GSE185911
Liver lipophagy ameliorates nonalcoholic steatohepatitis through lysosomal lipid exocytosis
Nonalcoholic steatohepatitis (NASH) is a progressive disorder with aberrant lipid accumulation and subsequent inflammatory and profibrotic response. Lipid reduction through cytoplasmic lipolysis might adversely worsen steatohepatitis, however, the effect of autophagic lipolysis, lipophagy, remains obscure. We engineered the adaptor protein to induce lipophagy with lipid droplet targeting signal and modified LC3 interacting region. Activating hepatocyte lipophagy obviously mitigated both steatosis and NASH pathology. Mechanistically, lipophagy promoted the excretion of lipid from liver via lysosomal exocytosis and attenuated harmful accumulation of nonesterified fatty acid. This exocytosis was dependent on Ca2+ signal unlike the lysosomal dysfunction-related exocytosis. High content compound screening identified alpelisib and digoxin, clinically-approved compounds, as effective activators of lipophagy. Administration of alpelisib or digoxin inhibited the transition to steatohepatitis in mice fed high fat with low methionine low choline diet. Given all these data, activating lipophagy may be a promising therapeutic approach to prevent NASH progression. Overall design: Liver mRNA profiles of control and lipophagy(LIR) induced NASH model mice