The liver is an important organ of the body. Although they are long lived and normally do not undergo cell division, adult hepatocytes maintain the ability to proliferate in response to toxic injury and infection. Therefore, an improved understanding of the regeneration of the compromised liver would benefit the development of therapeutic approach to prevent steatosis-related complications and improve the clinical outcome of liver transplantation.
Previous study by Prof. LI Yu's team from Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences revealed CREB/ATF bZIP transcription factor (CREBZF) as a novel regulator in the control of de novo lipogenesis via repressing Insig activity.
Given that hepatic steatosis is an independent risk factor for liver transplantation which increases morbidity and mortality, they sought to investigate the role of the novel metabolic regulator CREBZF in the progress of liver regeneration. They characterized CREBZF as a key regulator for liver regeneration.
In vivo and in vitro studies demonstrated that CREBZF deficiency stimulates the expression of cyclin gene family and enhances liver regeneration after partial hepatectomy or in response to carbon tetrachloride (CCl4) treatment. Flow cytometry analysis revealed that CREBZF regulates cell cycle progression during liver regeneration in a hepatocyte-autonomous manner.
Mechanistically, CREBZF is potently associated with the linker domain of STAT3 and repressed its dimerization and transcriptional activity in vivo and in vitro. Importantly, adeno-associated virus mediated overexpression of CREBZF in the liver inhibited the expression of cyclin gene family and attenuated liver regeneration.
These results characterized hepatic CREBZF as a novel coregulator of STAT3 to inhibit regenerative capacity, which may represent an essential cellular signal to terminate regeneration and maintain standard liver mass.
The study, published in Hepatology, may facilitate developing novel strategies to improve liver regeneration and clinical outcome of liver transplantation.
CREBZF regulates liver regeneration via inhibiting STAT3 pathway: potential therapeutic implication in improving liver regeneration and clinical outcome of liver transplantation. (Image by Dr. LI Yu’s lab)
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