Lipophagy Impairment Is Associated With Disease Progression in NAFLD

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liverdisease in Western countries and is associated with aging and features of metabolicsyndrome. 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 NAFLDpatient cohort by histomorphological and molecular analysis. High fat diet-fed C57BL/6Jmale mice and high-fat/high-glucose cultured Huh7 cells showed accumulation ofboth p62/SQSTM1 and LC3-II protein. In 59 NAFLD patients, lipid droplet-loadedlysosomes/lipolysosomes and p62/SQSTM1 clusters correlated with NAFLD activityscore (NAS) and with NAS and fibrosis stage, respectively, and levels of expression oflysosomal genes, as well as autophagy-related genes, correlated with NAS and fibrosis stage. An increased amount of lipid droplets, lipolysosomes and autophagosomes wasfound in subjects with NAFLD compared to healthy subjects at ultrastructural level. Inconclusion, here we observed that NAFLD is characterized by histological, ultrastructuraland 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.