Role of HNF4α-cMyc Interaction in CDE Diet-Induced Liver Injury and Regeneration

Abstract

Hepatocyte nuclear factor 4 alpha (HNF4α) is a nuclear factor essential for liver function that regulates the expression of cMyc and plays an important role in proliferation and differentiation during liver regeneration. This study investigated the role of the HNF4α-cMyc interaction in regulating liver injury and regeneration using the choline-deficient and ethionine-supplemented (CDE) diet model. Wild-type (WT), hepatocyte-specific HNF4α-knockout (KO), cMyc-KO, and HNF4α-cMyc double KO (DKO) mice were fed a CDE diet for 1 week to induce subacute liver injury. To study regeneration, the CDE diet was followed by a normal chow diet for 1 week. WT mice exhibited significant liver injury and decreased HNF4α mRNA and protein expression after 1 week of a CDE diet; HNF4α deletion resulted in significantly higher injury with increased inflammation, fibrosis, proliferation, and hepatic progenitor cell activation compared with WT mice after CDE diet feeding but similar recovery. Deletion of cMyc substantially lowered liver injury with activation of inflammatory genes compared with WT and HNF4α-KO mice after CDE diet feeding. DKO mice resulted in a phenotype comparable to that of the HNF4α-KO mice after CDE diet feeding and led to complete recovery. DKO mice exhibited a significant increase in hepatic progenitor cell markers both after CDE diet-induced injury and after 1 week of recovery. Taken together, these data show that HNF4α protects against inflammatory and fibrotic changes after CDE diet-induced injury, which is driven by cMyc.