| First Author | Lambrecht R | Year | 2023 |
| Journal | Cell Rep | Volume | 42 |
| Issue | 12 | Pages | 113513 |
| PubMed ID | 38039134 | Mgi Jnum | J:348154 |
| Mgi Id | MGI:7568709 | Doi | 10.1016/j.celrep.2023.113513 |
| Citation | Lambrecht R, et al. (2023) Liver receptor homolog-1 (NR5A2) orchestrates hepatic inflammation and TNF-induced cell death. Cell Rep 42(12):113513 |
| abstractText | The nuclear receptor liver receptor homolog-1 (LRH-1) has been shown to promote apoptosis resistance in various tissues and disease contexts; however, its role in liver cell death remains unexplored. Hepatocyte-specific deletion of LRH-1 causes mild steatosis and inflammation but unexpectedly shields female mice from tumor necrosis factor (TNF)-induced hepatocyte apoptosis and associated hepatitis. LRH-1-deficient hepatocytes show markedly attenuated estrogen receptor alpha and elevated nuclear factor kappaB (NF-kappaB) activity, while LRH-1 overexpression inhibits NF-kappaB activity. This inhibition relies on direct physical interaction of LRH-1's ligand-binding domain and the Rel homology domain of NF-kappaB subunit RelA. Mechanistically, increased transcription of anti-apoptotic NF-kappaB target genes and the proteasomal degradation of pro-apoptotic BCL-2 interacting mediator of cell death prevent mitochondrial apoptosis and ultimately protect mice from TNF-induced liver damage. Collectively, our study emphasizes LRH-1 as a critical, sex-dependent regulator of cell death and inflammation in the healthy and diseased liver. |
