Supplementation of amphiregulin improves fatty liver regeneration after partial hepatectomy (PHX): the role of c‐Jun N‐terminal kinase (JNK) and extracellular signal‐regulated kinases (ERK)

Abstract

In previous work, we reported that the growth factor, amphiregulin (AR), decreased in steatotic livers after PHX. In this study, we investigated whether supplementation of AR improved regeneration of remnant fatty livers. Mice were fed a high‐fat, high‐fructose diet (HFFr) or a low‐fat, low‐fructose control diet for 2 weeks and then underwent two‐thirds‐PHX. In contrast to the control diet, the HFFr diet caused moderate hepatic steatosis as indicated by Oil‐Red‐O staining (~40%). At 48 h after PHX, liver regeneration was suppressed in fatty livers. Treatment of mice with fatty livers with recombinant human AR (5 μg/mouse, iv immediately after PHX) improved liver regeneration and increased survival from 40 to 100% after PHX. The phosphorylation levels of EGFR, JNK and ERK were lower in fatty than lean remnant livers, and exogenous AR increased EGFR, JNK and ERK phosphorylation in fatty remnant livers. Phospho‐mTOR, phospho‐AKT, phospho‐p70S6 kinase, and phospho‐p38 MAP kinase were not significantly different between lean and fatty remnant livers. Together, these data reveal that fatty livers remain responsive to AR, which stimulates regeneration of fatty livers after PHX, at least in part, by activating EGFR and its downstream JNK and ERK pathways (NIDDK).