Genetic Ablation of C/EBPa-p300 Pathway Blocks Development of Obese Pregnancy Associated Liver Disorders in Offspring

BACKGROUND & AIMS: The obesity-associated nonalcoholic fatty liver disease represents a common cause of pediatric liver diseases, including the pediatric liver cancer hepatoblastoma. The mechanisms behind the development of fatty liver in children are not yet known. We examined the role of the C/ EBPa-p300 pathway in the development of maternal obesityassociated fatty liver phenotype in offspring. METHODS: Because the ability of C/EBPa to promote fatty liver phenotype is enhanced by CDK4-mediated phosphorylation of C/EBPa at Ser193 and subsequent formation of C/EBPa- p300 complexes, we used wild -type (WT) and C/EBPa-S193D and C/EBPa-S193A mutant mice to study the effects of maternal high -fat diet (HFD) on the liver health of offspring. The females of these mouse lines were fed an HFD before mating, and the pups were further subjected to either an HFD or a normal diet for 12 weeks RESULTS: WT female mice on the HFD before and during pregnancy and their subsequent offspring on the HFD had severe fatty liver, fibrosis, and an increased rate of liver proliferation. However, the HFD in C/EBPa-S193A mice did not cause development of these disorders. In HFD-HFD treated WT mice, C/EBPa is phosphorylated at Ser193 and forms complexes with p300, which activate expression of genes involved in development of fatty liver, fibrosis, and proliferation. However, S193A-C/EBPa mice do not have complexes of C/EBPa- S193A with p300, leading to a lack of activation of genes of fatty liver, fibrosis, and proliferation. The mutant C/EBPa-S193D mice have accelerated cdk4-dependent pathway and have developed steatosis at early stages. CONCLUSIONS: These studies identified the epigenetic cause of obese pregnancy-associated liver diseases and suggest a potential therapy based on inhibition of cdk4-ph-S193-C/EBPa- p300 pathway. (Cell Mol Gastroenterol Hepatol 2024;17:347-360; https://doi.org/10.1016/j.jcmgh.2023.11.006)