Abstract
Despite a young age and limited exposure to nutritional challenges and other diseases, young children can develop liver disorders such as fatty liver, fibrosis, and liver cancer. The preliminary stages of these disorders are silent, and the patients come to the clinic at a late stage. During studies of pediatric liver cancer hepatoblastoma (HBL), our group found that a portion of our fresh HBL biobank is characterized by the development of Non-Alcoholic Fatty Liver Disease (NAFLD) including fatty liver, fibrosis, and increased proliferation. Our studies and other recent reports revealed that liver cancer and these fatty liver-specific disorders are strongly correlated with epigenetic changes in gene expression independent of HBL mutations. One of the mutation-independent pathways we focused on is the phosphorylation/de-phosphorylation status of C/EBPα at Ser190 (Ser193 in the mouse C/EBPα protein). De-phosphorylated C/EBPα loses its ability to interact with the chromatin remodeling protein p300, reducing transcription of the genes containing C/EBPα binding sites in their promoters. We found that the lack of the S193 phosphorylation of C/EBPα in S193A mice prevents the development of NAFLD in mouse models of pre-natal and post-natal high-fat diet-mediated NAFLD [1]. In this review, we present extended studies of NAFLD in both mouse models and HBL patients, which revealed the critical role of proliferation in the development of pediatric fatty liver disorders. Since Ser190 of C/EBPα is phosphorylated by cyclin D1-dependent kinase CDK4, our findings provided a rationale for the consideration of CDK4 inhibitors as potential drugs for the prevention of NAFLD and liver cancer in young kids. This review summarizes our findings and available data from other groups demonstrating the critical role of C/EBPα-dependent epigenetic pathways in the development of liver disorders in young children.
Keywords
Maternal obesity, Fatty liver, Fibrosis, Liver proliferation, C/EBPα