Liver Receptor Homolog-1 (LRH-1/NR5A2) orchestrates hepatic inflammation and TNF-induced cell death

Liver Receptor Homolog-1 (LRH-1/NR5A2) is a nuclear receptor that has been shown to promote apoptosis resistance in various tissues and disease contexts, however, its role in liver cell death remains unexplored. Deletion of LRH-1 in hepatocytes developed into a mild steatosis and inflammation already under steady-state conditions. Unexpectedly, hepatocyte-specific deletion of LRH-1 also resulted in a profound protection of mice from TNF-induced hepatocyte apoptosis and associated hepatitis. LRH-1-deficient hepatocytes showed elevated NF-ⲕB activity, while LRH-1 overexpression inhibited NF-ⲕB activity. This inhibition was based on direct physical interaction of the ligand-binding domain of LRH-1 and the Rel homology domain of NF-ⲕB subunit RelA. Mechanistically, we found that increased transcription of anti-apoptotic NF-ⲕB target genes, together with proteasomal degradation of pro-apoptotic BIM via regeneration-driven EGF receptor signaling, prevented mitochondrial apoptosis, ultimately protecting mice from TNF-induced liver damage. Collectively, our study demonstrates that LRH-1 is a critical modulator of cell death and inflammation in the healthy and diseased liver. Highlights 1. Hepatic LRH-1 deletion causes mild liver steatosis, fibrosis, and inflammation. 2. Female LRH-1-deficient mice are protected from TNF-induced liver damage. 3. LRH-1 interacts with NF-ⲕB and inhibits its activity. 4. LRH-1 deletion-provoked inflammation causes degradation of pro-apoptotic protein BIM. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. * ActD : Actinomycin D APAP : Paracetamol, Acetaminophen BCL-2 : B-cell lymphoma protein 2 BID : BH3 interacting-domain death agonist BIM : BCL-2 Interacting Mediator of cell death cIAP : cellular inhibitor of apoptosis protein ConA : Concanavalin A DCs : dendritic cells F : Female FasL : Fas (CD95) Ligand GalN : N-Galactosamine I B : NF-B inhibitor protein ILCs : innate lymphoid cells KCs : Kupffer cells LBD : ligand binding domain LPS : Lipopolysaccharide LRH-1 : Liver Receptor Homolog 1 M : Male MAPK : mitogen-activated protein kinase MOMP : mitochondrial outer membrane permeabilization NF-B : nuclear factor kappa-light-chain-enhancer of activated B cells NKTs : natural killer T cells RHD : Rel homology domain SHP : small heterodimer partner SMAC : second mitochondria-derived activator of caspases TNF : tumor necrosis factor TNFR : TNF Receptor [1]: pending:yes