Hepatocyte nuclear factor 1β induced by chemical stress accelerates cell proliferation and increases genomic instability in mouse liver

Abstract

The liver has a considerable capacity of regeneration against the damage. The regulatory factors and molecular mechanism for the capacity are not fully appreciated. In developmental processes, hepatocyte nuclear factor 1β (HNF1β) is a cooperative factor for HNF6, which is a known stimulatory factor for hepatocyte proliferation after partial hepatectomy. We showed that carbon tetrachloride (CCl₄)-induced liver injury up-regulated HNF1β, whereas the expression of HNF6 was not affected by the chemical stress, indicating unknown physiological roles of HNF1β against the chemical stress, not in cooperation with HNF6. To determine whether HNF1β has a novel function in the liver regeneration, we overexpressed HNF1β in the mouse liver by adenoviral gene delivery. We revealed that overexpression of HNF1β resulted in accelerated cell proliferation with the protein level up-regulation of plasminogen and plasmin, a converted active form of plasminogen, which play a pivotal role in liver regeneration inducing hepatocyte proliferation. Despite this stimulatory effect for the liver regeneration, HNF1β overexpression significantly increased genomic instability with decreased protein level of mediator of DNA damage checkpoint 1 (MDC1) and dephosphorylation of SP1 transcription factor. The increased expression of HNF1β is associated with several types of hepatocyte carcinomas, indicating possible involvement of the factor in carcinogenesis. Our data extend the current understanding of the mechanism underlying liver regeneration against chemical stress, and identified HNF1β as a novel regulatory factor in this mechanism and as a potential initiator for carcinogenesis.

Keywords::

• Liver regeneration
• plasminogen
• plasmin
• mediator of DNA damage checkpoint 1

Acknowledgements

This work was supported by the Central Research Institute of Electric Power Industry. We thank Dr. Takamichi Nakamura for technical advices.

Declaration of interest

We have no potential conflicts of interest.