GO:1902121 lithocholic acid binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1902121 (lithocholic acid binding) is a molecular function defined as binding to lithocholic acid (LCA), a secondary bile acid produced by gut microbial 7α-dehydroxylation.
• LCA is a potent endogenous ligand for several nuclear receptors, including FXR, VDR, and TGR5, and can also bind the TULP3 protein to activate sirtuins and AMPK.
• Lithocholic acid binding controls diverse physiological processes such as T cell differentiation, ageing, lipid metabolism, and cholestatic liver injury.
• Dysregulated LCA signaling is implicated in metabolic dysfunction-associated steatotic liver disease (MASLD), cholestasis, and inflammatory disorders.
• Key proteins mediating lithocholic acid binding include NR1H4 (FXR), VDR, GPBAR1 (TGR5), and TULP3, which are attractive targets for CRISPR-based functional studies.
• CRISPR knockout, point mutation, knock-in, and overexpression models enable precise dissection of lithocholic acid binding in health and disease.
Description
Lithocholic acid (LCA) is a hydrophobic secondary bile acid generated by the gut microbiota from chenodeoxycholic acid. The Gene Ontology term GO:1902121, lithocholic acid binding, describes the molecular function of selectively interacting with LCA. This function is central to bile acid signaling because LCA acts as a hormone-like molecule that modulates nuclear receptors and membrane receptors, thereby influencing gene expression, metabolism, and immune responses. Understanding lithocholic acid binding is therefore critical for researchers studying gut microbiota-host interactions, metabolic diseases, and ageing. Recent studies have shown that LCA binds TULP3 to activate sirtuins and AMPK, extending lifespan in model organisms. Moreover, LCA and its derivatives control the balance between T helper 17 (TH17) and regulatory T (Treg) cells, linking bile acid metabolism to autoimmunity. These findings highlight lithocholic acid binding as a key molecular event at the interface of microbiology, immunology, and endocrinology.
lithocholic acid binding At A Glance
| GO ID | GO:1902121 |
|---|---|
| GO term | lithocholic acid binding |
| Ontology | molecular_function |
| Synonym | LCA binding |
| Major function | Binding to lithocholic acid, a secondary bile acid, to mediate signaling, transport, or metabolism |
| Related receptors | FXR (NR1H4), VDR, TGR5 (GPBAR1), TULP3 |
| Physiological processes | Bile acid homeostasis, lipid metabolism, immune cell differentiation, ageing |
| Disease relevance | MASLD/MASH, cholestasis, inflammatory bowel disease, cancer |
What Is GO:1902121?
GO:1902121 (lithocholic acid binding) is defined as the molecular function of binding to lithocholic acid (LCA), a secondary bile acid. In practice, this term is used to annotate proteins that physically interact with LCA, such as nuclear receptors (FXR, VDR), membrane receptors (TGR5), and intracellular carriers (TULP3). The binding event can trigger conformational changes, receptor activation, or transport of LCA, thereby initiating downstream signaling cascades.
Why Is lithocholic acid binding Important in Cell Biology?
Lithocholic acid binding is important because LCA is not merely a detergent-like metabolite but a potent signaling molecule that regulates nuclear receptors and membrane receptors. Through these interactions, LCA influences gene expression programs controlling lipid and glucose metabolism, immune cell fate, and longevity. Dysregulation of LCA binding is associated with cholestatic liver injury, metabolic dysfunction-associated steatohepatitis (MASH), and altered immune responses. Therefore, studying lithocholic acid binding provides mechanistic insights into microbiota-host crosstalk and identifies potential therapeutic targets for metabolic and inflammatory diseases.
• LCA binding to FXR regulates bile acid synthesis and enterohepatic circulation.
• LCA binding to VDR modulates calcium homeostasis and immune function.
• LCA binding to TGR5 promotes lipotoxicity and MASLD-MASH transition.
• LCA binding to TULP3 activates sirtuins and AMPK to slow ageing.
• LCA metabolites control TH17 and Treg cell differentiation, linking bile acids to autoimmunity.
• Parabacteroides distasonis produces LCA to alleviate obesity and metabolic dysfunctions.
• LCA binding is implicated in cholestatic liver injury and inflammation.
• Gut microbiota influences oral drug bioavailability via bile acid metabolism including LCA.
• LCA derivatives are being developed as VDR agonists for therapeutic applications.
• CRISPR-based models enable causal testing of LCA-binding proteins in disease.
Molecular Mechanism of lithocholic acid binding
Ligand recognition by nuclear receptors
In simple terms: LCA fits into a pocket in certain nuclear receptors, like a key in a lock, to turn genes on or off.
Lithocholic acid binds to the ligand-binding domain of nuclear receptors such as FXR (NR1H4) and VDR, inducing conformational changes that recruit coactivators and modulate transcription of target genes involved in bile acid and lipid metabolism. This binding is highly specific and is a prerequisite for downstream physiological effects.
Membrane receptor activation
In simple terms: LCA can also bind to receptors on the cell surface, triggering rapid signaling inside the cell.
Conjugated LCA activates the membrane receptor TGR5 (GPBAR1), leading to cAMP accumulation and downstream effects on energy metabolism and inflammation. This binding event promotes lipotoxicity and contributes to MASLD-MASH transition by disrupting carnitine biosynthesis.
Intracellular carrier interaction
In simple terms: Inside cells, LCA binds to carrier proteins that help it reach specific compartments or activate signaling pathways.
LCA binds TULP3, a tubby-like protein, to activate sirtuins and AMPK, thereby slowing ageing in model organisms. This interaction represents a novel mechanism linking bile acid binding to longevity pathways.
Immune cell modulation
In simple terms: LCA binding can change the behavior of immune cells, promoting or suppressing inflammation.
LCA and its derivatives modulate the balance between TH17 and Treg cells, with LCA binding to receptors on T cells influencing their differentiation. This highlights the role of lithocholic acid binding in immune homeostasis and autoimmunity.
Microbial production and host sensing
In simple terms: Gut bacteria produce LCA, which then binds to host proteins to send signals.
Gut microbiota, such as Parabacteroides distasonis, produce secondary bile acids including LCA, which then bind to host receptors to alleviate obesity and metabolic dysfunctions. The bioavailability of oral drugs can also be influenced by microbial bile acid metabolism.
Key Genes Involved in GO:1902121 lithocholic acid binding
The following genes encode proteins that directly or indirectly mediate lithocholic acid binding and its downstream effects.
| Gene | Major Role | Research Relevance |
|---|---|---|
| NR1H4 (FXR) | Nuclear receptor that binds LCA and regulates bile acid synthesis | Target for cholestasis and metabolic liver disease |
| VDR | Nuclear receptor activated by LCA derivatives | Therapeutic target for calcium disorders and cancer |
| GPBAR1 (TGR5) | Membrane receptor activated by conjugated LCA | Mediates lipotoxicity and MASLD-MASH transition |
| TULP3 | Intracellular protein that binds LCA to activate sirtuins/AMPK | Link between bile acids and ageing |
| CYP3A4 | Cytochrome P450 enzyme that metabolizes LCA | Determines LCA bioavailability and drug interactions |
| SULT2A1 | Sulfotransferase that sulfates LCA | Regulates LCA detoxification and signaling |
| ABCB11 (BSEP) | Bile salt export pump | LCA transport and cholestasis |
| SLCO1B1 | OATP transporter for bile acids | Hepatic uptake of LCA |
| NR0B2 (SHP) | Orphan nuclear receptor induced by FXR | Feedback regulation of bile acid synthesis |
| FGF19 | Intestinal hormone induced by FXR | Regulates bile acid homeostasis |
| IL-17 | Cytokine produced by TH17 cells | LCA modulates TH17/Treg balance |
| FOXP3 | Transcription factor for Treg cells | LCA influences Treg differentiation |
| AMPK | Energy sensor activated by LCA-TULP3 axis | Mediates anti-ageing effects |
| SIRT1 | Deacetylase activated by LCA-TULP3 axis | Mediates anti-ageing effects |
| NF-κB | Inflammatory transcription factor suppressed by FXR activation | LCA-FXR signaling reduces inflammation |
| Carnitine biosynthesis enzymes | Disrupted by TGR5 activation | Contributes to lipotoxicity |
| Parabacteroides distasonis | Gut bacterium producing LCA | Alleviates obesity and metabolic dysfunctions |
How Is lithocholic acid binding Regulated?
Lithocholic acid binding and its downstream effects are regulated at multiple levels. The expression of nuclear receptors such as FXR and VDR is controlled by feedback loops involving SHP and FGF19. Post-translational modifications, including phosphorylation and ubiquitination, can modulate receptor activity. Additionally, the gut microbiota composition determines the amount of LCA available for binding, and microbial enzymes such as 7α-dehydroxylase are regulated by diet and host factors. The TULP3-LCA interaction activates AMPK and sirtuins, which in turn regulate energy metabolism and ageing. In immune cells, LCA binding influences the balance between TH17 and Treg differentiation, which is subject to cytokine and metabolic regulation.
lithocholic acid binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| GPBAR1 (TGR5) | MASLD/MASH | Liver-specific knockout mice |
| NR1H4 (FXR) | Cholestatic liver injury | FXR knockout mice treated with ANIT |
| TULP3 | Ageing | Tulp3 knockout or knock-in mice |
| VDR | Calcium disorders, cancer | VDR knockout mice |
| IL-17/FOXP3 | Autoimmune diseases | T cell-specific knockout mice |
Metabolic dysfunction-associated steatotic liver disease (MASLD/MASH)
Conjugated LCA activates hepatic TGR5 to promote lipotoxicity and MASLD-MASH transition by disrupting carnitine biosynthesis. This implicates lithocholic acid binding in the pathogenesis of fatty liver disease and identifies TGR5 as a potential therapeutic target.
Cholestatic liver injury
Herpetrione alleviates ANIT-induced cholestatic liver injury by targeting FXR to suppress NF-κB signaling, highlighting the role of FXR and its ligand LCA in cholestasis. Dysregulated LCA binding may contribute to bile acid accumulation and liver damage.
Inflammatory and autoimmune diseases
Bile acid metabolites including LCA control TH17 and Treg cell differentiation, linking lithocholic acid binding to autoimmune and inflammatory conditions. Modulation of LCA binding could offer new strategies for treating inflammatory diseases.
Ageing and metabolic syndrome
LCA binds TULP3 to activate sirtuins and AMPK, slowing ageing in model organisms. This suggests that lithocholic acid binding plays a role in longevity and age-related metabolic decline.
From lithocholic acid binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does TULP3 mediate LCA-induced AMPK activation? | TULP3 knockout cell line |
| Does FXR ligand-binding domain mutation affect LCA binding? | Point mutation knock-in mice |
| Can LCA binding to TGR5 be blocked by a specific antagonist? | TGR5 overexpression and knockout cells |
| Does LCA modulate TH17/Treg balance in vivo? | Adoptive transfer of T cells from knockout mice |
| Does VDR activation by LCA derivatives require specific residues? | VDR point mutation knock-in |
| Does gut microbiota-derived LCA affect host metabolism? | Germ-free mice colonized with P. distasonis |
How to Study the lithocholic acid binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Isothermal titration calorimetry (ITC) | Binding affinity (Kd) between protein and LCA | Validate direct binding of TULP3 to LCA |
| Surface plasmon resonance (SPR) | Real-time binding kinetics | Screen LCA analogs for receptor binding |
| RNA-seq | Transcriptional changes upon LCA treatment | Identify FXR target genes |
| Proteomics | Protein expression and post-translational modifications | Discover signaling pathways activated by LCA |
| CRISPR knockout screening | Genes essential for LCA-induced phenotypes | Identify novel mediators of LCA signaling |
| Metabolomics | Levels of LCA and related metabolites | Assess gut microbial production of LCA |
| Immunophenotyping | TH17/Treg cell frequencies | Evaluate immune modulation by LCA |
| Reporter assays | Receptor activation (e.g., FXR, VDR) | Test LCA derivatives as agonists |
Ligand-binding assays
Radioligand binding assays, isothermal titration calorimetry (ITC), and surface plasmon resonance (SPR) can directly measure the affinity of proteins for lithocholic acid. These methods are essential for validating GO:1902121 annotations.
Transcriptomics and proteomics
RNA-seq and proteomics can identify downstream transcriptional and signaling changes upon LCA treatment in wild-type versus knockout cells, revealing pathways regulated by lithocholic acid binding.
CRISPR screening
Genome-wide CRISPR knockout screens can identify genes required for LCA-mediated phenotypes, such as AMPK activation or T cell differentiation.
Metabolomics and lipidomics
Mass spectrometry-based metabolomics can quantify LCA and its derivatives in biological samples, linking binding events to metabolic outcomes.
How CRISPR Can Be Used to Study GO:1902121 lithocholic acid binding
Knockout
CRISPR knockout of genes encoding LCA-binding proteins (e.g., TULP3, FXR, TGR5) enables loss-of-function studies to determine their causal role in LCA-mediated phenotypes. For example, TULP3 knockout abolishes LCA-induced AMPK activation.
Point Mutation
Introducing point mutations in the ligand-binding domain of nuclear receptors can disrupt LCA binding while preserving other functions, allowing precise mapping of binding sites. This approach is useful for dissecting receptor-specific effects.
Knock-in
Knock-in of tagged versions of LCA-binding proteins (e.g., HA-TULP3) facilitates affinity purification and interactome studies. Knock-in of humanized receptors can also model human-specific LCA responses.
Overexpression
Overexpression of LCA-binding proteins such as TGR5 or VDR in cell lines can amplify signaling and enable high-throughput screening for agonists or antagonists. This is particularly useful for drug discovery.
How EDITGENE Supports lithocholic acid binding Research
Researchers studying lithocholic acid binding-related genes often need to determine whether a candidate gene is causally involved in LCA sensing, signaling, or metabolism. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this research, from gene knockout to precise point mutations and library screening.
Contact EDITGENE today to design your custom CRISPR model for lithocholic acid binding research.
Frequently Asked Questions About lithocholic acid binding
What is lithocholic acid binding?
Lithocholic acid binding (GO:1902121) is the molecular function of selectively interacting with lithocholic acid (LCA), a secondary bile acid, to mediate signaling, transport, or metabolism.
What genes are involved in lithocholic acid binding?
Key genes include NR1H4 (FXR), VDR, GPBAR1 (TGR5), and TULP3, which encode proteins that bind LCA and trigger downstream effects.
How does lithocholic acid binding affect ageing?
LCA binds TULP3 to activate sirtuins and AMPK, which slows ageing in model organisms.
What diseases are associated with lithocholic acid binding?
Dysregulated LCA binding is linked to MASLD/MASH, cholestatic liver injury, inflammatory diseases, and metabolic syndrome.
Which receptors bind lithocholic acid?
FXR, VDR, TGR5, and TULP3 are known to bind LCA or its derivatives.
How can I study lithocholic acid binding in the lab?
Use ligand-binding assays (ITC, SPR), CRISPR knockout models, and transcriptomics to dissect LCA signaling.
What is the role of gut microbiota in lithocholic acid binding?
Gut bacteria such as Parabacteroides distasonis produce LCA, which then binds host receptors to influence metabolism.
Can lithocholic acid binding be targeted therapeutically?
Yes, modulating LCA binding to FXR, TGR5, or VDR is being explored for metabolic and inflammatory diseases.
What are the synonyms for lithocholic acid binding?
The synonym is LCA binding.
How does lithocholic acid binding affect immune cells?
LCA binding modulates TH17 and Treg cell differentiation, influencing autoimmune responses.
Conclusion
Lithocholic acid binding (GO:1902121) is a critical molecular function that bridges gut microbial metabolism and host physiology. Through interactions with nuclear receptors, membrane receptors, and intracellular carriers, LCA regulates diverse processes including metabolism, immunity, and ageing. Dysregulation of these interactions contributes to MASLD/MASH, cholestasis, and inflammatory diseases. CRISPR-based models and advanced biochemical assays are essential tools for dissecting the mechanisms and therapeutic potential of lithocholic acid binding.
References
- 1. Qu Q et al.. 2025. Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing.. Nature 643(8070):201-209 PMID: 39695235
- 2. Hang S et al.. 2019. Bile acid metabolites control T(H)17 and T(reg) cell differentiation.. Nature 576(7785):143-148 PMID: 31776512
- 3. Ding L et al.. 2015. Bile acid nuclear receptor FXR and digestive system diseases.. Acta Pharm Sin B 5(2):135-44 PMID: 26579439
- 4. Zhang X et al.. 2021. The influence of the gut microbiota on the bioavailability of oral drugs.. Acta Pharm Sin B 11(7):1789-1812 PMID: 34386321
- 5. Lian S et al.. 2025. Conjugated Lithocholic Acid Activates Hepatic TGR5 to Promote Lipotoxicity and MASLD-MASH Transition by Disrupting Carnitine Biosynthesis.. Adv Sci (Weinh) 12(20):e2410602 PMID: 40344326
- 6. Wang K et al.. 2019. Parabacteroides distasonis Alleviates Obesity and Metabolic Dysfunctions via Production of Succinate and Secondary Bile Acids.. Cell Rep 26(1):222-235.e5 PMID: 30605678
- 7. Jing L et al.. 2026. Herpetrione alleviates ANIT-induced cholestatic liver injury by targeting FXR to suppress NF-κB signaling.. J Ethnopharmacol 356:120839 PMID: 41176140
- 8. Yoshihara A et al.. 2022. Lithocholic Acid Amides as Potent Vitamin D Receptor Agonists.. Biomolecules 12(1) PMID: 35053278
