Liver receptor homolog-1 (NR5A2) orchestrates hepatic inflammation and TNF-induced cell death

• Published in: Cell reports (Cambridge) Vol. 42; no. 12; p. 113513
• Main Authors: Lambrecht, Rebekka, Delgado, M. Eugenia, Gloe, Vincent, Schuetz, Karina, Plazzo, Anna Pia, Franke, Barbara, San Phan, Truong, Fleming, Jennifer, Mayans, Olga, Brunner, Thomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.12.2023; Elsevier
• Subjects: apoptosis; BIM; CP: Immunology; ERα; hepatitis; inflammation; liver; LRH-1; NF-κB; TNF; CP: Immunology; NF-κB; LRH-1; liver; ERα; inflammation; BIM; apoptosis; hepatitis; TNF
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113513

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 κB (NF-κB) activity, while LRH-1 overexpression inhibits NF-κB activity. This inhibition relies on direct physical interaction of LRH-1’s ligand-binding domain and the Rel homology domain of NF-κB subunit RelA. Mechanistically, increased transcription of anti-apoptotic NF-κB 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. [Display omitted] •Hepatic LRH-1 deletion causes mild liver steatosis, fibrosis, and inflammation•Female LRH-1-deficient mice are protected from TNF-induced liver damage•LRH-1 deletion reduces estrogen receptor activity and increases NF-κB activity•LRH-1 deletion-induced inflammation causes degradation of pro-apoptotic protein BIM Lambrecht et al. report that liver-restricted deletion of LRH-1 sparks spontaneous inflammation but shields female mice from TNF-induced hepatitis. LRH-1 influences hepatic ERα and NF-κB activity, thereby impacting the apoptotic BCL-2 protein family. The study emphasizes LRH-1’s central and sex-related role in the hepatic transcription network.