Background and aims: Previous studies demonstrated that autophagy is protective in hepatocytes and macrophages, but detrimental in hepatic stellate cells in chronic liver diseases. The role of autophagy in liver sinusoidal endothelial cells (LSECs) in nonalcoholic steatohepatitis (NASH) is unknown. Our aim was to analyze the potential implication of autophagy in LSECs in NASH and liver fibrosis.
Methods: We analyzed autophagy in LSECs from patients using transmission electron microscopy. We determined the consequences of a deficiency in autophagy: (a) on LSECs phenotype, using primary LSECs and an LSECs line; (b) on early stages of NASH and on advanced stages of liver fibrosis, using transgenic mice deficient in autophagy specifically in endothelial cells and fed a high-fat diet or chronically treated with carbon tetrachloride, respectively.
Results: Patients with NASH had twice less LSECs containing autophagic vacuoles than patient without liver histological abnormalities, or with simple steatosis. LSECs from mice deficient in endothelial autophagy displayed an up-regulation of genes implicated in inflammatory pathways. In LSEC line, deficiency in autophagy enhanced inflammation (CCL2, CCL5, IL-6 and VCAM-1 expression), features of endothelial-to-mesenchymal transition (α-SMA, Tgf-β1, Collagen-1α2 expression) and apoptosis (cleaved Caspase 3). In mice fed a high-fat diet, deficiency in endothelial autophagy induced liver expression of inflammatory markers (Ccl2, Ccl5, Cd68, VCAM-1), liver cell apoptosis (cleaved Caspase-3) and perisinusoidal fibrosis. Mice deficient in endothelial autophagy treated with carbon tetrachloride also developed more perisinusoidal fibrosis.
Conclusions: A defect in autophagy in LSECs occurs in patients with NASH. Deficiency in endothelial autophagy promotes the development of liver inflammation, features suggesting endothelial-to-mesenchymal transition, apoptosis and liver fibrosis at early stages of NASH, but also favors more advanced stages of liver fibrosis.