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

非酒精性脂肪性肝炎（Nonalcoholic steatohepatitis, NASH）是一类以脂质异常蓄积并继发炎症与促纤维化反应的进展性疾病。通过胞质脂解作用降低脂质水平，可能会加重脂肪性肝炎，但自噬性脂解作用即脂噬（Lipophagy）的相关效应仍不明确。我们通过基因工程改造了衔接蛋白，使其携带脂滴靶向信号并修饰了LC3互作结构域（LC3 interacting region），以诱导脂噬。激活肝细胞脂噬可显著缓解肝脏脂肪变性与NASH病理损伤。从机制层面分析，脂噬通过溶酶体胞吐作用促进肝脏脂质排泄，并减少非酯化脂肪酸的有害蓄积。与溶酶体功能异常相关的胞吐作用不同，该胞吐过程依赖钙信号通路。高内涵化合物筛选发现，阿培利司（alpelisib）与地高辛（digoxin）这两种已获临床批准的化合物，可作为脂噬的有效激活剂。在喂食高脂低甲硫氨酸低胆碱饲料的小鼠中，给予阿培利司或地高辛可抑制其向脂肪性肝炎的病情进展。综上，激活脂噬或是预防NASH进展的极具潜力的治疗策略。实验整体设计：对照小鼠与经LIR修饰诱导脂噬的NASH模型小鼠的肝脏mRNA表达谱