Type I Interferon Signaling Accelerates Liver Regeneration by Metabolic Modulation in Noninfectious Conditions.

ABSTRACT Type I interferon (IFN-I) has a well-known function in controlling viral infections, but its contribution in hepatocyte proliferation and hepatocellular carcinoma (HCC) formation remains unclear. Mice deficient in IFN α receptor expression in whole mice or only in hepatocytes (Ifnar-/- and IfnarΔliver) were used to investigate the role of IFN-I signaling in cell proliferation and cancer formation in the liver. We found that Ifnar-/- mice were resistant to chemical-induced HCC formation in the absence of infection. Our results showed that low grade of IFN-I and interferon-stimulated gene (ISG) were expressed substantially in naive mouse liver. The low level of IFN-I activation is constantly present in mouse liver after weaning and negatively modulates Forkhead box O (FOXO) hepatic expression. The IFN-I signaling can be partially blocked by the clearance of lipopolysaccharide (LPS). Mice lacking IFN-I signaling have lower basal proliferation activity and delayed liver regeneration processes after two third partial hepatectomy. The activation of IFN-I signaling on hepatocyte controls glucose homeostasis and lipid metabolism to support proliferation potency and long term tumorigenesis. Our results reveal a positive role of low-grade IFN-I singling to hepatocyte proliferation and HCC formation by modulating glucose homeostasis and lipid metabolism.