Lipophagy Impairment Is Associated With Disease Progression in NAFLD.

Simone Carotti,Daniele Lettieri-Barbato,Francesca Zalfa,Katia Aquilano,Giuseppe Perrone,Antonio Picardi,Sergio Ruggiero,Maria Zingariello,Sergio Morini,Francesco Valentini,Francesca Alletto,Raffaele Antonelli-Incalzi,Maria Francesconi,Umberto Vespasiani-Gentilucci

doi:10.3389/fphys.2020.00850

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries and is associated with aging and features of metabolic syndrome. Lipotoxicity and oxidative stress are consequent to dysregulation of lipid metabolism and lipid accumulation, leading to hepatocyte injury and inflammation. Lipophagy consists in selective degradation of intracellular lipid droplets by lysosome and mounting evidence suggests that lipophagy is dysregulated in NAFLD. Here we demonstrate lipophagy impairment in experimental models of NAFLD and in a NAFLD patient cohort by histomorphological and molecular analysis. High fat diet-fed C57BL/6J male mice and high-fat/high-glucose cultured Huh7 cells showed accumulation of both p62/SQSTM1 and LC3-II protein. In 59 NAFLD patients, lipid droplet-loaded lysosomes/lipolysosomes and p62/SQSTM1 clusters correlated with NAFLD activity score (NAS) and with NAS and fibrosis stage, respectively, and levels of expression of lysosomal genes, as well as autophagy-related genes, correlated with NAS and fibrosis stage. An increased amount of lipid droplets, lipolysosomes and autophagosomes was found in subjects with NAFLD compared to healthy subjects at ultrastructural level. In conclusion, here we observed that NAFLD is characterized by histological, ultrastructural and molecular features of altered autophagy that is associated with an impaired lipid degradation. Impaired autophagy is associated with features of advanced disease. Lipopolysosomes, as individuated with light microscopy, should be further assessed as markers of disease severity in NAFLD patients.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is becoming the most common hepatic disorder in Western populations and is emerging as one of the principal causes for liver cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation (Bedogni et al, 2014)
In order to generate a preclinical model of NAFLD, C57BL/6J mice were fed with high fat diet (HFD) for 4 or 8 months
Lipophagy represents the main lipid degrading system in the liver and its impairment was recently associated with the pathogenesis of NAFLD (Sinha et al, 2014; Zhang et al, 2018)

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is becoming the most common hepatic disorder in Western populations and is emerging as one of the principal causes for liver cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation (Bedogni et al, 2014). The majority of NAFLD patients have simple steatosis or steatosis with non-specific changes and do not progress or evolve very slowly to advanced liver disease (Vernon et al, 2011). A subgroup of patients with NAFLD presents the histological criteria for non-alcoholic steatohepatitis (NASH) and has a significant risk of progression toward cirrhosis and HCC (Vernon et al, 2011)

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Results

Conclusion