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Войти в исследования Life sciences · 2025
Progesterone receptor membrane component 1 accelerates liver fibrosis by interacting with transforming growth factor β receptor.
СтатьяНазвание и аннотация: Перевод в очереди
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Mukae Moeka, Ko Je-Won, Kwun Hyo-Jung, Baek In-Jeoung, Lee Sang R, Hong Eui-Ju
Аннотация
AIMS: Transforming growth factor-beta (TGF-β) is a central driver of hepatic stellate cell (HSC) activation via SMAD signaling, ultimately contributing to liver fibrosis and cirrhosis. While progesterone receptor membrane component 1 (Pgrmc1), a non-canonical progesterone receptor, has been implicated in liver metabolism, its role in liver fibrosis remains poorly understood.
MAIN METHODS: To investigate the involvement of PGRMC1 in liver fibrosis, we analyzed public Gene Expression Omnibus (GEO) datasets from cirrhotic patients. A carbon tetrachloride (CCl₄)-induced liver fibrosis model was established in wild-type and Pgrmc1-knockout (KO) mice. Additionally, primary hepatocytes and Lx-2 cells were used to explore cell-type specific signaling pathways.
KEY FINDINGS: Public dataset analysis revealed that higher PGRMC1 expression is associated with cirrhosis development and shorter survival in cirrhotic patients. In a CCl₄-induced model, Pgrmc1-KO mice exhibited significant resistance to liver fibrosis with suppression of TGF-β signaling. However, Pgrmc1-KO primary hepatocytes were prone to CCl₄-induced apoptosis. Instead, PGRMC1 knockdown significantly reduced TGF-β receptor (TGF-βR) protein levels and SMAD phosphorylation. Inhibition of TGF-βR1 abrogated the reduction in SMAD phosphorylation observed in PGRMC1-knockdown cells and co-immunoprecipitation assay revealed the interaction between PGRMC1 and TGF-βR.
SIGNIFICANCE: Collectively, our findings demonstrate that PGRMC1 plays a crucial role in liver fibrosis progression by regulating TGF-βR, highlighting its potential as a promising therapeutic target for antibody-based treatment.
MAIN METHODS: To investigate the involvement of PGRMC1 in liver fibrosis, we analyzed public Gene Expression Omnibus (GEO) datasets from cirrhotic patients. A carbon tetrachloride (CCl₄)-induced liver fibrosis model was established in wild-type and Pgrmc1-knockout (KO) mice. Additionally, primary hepatocytes and Lx-2 cells were used to explore cell-type specific signaling pathways.
KEY FINDINGS: Public dataset analysis revealed that higher PGRMC1 expression is associated with cirrhosis development and shorter survival in cirrhotic patients. In a CCl₄-induced model, Pgrmc1-KO mice exhibited significant resistance to liver fibrosis with suppression of TGF-β signaling. However, Pgrmc1-KO primary hepatocytes were prone to CCl₄-induced apoptosis. Instead, PGRMC1 knockdown significantly reduced TGF-β receptor (TGF-βR) protein levels and SMAD phosphorylation. Inhibition of TGF-βR1 abrogated the reduction in SMAD phosphorylation observed in PGRMC1-knockdown cells and co-immunoprecipitation assay revealed the interaction between PGRMC1 and TGF-βR.
SIGNIFICANCE: Collectively, our findings demonstrate that PGRMC1 plays a crucial role in liver fibrosis progression by regulating TGF-βR, highlighting its potential as a promising therapeutic target for antibody-based treatment.