Endothelial autophagy is not required for liver regeneration after partial hepatectomy in mice with fatty liver

Abstract

Background & aims: Patients with non-alcoholic fatty liver disease (NAFLD) have impaired liver regeneration. Liver endothelial cells play a key role in liver regeneration. In non-alcoholic steatohepatitis (NASH), liver endothelial cells display a defect in autophagy, contributing to NASH progression. We aimed to determine the role of endothelial autophagy in liver regeneration following liver resection in NAFLD.

Methods: First, we assessed autophagy in primary endothelial cells from wild type mice fed a high fat diet and subjected to partial hepatectomy. Then, we assessed liver regeneration after partial hepatectomy in mice deficient (Atg5^lox/lox ;VE-cadherin-Cre⁺ ) or not (Atg5^lox/lox ) in endothelial autophagy and fed a high fat diet. The role of endothelial autophagy in liver regeneration was also assessed in ApoE^-/- hypercholesterolemic mice and in mice with NASH induced by methionine- and choline-deficient diet.

Results: First, autophagy (LC3II/protein) was strongly increased in liver endothelial cells following hepatectomy. Then, we observed at 40 and 48 h and at 7 days after partial hepatectomy, that Atg5^lox/lox ;VE-cadherin-Cre⁺ mice fed a high fat diet had similar liver weight, plasma AST, ALT and albumin concentration, and liver protein expression of proliferation (PCNA), cell-cycle (Cyclin D1, BrdU incorporation, phospho-Histone H3) and apoptosis markers (cleaved Caspase-3) as Atg5^lox/lox mice fed a high fat diet. Same results were obtained in ApoE^-/- and methionine- and choline-deficient diet fed mice, 40 h after hepatectomy.

Conclusion: These results demonstrate that the defect in endothelial autophagy occurring in NASH does not account for the impaired liver regeneration occurring in this setting.

Keywords: LSECs; NAFLD; autophagy; hepatectomy; liver regeneration.