Liver X Receptors (LXRs) first came to my attention in the mid-1990s, researched by various scientific teams under different names. However, it wasn’t until the mid-2000s that research into these receptors intensified, with scientists documenting some eye-opening mechanisms. My collaborators frequently share new studies and review papers, asking me to disseminate knowledge and facilitate collaboration within the scientific and practitioner communities.
Given their potential to inform treatment strategies for major cardiometabolic and immune health issues like obesity, fatty liver, diabetes, osteoporosis, cardiovascular disease, dementia, and cancer, there has been a significant emphasis on exploring their therapeutic applications as pharmaceuticals. Preclinical studies have shown promise, prompting various groups of scientists and clinicians to investigate diverse possibilities.
Animal studies, particularly those involving mice, have yielded promising findings regarding the activation of LXRs. For instance, numerous animal studies suggest that activating LXRs can boost HDL levels, decrease artery blockage, enhance insulin sensitivity, balance blood sugar levels, and regulate stress hormones, potentially improving insulin response and aiding in weight management.
As documented in this paper in the Journal of Biological Chemistry. “The nuclear hormone receptor liver X receptor (LXR) is induced by insulin and is a key regulator of lipid metabolism. It promotes lipogenesis (fat synthesis) and cholesterol efflux (removing cholesterol from cells) but suppresses endoplasmic reticulum stress and inflammation.”
More importantly, studies highlighting their potential implications for conditions like diabetes, heart disease, dementia, and cancer truly caught my attention. In response, I wrote this high-level story to raise awareness among scientists, clinicians, and the public.
Rather than citing hundreds of papers dating back to the 1990s, I will summarize critical insights from prominent studies published in the last few years, encapsulating significant advancements in the field.
For example, yesterday, a comprehensive review was published in Frontiers’ Cell and Development Biology. It is titled “Liver X Receptors (LXRs) in cancer: An Eagle’s view on molecular insights and therapeutic opportunities” Although publicly accessible, the paper’s intricate nature calls for a summary, which I will provide after briefly introducing LXRs.
What are the Liver X Receptors, and how do they work?
The physiology of the liver x receptors is complex. In simple terms, the liver x receptors (LXRα and LXRβ) are proteins that belong to a family of molecules that control gene activity. Both LXRα and LXRβ bind to DNA alongside another protein called retinoid x receptors (RXRs). They prefer specific patterns in the DNA sequence, which have been confirmed by experiments.
As documented in this 2021 paper, “the liver x receptors LXRα (NR1H3) and LXRβ (NR1H2) are members of the nuclear hormone receptor superfamily of ligand-dependent transcription factors that regulate transcription in response to the direct binding of cholesterol derivatives.”
The research paper explained that through experiments involving genetic modifications and synthetic substances, scientists have discovered that LXRs play a crucial role in maintaining the balance of fats (lipid homeostasis) in the body.
LXRα is found in various tissues besides the liver, while LXRβ is found everywhere in the body. Interestingly, when mice are treated with a potent synthetic substance called T0901317, LXRs bind to DNA more widely than usual, including many new locations.
Synthetic T0901317 is much more potent than natural substances in activating LXRs. It is uncertain if natural substances in the body also affect LXRs’ DNA binding. New studies investigate this further by removing natural substances from tissues or altering LXRs to see how their DNA binding changes.
As documented in a 2019 paper in Nature, both LXRα and LXRβ have similar structures with slight differences. Specific oxidized cholesterol or other cholesterol-related molecules can directly activate LXRs, acting like keys that turn them on. However, synthetic ligands cause significant adverse effects like increased lipogenesis, which are challenging to dissect from their beneficial activities.
LXRα and LXRβ are naturally occurring molecules within the body. They act as ligands, meaning they bind to and activate LXR receptors. This activation can trigger regulatory processes related to cholesterol, fat, and sugar metabolism.
As I documented in previous articles, cholesterol is crucial in the body, including maintaining cell membrane flexibility and acting as a precursor for essential molecules like hormones and bile acids. However, excessive cholesterol within cells can be harmful, so the body tightly regulates its levels. The liver is the main organ responsible for maintaining cholesterol balance, and both LXRα and LXRβ play essential roles in this process.
LXRs act as sensors, responding to changes in cholesterol levels. When cholesterol levels rise, LXRs activate and trigger the expression of genes that help remove and break down excess cholesterol, thereby restoring balance. LXRs and SREBP2 work together to regulate cholesterol levels.
LXRs promote cholesterol removal from cells, while SREBP2 controls cholesterol production. Both proteins influence the LDL receptor, which helps cells take in cholesterol. LXRs facilitate reverse cholesterol transport, moving cholesterol from tissues to HDL. This process helps maintain a healthier cholesterol balance.
This process is critical in macrophages and immune cells with fluctuating cholesterol levels. In the liver, LXRs are crucial in controlling cholesterol movement throughout the body and increasing cholesterol transfer to HDL, potentially reducing the risk of atherosclerosis.
As documented in this paper, “LXRs respond to elevated cholesterol levels via transactivation of genes involved in sterol transport (ABCA1, ABCG1, ABCG5, and ABCG8), cholesterol efflux and high-density lipoprotein (HDL) metabolism, and sterol catabolism (CYP7A1).”
In summary, XRs are essential for managing fat and cholesterol in the body. LXRs also affect how cells transport fats and deal with stress, making them potential targets for treating cholesterol issues. They control genes related to making fatty acids and triglycerides, even without help from other regulators.
When activated, synthetic LXRs can increase fat and triglyceride production. This may lead to more triglycerides in the blood, affecting cholesterol levels differently in animals than humans. Creating drugs that activate LXRs without causing this problem looks tricky.
How about their role in glucose (sugar) metabolism?
LXRs act like insulin in the liver by influencing fat and glucose metabolism. They also seem to regulate glucose transport in fat tissue. This suggests LXRs may play a broader role in sensing the body’s metabolic state, possibly even responding to glucose levels directly.
As pointed out in this 2015 paper on JBC, “insulin is required specifically for the lipogenic effects of LXRα, and that manipulation of the insulin signaling pathway could dissociate the beneficial effects of LXR on cholesterol efflux, inflammation, and ER (endoplasmic reticulum) stress from the negative effects on lipogenesis.”
In 2006, Nature published a paper titled The nuclear receptor LXR is a glucose sensor. They said that both glucose and its derivative glucose-6-phosphate act as direct activators of LXRs. Even at normal liver glucose levels, glucose can activate LXRs, prompting the expression of LXR-controlled genes similar to how known LXR activators like oxysterols work.
They informed that when mice are fasted and fed a glucose-rich diet, genes involved in cholesterol balance, which rely on LXR, are boosted in the liver and intestine. This suggests that glucose is a natural activator of LXRs, switching on liver fat and cholesterol regulation genes.
As I touched on in my previous stories, in addition to glucose, type II diabetes also involves high liver fat production and increased blood triglyceride levels. Surprisingly, synthetic LXR agonists (which I will cover in the next section), despite causing high triglycerides, have shown promise in treating type II diabetes in animal models.
Studies suggest they work by reducing liver glucose production, mainly by lowering the expression of enzymes involved in making glucose. While LXRs may directly or indirectly affect genes related to glucose production, their role in regulating carbohydrate metabolism is still not fully understood.
LXR agonists might help with weight management by regulating glucose and lipids. I recently read an article related to researched compounds on glucose metabolism and lowering visceral fat: Scientists Develop Powerful New Compounds to Address Visceral Fat and Inflammation.
How do LXRs relate to cancer?
As I mentioned earlier, Frontiers published a comprehensive review on 14 May 2024 with over 100 citations. Researchers investigated multiple cancer types like lung, blood, breast, colorectal, pancreatic, and liver. They informed that cancer rates are rising due to cellular changes, including dysregulation of liver X receptors (LXRs), which control cholesterol, lipid metabolism, and inflammation.
LXRs are a type of nuclear receptor regulating various biological processes. Nuclear receptors are a class of proteins that act as eukaryotic transcription factors, regulate gene expression, mediate the transduction of signaling pathways, and are associated with cancer. So far, 48 NRs have been identified.
In summary, LXRs are found in various cancers and influence signaling pathways like Wnt and PI3K/AKT/MAPK. Activated LXRs can inhibit cancer cell growth and progression by regulating genes involved in the cell cycle, cholesterol efflux, apoptosis, cytokines, and chemokines levels.
LXRs impact processes like lipogenesis, angiogenesis, and antitumor immunity. However, depending on the cancer's microenvironment and diversity, LXRs can act as both tumor suppressors and promoters. Certain molecules in LXR-activated cells can be upregulated and serve as biomarkers.
LXRs are promising targets in cancer therapy, reducing proliferation, invasion, and metastasis in melanoma, oral, and breast carcinoma. LXR ligands affect cancer metabolism and the tumor microenvironment, especially concerning fatty acids and oxysterols.
They advised that future research should focus on understanding LXRs in the tumor microenvironment, exploring their potential in combination therapies, and identifying new biomarkers through advanced sequencing techniques. With these efforts, LXRs could become promising targets for innovative cancer treatments.
How about Inflammation and Autoimmune Disorders?
As documented in this 2017 paper, LXRs also inhibit proinflammatory gene expression in immune cells, particularly in macrophages. LXRs can regulate inflammation and autoimmune disorders. When activated, they can suppress pro-inflammatory genes while promoting anti-inflammatory ones, helping to calm inflammation and aid healing.
Disruptions in LXR activity may worsen chronic inflammation-related conditions, such as autoimmune diseases (rheumatoid arthritis or inflammatory bowel disease). Thus, targeting LXRs to normalize their function might ease inflammation and improve symptoms.
In autoimmune diseases, the immune system mistakenly attacks healthy tissues, causing inflammation and damage. LXRs help regulate immune responses, including the function of T cells and macrophages.
LXRs could influence the progression of autoimmune diseases by influencing these immune cells. Targeting LXR pathways might help rebalance the immune system and reduce autoimmune reactions.
In Circulation Research, it is noted that LXR may combat atherosclerosis via two pathways: boosting reverse cholesterol transport through direct activation of genes for cholesterol export and inhibiting pro-inflammatory genes. This inhibition occurs as agonist-bound LXR, when sumo-modified, recruits negative co-regulatory proteins to NF-κB at immune response gene promoters through protein-protein interactions.
How about the effect of liver X receptors on the brain?
LXR receptors play crucial roles in the brain. They are believed to have neuroprotection effects against neuroinflammation. LXRs exhibit anti-inflammatory effects, regulate cholesterol levels, reduce oxidative stress, and may influence neurotransmitters like dopamine and serotonin, which are essential for mood and cognition.
For example, a 2023 paper in Molecular Neurobiology reported that LXRs have neuroprotective effects against the development of neuroinflammation in different neurodegenerative diseases. LXRs regulate cholesterol brain biosynthesis via controlling the expression of ApoE and ABC transporters. I introduced the ApoE gene’s impact on Alzheimer’s in a previous story.
LXRs are being explored as potential therapeutic targets for various brain disorders, including Alzheimer’s, Parkinson’s, stroke, and multiple sclerosis. LXR agonists have shown promise in reducing amyloid beta production, protecting dopamine-producing neurons, and reducing brain damage.
For example, a 2024 paper published in Nature’s Neuroinflammation Journal summarized the signal transduction of the LXR pathway, discussed the therapeutic potentials of LXR agonists based on preclinical data using different disease models, and analyzed the dilemma and possible resolutions for clinical translation to encourage further investigations of LXR-related therapies in central nervous system disorders.
The paper is very complex, but in summary and in simpler terms, researchers are investigating how specific genetic variations, like the 15q11.2 copy number variation (CNV) that involves the CYFIP1 gene, contribute to conditions such as autism and schizophrenia.
They have found that these genetic changes affect how brain cells develop and function. Specifically, when there is a deletion or loss of function in CYFIP1, brain cells start differentiating early, whereas when CYFIP1 is overactive, neural progenitor cells remain active. Interestingly, these changes also impact cholesterol metabolism in the brain, leading to altered levels of a molecule called 24S,25-epoxycholesterol.
The beneficial effects of 24S,25-epoxycholesterol in brain cell development depend on the liver X receptor (LXRβ). When this protein is absent, the positive effects of this molecule are reduced. Understanding these mechanisms could potentially lead to new treatments for conditions related to these genetic variations.
Are we ready to use LXR modulators yet?
There has been some progress, but several early products were discontinued during the preclinical trial, and some are still in the phase I or II clinical trial stage.
In 2020, the British Journal of Pharmacology published a comprehensive review paper titled “Screening for liver X receptor modulators: Where are we and for what use?” The paper provided a historical review of animal studies, preclinical, and clinical studies, some of which were stopped.
They said that researchers have sought molecules called SLiMs that specifically modulate LXRs. Despite decades of interest, the development of LXR modulators has faced challenges.
The first generation of LXR modulators, like T0901317 and GW3965, as documented in this 2015 study, showed promise in preclinical trials. However, few have progressed to clinical use due to significant side effects like increased lipogenesis, hepatic steatosis, and high triglyceride levels.
For example, LXR-623 and Compound 8, selective LXRα and LXRβ agonists with high potency were discontinued during preclinical trials for atherosclerosis. Likewise, GSK-2033 was also discontinued during preclinical trials for treating non-alcoholic fatty liver disease. These challenges highlight the need for further translational research in this area.
Here is a summary of the currently tested LXRα and LXRβ agonists detailed in this paper.
Rovazolac (ALX-101): for atopic dermatitis. Phase IIb clinical trials
VTP-38543: for atopic dermatitis. Phase II clinical trials
RGX-104: for non-small cell lung cancer & lymphoma. Phase I clinical trials
BMS-779788: for atherosclerosis. Phase I clinical trials
Compound 9: for Alzheimer’s disease. Preclinical development
IMB-808: for atherosclerosis. Preclinical development
Compound 17l: for dermatitis eczema. Preclinical trials
SR-9238: for liver steatosis and NAFLD/NASH. Preclinical development
SR-9243: for NAFLD/NASH, prostate, colorectal, and lung cancers. Preclinical development
PXL-665: An LXR inverse agonist in preclinical development with potent activity against both LXRα and LXRβ.
Summary and Conclusions
The study of Liver X Receptors (LXRs) represents a significant advancement in health research, offering insights into various metabolic disorders and potential therapeutic avenues. Animal studies have provided promising evidence of LXRs’ potential benefits, including elevated HDL levels, improved insulin sensitivity, and reduced inflammation.
LXRs’ role extends beyond metabolic health, with implications in neuroprotection, autoimmune diseases, and inflammation regulation. They are emerging as potential targets for innovative therapies, offering hope for improved treatments in diverse medical fields.
Recent reviews shed light on the molecular insights and therapeutic opportunities LXRs offer, particularly in cancer treatment. While challenges remain in developing safe and effective LXR modulators, ongoing research holds promise for addressing metabolic disorders and advancing cancer therapy.
LXR agonists, which activate LXR receptors, have demonstrated potential in animal models for various diseases, including atherosclerosis by lowering cholesterol levels and preventing artery blockages, diabetes by improving glucose tolerance and reducing inflammation, Alzheimer’s Disease by reducing amyloid beta production, and cancer by inhibiting the growth of certain cancer cells and potentially slowing cancer progression.
Challenges associated with LXR activation include exacerbating inflammation and atherosclerosis due to abnormal signaling in immune cells, potential alterations in lipid metabolism leading to increased harmful cholesterol production, and the possibility of raising triglyceride levels in the blood and liver with certain LXR agonists.
Scientific and clinical efforts are underway to develop safer and more effective LXR agonists that maximize benefits while minimizing side effects. Researchers aim to leverage LXRs’ therapeutic potential to combat heart disease, diabetes, atherosclerosis, Alzheimer’s, and cancer.
Thank you for reading my perspectives. I wish you a healthy and happy life.
If you found this story helpful, you may also check out my other articles on NewsBreak. As a postdoctoral researcher and executive consultant, I write about important life lessons based on my decades of research and experience in cognitive, metabolic, and mental health.
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