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

• Published in: Liver international 2023-10, Vol.43 (10), p.2309-2319
• Main Authors: Hammoutene, Adel, Tanguy, Marion, Calmels, Mélanie, Pravisani, Riccardo, Albuquerque, Miguel, Casteleyn, Christophe, Slimani, Lotfi, Sadoine, Jeremy, Boulanger, Chantal M, Paradis, Valérie, Gilgenkrantz, Hélène, Rautou, Pierre-Emmanuel
• Format: Article
• Language: English
• Subjects: Apolipoprotein E; Apoptosis; Autophagy; Caspase; Choline; Cyclin D1; Defects; Diet; Endothelial cells; Fatty liver; Hepatectomy; Hepatocytes; High fat diet; Histone H3; Histones; Liquid oxygen; Liver; Liver diseases; Methionine; Nutrient deficiency; Proteins; Regeneration
• ISSN: 1478-3223; 1478-3231
• DOI: 10.1111/liv.15665

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. 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 ;VE-cadherin-Cre ) or not (Atg5 ) 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. 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 ;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 mice fed a high fat diet. Same results were obtained in ApoE and methionine- and choline-deficient diet fed mice, 40 h after hepatectomy. These results demonstrate that the defect in endothelial autophagy occurring in NASH does not account for the impaired liver regeneration occurring in this setting.