Nonalcoholic steatohepatitis (NASH) is a progressive disorder with aberrant lipid accumulation and subsequent inflammatory and profibrotic response. Therapeutic efforts at lipid reduction via increasing cytoplasmic lipolysis unfortunately worsens hepatitis due to toxicity of liberated fatty acid. An alternative approach could be lipid reduction through autophagic disposal, i.e., lipophagy. We engineered a synthetic adaptor protein to induce lipophagy, combining a lipid droplet-targeting signal with optimized LC3-interacting domain. Activating hepatocyte lipophagy in vivo strongly mitigated both steatosis and hepatitis in a diet-induced mouse NASH model. Mechanistically, activated lipophagy promoted the excretion of lipid from hepatocytes, thereby suppressing harmful intracellular accumulation of nonesterified fatty acid. A high-content compound screen identified alpelisib and digoxin, clinically-approved compounds, as effective activators of lipophagy. Administration of alpelisib or digoxin in vivo strongly inhibited the transition to steatohepatitis. These data thus identify lipophagy as a promising therapeutic approach to prevent NASH progression.

非酒精性脂肪性肝炎 (NASH) 是一种进行性疾病，伴有异常的脂质积累以及随后的炎症和促纤维化反应。不幸的是，通过增加细胞质脂肪分解来降低脂质的治疗努力由于释放的脂肪酸的毒性而使肝炎恶化。另一种方法是通过自噬处理（即脂肪吞噬）来减少脂质。我们设计了一种合成接头蛋白来诱导脂肪自噬，将脂滴靶向信号与优化的 LC3 相互作用结构域相结合。在饮食诱导的小鼠 NASH 模型中，激活体内肝细胞自噬可显着减轻脂肪变性和肝炎。从机制上讲，激活的自噬促进了肝细胞中脂质的排泄，从而抑制了有害的非酯化脂肪酸在细胞内的积累。高内涵化合物筛选确定了临床批准的化合物 alpelisib 和地高辛是有效的脂肪吞噬激活剂。体内给予alpelisib或地高辛可强烈抑制向脂肪性肝炎的转变。因此，这些数据表明，自噬是一种有前途的预防 NASH 进展的治疗方法。