HCMV-encoded IE2 promotes NAFLD progression by up-regulation of SREBP1c expression in UL122 genetically modified mice.

Non-alcoholic fatty liver disease (NAFLD), a liver manifestation of metabolic syndrome, is associated with considerable health and socioeconomic burdens in many populations worldwide. Recent studies suggest that human cytomegalovirus (HCMV) infection might play a role in the pathogenesis of metabolic diseases, including NAFLD, but it is still unclear whether HCMV-encoded IE2 plays an important role in this process. Interestingly, SREBP1c was recently reported to play critical roles in the development of hepatic steatosis. In this study, we aimed to study the IE2 effect on the expression levels of SREBP1c and on lipid metabolism in the liver of UL122 genetically modified mice. First, UL122 genetically modified mice models that can steadily and continuously express IE2 protein were established. Then, the mice were divided into the experimental group (positive mice identified) and the control group (wild-type mice, n=16 per group). The establishment of UL122 genetically modified mice was identified by PCR technology. The triglyceride content in their livers was measured using a colorimetric assay and oil red O-stain. Real-time PCR and immunohistochemistry were performed to detect the expression levels of SREBP1c mRNA and protein after HCMV infection. We found that SREBP1c expression was significantly elevated in the experimental group, and its overexpression in the liver cells can promote triglyceride accumulation and hepatic steatosis. Taken together, our data collectively demonstrate that HCMV infection is highly associated with NAFLD, SREBP1c overexpression promotes hepatic steatosis, and this up-regulation is most likely mediated by IE2.