ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the global population. However, its pathogenesis is not completely understood. In our recent study, we have demonstrated that in a high-fat diet-induced liver steatosis model, the activation of SREBF1/SREBP-1c (sterol regulatory element binding transcription factor 1) directly upregulates Mir216a transcription, which inhibits CTH/CSE (cystathionase (cystathionine gamma-lyase)) expression and its function in hydrogen sulfide (H₂S) production. Reduced H₂S production suppresses the sulfhydration of ULK1 (unc-51 like autophagy activating kinase 1), consequently inhibiting autophagic flux and lipid droplet turnover. A single substitution mutation (C951S) in ULK1 or the silencing of CTH impairs ULK1 sulfhydration-mediated lipophagy, thereby promoting hepatic steatosis in mice. Interestingly, the sulfhydration of ULK1 increases its intrinsic kinase activity to modulate autophagy at both initiation and progression stages of autophagic catabolic flux. This study reveals that SREBF1/SREBP-1c contributes to hepatic lipid accumulation through its combined effect of increased lipid synthesis coupled with decreased lipid degradation mediated by autophagic dysregulation.

摘要

非酒精性脂肪性肝病 (NAFLD) 影响全球四分之一的人口。然而，其发病机制尚不完全清楚。在我们最近的研究中，我们已经证明，在高脂饮食诱导的肝脂肪变性模型中，SREBF1/SREBP-1c（甾醇调节元件结合转录因子 1）的激活直接上调Mir216a转录，从而抑制 CTH/CSE（胱硫醚酶(胱硫醚 γ-裂解酶)) 的表达及其在硫化氢 (H ₂ S) 产生中的作用。还原 H ₂S 产生抑制 ULK1（unc-51 样自噬激活激酶 1）的硫化，从而抑制自噬通量和脂滴周转。ULK1 中的单一取代突变 (C951S) 或 CTH 的沉默会损害 ULK1 硫化介导的脂肪吞噬，从而促进小鼠肝脏脂肪变性。有趣的是，ULK1 的硫化增加了其内在激酶活性，从而在自噬分解代谢通量的起始和进展阶段调节自噬。这项研究表明，SREBF1/SREBP-1c 通过增加脂质合成和减少自噬失调介导的脂质降解的综合作用，促进肝脏脂质积累。