Table 1.
Pathophysiological effects of NR1D1 in different organs
| Organ | Disease | Models/Materials | Effects | References |
|---|---|---|---|---|
| Heart | MI | Nr1d1−/− mice | SR9009 lowers NLRP3 inflammasome level in myocardial fibroblasts and immunocyte recruitment to heal the vulnerable infarct | [61] |
| HF | MI mouse model induced by the permanent ligation of the left LAD | SR9009 reduces adverse cardiac remodeling through alleviating inflammation | [62] | |
| Pressure overload mouse model caused by the constriction of aortic arch between the right and the left carotid arteries | NR1D1 represses the transcription of numerous genes involved in cardiomyocyte hypertrophy in vitro. SR9009 enhances fatty acid oxidation via increasing PDK4 expression, and blocks the cellular remodeling induced by pressure overload in vivo | [8] | ||
| Thrombus | BMDMs and NR1D1−/− mouse model of rupture-prone vulnerable plaques induced by partly ligating the left renal artery and the left internal and the external carotid arteries | NR1D1 activation inhibits macrophage pyroptosis in a NF-κB/NLRP3 inflammasome-dependent manner in BMDMs, and mitigates macrophage infiltration, inflammation, and oxidative stress to stabilize rupture-prone vulnerable plaques | [63] | |
| Acute MI mouse model induced by ligation of LAD | NR1D1 potentiate platelet aggregation and activation via the OPHN-1/RhoA/ERM signaling mediated by oligophrenin-1 | [64] | ||
| Liver | FH | Naïve peritoneal macrophages and primary BMDMs from Nr1d1−/− mice and Nr1d1+/+ littermates | NR1D1 inhibits the NLRP3 inflammasome signaling, reduces inflammatory cytokines and CCL2-mediated hepatic infiltration of innate immune cells | [7] |
| ALD | Shp−/− mice fed modified ethanol-binge | NR1D1 reduces lipid accumulation and oxidative stress via SHP / REV-ERBα / CYP4A axis | [53] | |
| NAFLD | Whole-body or hepatocyte-specific mPGES-2-deficient mice fed a high-fat or methionine-choline-deficient diet | NR1D1 decreases CYP4A14 and increases acyl-CoA thioesterase 4 levels to potentiate lipid metabolism | [65] | |
| NAFLD | Nr1d1 Δex3/4 mice fed high fat diet | The deletion of exons 3 and 4 in the mouse Nr1d1 gene worsens HFD-induced hepatic steatosis | [66] | |
| Apoptotic liver injury | Acute hepatic damage mouse model induced by Fas | GSK4112 decreases the level of Fas and the activity of caspase-3 and caspase-8, suppressing hepatocyte apoptosis | [67] | |
| Lung | ALI | ALI mouse model made by intraperitoneal injection of LPS | NR1D1 reduces lung vascular permeability and inflammatory cells infiltration via inhibiting the NF-κB /NLRP3 pathway | [9] |
| Cigarette smoke -induced lung inflammation | Lung inflammation mouse model induced by cigarette smoke | GSK4112 decreases the release of inflammatory cytokines | [68] | |
| Lung adenocarcinoma | Lung adenocarcinoma cell line A549 | Downregulation of NR1D1 stimulates the invasion and promotes the proliferation of lung adenocarcinoma cell line A549 | [69] | |
| Lung adenocarcinoma | Nontumorigenic mouse hepatocyte cell line AML12 | NR1D1 is targeted and destabilized by PKA, resulting in increased glucose production | [70] | |
| SCLC | Chemosensitive SCLC cells (H69 and H446) and the corresponding chemoresistant SCLC cells (H69AR and H446DDP) | SR9009 directly represses the autophagy gene Atg5 to suppress SCLC cell autophagy activity | [71] | |
| Kidney | AKI | NR1D1−/− mice and AKI mouse model induced by folic acid and AAI | NR1D1 represses the transcription of Slc7a11 and HO1 to promote ferroptosis, and loss of NR1D1 reduces the sensitivity of mice to AKI and eliminates the circadian time dependency in disease severity | [72, 73] |
| Colon | Colitis | BMDMs and colitis mouse model induced by dextran sulfate sodium salt | NR1D1 plays an anti-inflammatory role and affects the circadian rhythm of colitis through direct activation by berberine | [74] |
AAI aristolochic acid I, AKI acute kidney injury, Atg5 Autophagy protein 5, BMDMs bone marrow-derived macrophages, ERM ezrin/radixin/moesin, HF heart failure, HO1 heme oxygenase, LAD left anterior descending coronary artery, LPS lipopolysaccharide, MI myocardial infarction, mPGES-2 microsomal prostaglandin E synthase-2, NLRP3 NOD-like receptor thermal protein domain associated protein 3, NF-κB nuclear factor kappa-B, NR1D1 nuclear receptor subfamily 1, group D, member 1, OPHN-1 oligophrenin 1, PDK4 pyruvate dehydrogenase kinase 4, PKA protein kinase A, RhoA Ras homolog gene family, member A, SCLC small-cell lung cancer, Slc7a11 solute carrier family 7 member 11, SHP small heterodimer partner