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

Summary: 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 unexpected...

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Bibliographic Details
Main Authors: Rebekka Lambrecht, M. Eugenia Delgado, Vincent Gloe, Karina Schuetz, Anna Pia Plazzo, Barbara Franke, Truong San Phan, Jennifer Fleming, Olga Mayans, Thomas Brunner
Format: Article
Language:English
Published: Elsevier 2023-12-01
Series:Cell Reports
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Online Access:http://www.sciencedirect.com/science/article/pii/S2211124723015255
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Summary:Summary: 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.
ISSN:2211-1247