CREBZF as a Key Regulator of STAT3 Pathway in the Control of Liver Regeneration in Mice.

BACKGROUND AND a member of the signal transducer and activator of transcription family, is strongly associated with liver injury, inflammation, regeneration, and hepatocellular carcinoma development. However, the signals that regulate activity are not completely understood. APPROACH AND RESULTS:Here we characterize CREB/ATF bZIP transcription factor CREBZF as a critical regulator of duanyu18133 in the hepatocyte to repress liver regeneration. We show that CREBZF deficiency stimulates the expression of the cyclin gene family and enhances liver regeneration after partial hepatectomy. Flow cytometry analysis reveals that CREBZF regulates cell cycle progression during liver regeneration in a hepatocyte-autonomous manner. Similar results were observed in another model of liver regeneration induced by intraperitoneal injection of carbon tetrachloride (CCl₄ ). Mechanistically, CREBZF potently associates with the linker domain of duanyu18133 and represses its dimerization and transcriptional activity in vivo and in vitro. Importantly, hepatectomy-induced hyperactivation of cyclin D1 and liver regeneration in CREBZF liver-specific knockout mice was reversed by selective duanyu18133 inhibitor cucurbitacin I. In contrast, adeno-associated virus-mediated overexpression of CREBZF in the liver inhibits the expression of the cyclin gene family and attenuates liver regeneration in CCl₄ -treated mice. CONCLUSIONS:These results characterize CREBZF as a coregulator of duanyu18133 to inhibit regenerative capacity, which may represent an essential cellular signal to maintain liver mass homeostasis. Therapeutic approaches to inhibit CREBZF may benefit the compromised liver during liver transplantation. © 2019 by the American Association for the Study of Liver Diseases.

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