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HPS is a hepatic growth factor which can accelerate hepatocyte proliferation in vivo and protect against liver injury. These data point to the potential interest of HPS in the treatment of fulminant hepatic failure.

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Hepassocin (HPS), is a liver-specific gene with mitogenic activity on isolated hepatocytes. It is up-regulated following partial hepatectomy and down-regulated frequently in heptocellular carcinoma (HCC). However, very little is known about the HPS transcription regulation mechanism. In this study, we identified HNF1␣ (hepatocyte nuclear factor-1␣) as an important liver-specific cis-acting element for HPS using in vivo luciferase assays. Deletion of the HNF1 binding site not only led to a complete loss of HPS promoter activity in vivo but also abolished the induction of the HPS promoter by HNF1␣. An electrophoretic mobility shift assay demonstrated that HNF1␣ interacted with the HPS gene promoter in vitro. Chromatin immunoprecipitation showed that HNF1␣ interacted with HMGB1 and CREBbinding protein, and all of them were recruited to the HPS promoter in vivo. Moreover, HNF1␣ expression was lower in HCC cell lines and tissues and correlated significantly with the downregulation of HPS expression. Re-expression of HNF1␣ in human hepatoma HepG2 cells reinduced HPS expression. In contrast, knockdown of endogenous HNF1␣ expression by small interfering RNA resulted in a significant reduction of HPS expression. Furthermore, we found that partial hepatectomy and IL-6 significantly induced promoter activity of HPS, depending on STAT3 and HNF1 binding sites in the HPS promoter. These results demonstrate that the HNF1 binding site and HNF1␣ are critical to liver-specific expression of HPS, and down-regulation or loss of HNF1␣ causes, at least in part, the transcriptional down-regulation of HPS in HCC.