A pivotal role of BEX1 in liver progenitor cell expansion in mice.

Background: The activation and expansion of bipotent liver progenitor cells (LPCs) are indispensable for liver regeneration after severe or chronic liver injury. However, the underlying molecular mechanisms regulating LPCs and LPC-mediated liver regeneration remain elusive. Methods: Hepatic brain-expressed X-linked 1 (BEX1) expression was evaluated using microarray screening, real-time polymerase chain reaction, immunoblotting and immunofluorescence. LPC activation and liver injury were studied following a choline-deficient, ethionine-supplemented (CDE) diet in wild-type (WT) and <italic>Bex1</italic>−/− mice. Proliferation, apoptosis, colony formation and hepatic differentiation were examined in LPCs from WT and <italic>Bex1</italic>−/− mice. Peroxisome proliferator-activated receptor gamma was detected in <italic>Bex1</italic>-deficient LPCs and mouse livers, and was silenced to analyse the expansion of LPCs from WT and <italic>Bex1</italic>−/− mice. Results: Hepatic BEX1 expression was increased during CDE diet-induced liver injury and was highly elevated primarily in LPCs. <italic>Bex1</italic>−/− mice fed a CDE diet displayed impaired LPC expansion and liver regeneration. <italic>Bex1</italic> deficiency inhibited LPC proliferation and enhanced LPC apoptosis in vitro. Additionally, <italic>Bex1</italic> deficiency inhibited the colony formation of LPCs but had no effect on their hepatic differentiation. Mechanistically, BEX1 inhibited peroxisome proliferator-activated receptor gamma to promote LPC expansion. Conclusion: Our findings indicate that BEX1 plays a pivotal role in LPC activation and expansion during liver regeneration, potentially providing novel targets for liver regeneration and chronic liver disease therapies. [ABSTRACT FROM AUTHOR]