exposed to a Western diet, the mice experienced significant elevations in liver enzymes and cholesterol levels despite suppressed triglyceride levels. Histological analyses revealed xanthogranulomatous inflammation, increased lipid peroxidation, and fibrosis in the liver.
Overall, the LXRα W441R variant was found to result in hepatotoxicity, characterized by hepatic inflammation and cholesterol accumulation, highlighting the variant's detrimental impact on liver function.
Conclusion
In conclusion, the study suggests that LXRα mutations are hepatotoxic by elevating cholesterol levels in hepatocytes, underscoring the importance of proper cholesterol sensing for liver health.
These findings raise concerns about the potential risks of using inverse LXR agonists, which are under development for treating MASLD and dyslipidemia. Although limited by the small number of liver disease cases and rare LXRα mutations in the UK Biobank, an increased risk of alcohol-related liver disease was observed in mutation carriers.
However, further large-scale studies are needed to assess the broader effects of LXRα haploinsufficiency on liver disease, including cirrhosis risk.
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