Liver X receptor beta offers new hope in treating depression and anxiety

New research highlights how activating LXRβ can restore brain function and improve symptoms of anxiety and depression, suggesting novel therapeutic strategies for mental health treatment.

In a recent review published in the journal Brain Medicine, researchers investigate the role of liver X receptor beta (LXRβ) in anxiety and depression.

What is LXRβ?

LXRβ, which belongs to the nuclear receptor family of ligand-activated transcription factors, controls cholesterol metabolism and inflammation. Several studies have elucidated molecular mechanisms linking LXR activity to mental disorder symptoms, including anxiety and depression.

LXRβ protects fetal neurons in the peripheral and central nervous systems. In the central nervous systems of adults, LXRβ can be found in various cell types, some of which include microglia, astrocytes, and oligodendrocytes.

Antidepressant effects of LXRβ

LXRβ is not only a regulator of cholesterol metabolism but also influences water, glucose, and thyroid hormone transport, indicating its widespread physiological role beyond mental health disorders

Rodent studies have demonstrated that LXRβ protects microglia, neurons, astrocytes, and oligodendrocytes from depression-like behaviors. In chronic stress, LXRβ expression levels are reduced in rats' hippocampus.

GW3965 improves hippocampal neurogenesis, thereby preventing microglial activity and reducing neuronal inflammation. Moreover, GW3965 encourages oligodendrocyte development and myelination, both of which enhance cognitive and emotional processes to ultimately ameliorate depression-like behaviors.

Anxiolytic effects of LXRβ

Mice lacking LXRβ exhibit anxiety-like behaviors and poor behavioral responses. These mice express lower levels of the enzyme glutamate decarboxylase, which synthesizes gamma-aminobutyric acid (GABA) within the ventromedial region of the prefrontal cortex (PFC). LXRβ loss causes anomalies in locomotor activities, exploratory behavior, and anxiety symptoms.

In a previous study, researchers induced forced swimming stress-related anxiety in mice. GW3965 reduced anxiety by reinstating the balance between inhibitory and excitatory neurotransmission. GW3965 has also been shown to activate LXRβ signaling pathways within the amygdala, a part of the brain associated with memory, emotions, and social stimulus.

LXRβ expression, anxiety, and depression

LXRβ’s protective effects extend to dopaminergic neurons in the substantia nigra, suggesting potential benefits for neurodegenerative diseases such as Parkinson's​

Anxiety and depression are often present in individuals with autism spectrum disorders (ASD) and schizophrenia. Animals lacking LXRβ exhibit early changes in neurogenesis that lead to autistic-like behaviors.

T0901317, an LXR agonist, can reduce ASD-related repetitive behaviors and social interaction impairments. In mice, T0901317 inhibited the nuclear factor kappa B (NF-κB) pathways to lower neuroinflammation. T0901317 also activated NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes, all of which regulate innate immune responses.

A 2019 study showed 24(S),25-epoxycholesterol as the most effective LXR ligand in the developing mouse midbrain. Recent research has identified a relationship between the loss of LXR2 and neurological issues.

LXRβ signaling promotes neurogenesis and improves cognitive function. Moreover, LXR-mediated oxysterols control neurogenesis in brain cells with the copy number variation (CNV) 15q11.2.

In one study conducted in 2024, no association was observed between the rs2695121/rs17373080 mutation in LXRβ and ASD. This study included 107 autistic children and 103 controls between 24 months and 18 years of age. Autistic children exhibited elevated triglycerides, total cholesterol, and low-density lipoprotein cholesterol (LDL-C) levels, as well as significantly lower 27-hydroxycholesterol levels, thus indicating the potential utility as a biomarker to diagnose ASD.

One study involving human participants found that poor LXR signaling is associated with schizophrenia. The study showed that individuals with schizophrenia have irregularities in LXR-regulated lipid metabolism pathways, thereby leading to lower lipid content in the prefrontal cortex. Reduced lipid content is related to cognitive impairment in schizophrenia.

Conclusions

LXRβ levels in the hippocampus decline during stressful events, such as depression. Thus, treatment with LXR agonists may improve depression-like symptoms. LXR agonists can also reduce neuronal inflammation and promote oligodendrocyte development and myelination, all of which can enhance cognitive and affective functioning.

Mice lacking LXRβ exhibit anxiety-like behaviors due to lower levels of glutamate decarboxylase, an enzyme responsible for GABA production in the ventromedial prefrontal cortex. The LXR agonist GW3965 can alleviate anxiety by restoring a balance of excitatory and inhibitory neurotransmission.

The study findings emphasize the neuroprotective functions of LXRβ in rodents; however, additional studies on human participants are needed to confirm these observations and elucidate the beneficial properties of LXR agonists in humans. LXR benefits in human participants would likely support the use of LXRβ as a potential therapeutic target for neuropsychiatric diseases characterized by depression or anxiety.

Journal reference:

• Song, X., & Gustafsson. J. (2024). Therapeutic potential of liver X receptor beta in depression and anxiety. Brain Medicine 1-4. doi:10.61373/bm024b.0085