Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
Nat Commun. 2023 Jul 13;14(1):4084. doi: 10.1038/s41467-023-39404-6.
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，其特征为异常脂质积聚，随后发生炎症和纤维化反应。通过增加细胞质脂肪分解来减少脂质的治疗方法不幸地由于释放的游离脂肪酸的毒性而使肝炎恶化。替代方法可以是通过自噬作用（即脂噬作用）减少脂质，我们设计了一种合成衔接蛋白来诱导脂噬作用，将脂滴靶向信号与优化的 LC3 相互作用域结合在一起。在饮食诱导的 NASH 小鼠模型中，体内激活肝细胞的脂噬作用强烈减轻了脂肪变性和肝炎。从机制上讲，激活的脂噬作用促进了肝细胞中脂质的排泄，从而抑制了非酯化脂肪酸在细胞内的有害积聚。高内涵化合物筛选鉴定了阿培利司和地高辛这两种临床批准的化合物是脂噬作用的有效激活剂。体内给予阿培利司或地高辛可强烈抑制向脂肪性肝炎的转变。这些数据表明，脂噬作用是预防 NASH 进展的一种很有前途的治疗方法。
