Role of HNF4 a-cMyc Interaction in CDE Diet- Induced Liver Injury and Regeneration

Hepatocyte nuclear factor 4 alpha (HNF4 a ) is a nuclear factor essential for liver function that regulates the expression of cMyc and plays an important role during liver regeneration. This study investigated the role of the HNF4 a- cMyc interaction in regulating liver injury and regeneration using the choline-de fi cient and ethionine-supplemented (CDE) diet model. Wild -type (WT), hepatocytespeci fi c HNF4 a- knockout (KO), cMyc-KO, and HNF4 a- cMyc double KO (DKO) mice were fed a CDE diet for 1 week to induce subacute liver injury. To study regeneration, normal chow diet was fed for 1 week after CDE diet. WT mice exhibited signi fi cant liver injury and decreased HNF4 a mRNA and protein expression after CDE diet. HNF4 a deletion resulted in signi fi cantly higher injury with increased in fl ammation, fi brosis, proliferation, and hepatic progenitor cell activation compared with WT mice after CDE diet but indicated similar recovery. Deletion of cMyc lowered liver injury with activation of in fl ammatory genes compared with WT and HNF4 a- KO mice after CDE diet. DKO mice had a phenotype comparable to that of the HNF4 a- KO mice after CDE diet and a complete recovery. DKO mice exhibited a signi fi cant increase in hepatic progenitor cell markers both after injury and recovery phase. Taken together, these data show that HNF4 a protects against in fl ammatory and fi brotic changes after CDE diet -induced injury, which is driven by cMyc. (Am J Pathol 2024, 194: 1218 - 1229; https://doi.org/ 10.1016/j.ajpath.2024.03.008)