Apolipoprotein E4-Mediated Metabolic Dysfunction Correction via Liver X Receptor Agonism
Curated pathway from expert analysis
flowchart TD
A["LXR-beta/NR1H2<br/>Nuclear Receptor"]
B["Oxysterol Ligand Binding<br/>24S-HC, 27-HC, GW3965"]
C["LXR/RXR Heterodimer<br/>DR4 Response Element"]
D["ABCA1/ABCG1<br/>Transcriptional Activation"]
E["APOE Lipidation<br/>Cholesterol Efflux"]
F["APOE4 Astrocytes<br/>LXR-beta Activity Reduced"]
G["Selective LXR-beta Agonist<br/>Avoids LIPID Toxicity"]
H["Cholesterol Homeostasis<br/>Neuroprotection"]
A --> B
B --> C
C --> D
D --> E
E --> H
F -.->|"impairs"| D
G --> C
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#81c784,color:#81c784
style H fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for NR1H2 yet. Search RCSB →
Median TPM across 13 brain regions for NR1H2 (LXRβ), APOE from GTEx v10.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for NR1H2 (LXRβ), APOE.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF male E4-targeted replacement (E4-TR) mice on 60% high-fat diet receive LXRβ agonist T0901317 at 30 mg/kg/day via oral gavage for 16 weeks starting at 8 weeks of age, THEN hepatic triglyceride conte | Hepatic triglyceride content reduction ≥40%; serum β-hydroxybutyrate increase ≥50%; hepatic steatosis score reduction from NASH/NAFLD to normal or mild (score ≤ | — no observation — | pending | 0.60 |
| IF cognitively unimpaired APOE4 homozygous adults aged 50-70 with metabolic syndrome (HOMA-IR >2.5) receive oral LXRβ agonist GW3965 at 10 mg/kg/day for 12 weeks, THEN plasma ApoE4 concentrations will | Plasma ApoE4 concentration decrease ≥25%; HOMA-IR reduction ≥30%; fasting glucose decrease ≥15 mg/dL; LDL-C reduction ≥20 mg/dL | — no observation — | pending | 0.55 |