TGF-β signaling and cholesterol: interdependent and druggable targets in NASH

目前针对非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)等多层疾病的单一因素的治疗，由于治疗靶点的可能相互依赖，注定会取得有限的成功。具体地说，转化生长因子-β(转化生长因子-β)信号和胆固醇在这些肝脏疾病的不同进展阶段的肝细胞中在不同水平上被涉及。然而，它们的相互依赖程度、机制联系以及对肝病预后的影响尚不清楚。我们在这里提出了一个跨学科的合作项目，将来自德国和以色列的领先科学家与转化生长因子-β信号、胆固醇/膜生物学及其在肝脏疾病中的作用方面的独特和互补的专业知识结合在一起。我们将采用跨学科的方法来解决转化生长因子-β超家族(T-βSF)配体，特别是转化生长因子-β1，在非酒精性脂肪肝/非酒精性脂肪肝中对信号的多层调控，重点关注胆固醇的作用。我们的工作假设有三个方面：(1)非酒精性脂肪肝的进展涉及肝细胞对转化生长因子-β刺激的反应的改变。这些参数可能包括多个参数，包括转化生长因子-β受体相互作用(复合体形成)、受体定位于膜微区、内吞作用、蛋白水解性修饰(脱落)、外切体转移和下游转化生长因子-β信号通过Smad和非Smad途径。(Ii)胆固醇水平和动态平衡在非酒精性脂肪肝/非酒精性脂肪肝进展过程中改变，并可能在上述从受体结合到转录调控的步骤中调节对转化生长因子-β刺激的反应。(Iii)胆固醇/转化生长因子-β信号的共同调节和相互作用有助于决定肝细胞的命运，导致细胞应激、细胞死亡和自噬，从而诱导肝损伤或存活和上皮-间充质转化(EMT)介导的癌变。

Current therapies directed towards single elements of multi-layered diseases like non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are destined to limited success due to possible interdependence of the therapeutic targets. Specifically, transforming growth factor-β (TGF-β) signaling and cholesterol were implicated at several levels in liver cells at different progression stages of these liver disorders. However, the degree of their interdependence, mechanistic linkage and implications for liver disease outcome are not known. We here propose a collaborative interdisciplinary project, combining leading scientists from Germany and Israel with distinct and complementary expertise in TGF-β signaling, cholesterol/membrane biology and their role in hepatic diseases. We will employ an interdisciplinary approach to tackle the multilayered regulation of signaling by TGF-β superfamily (TβSF) ligands, specifically TGF-β1, in NAFLD/NASH with focus on the role of cholesterol. Our working hypothesis has three aspects:(i) NAFLD progression involves alterations in hepatocellular responses to TGF-β stimuli. These may comprise multiple parameters, including TGF-β receptor interactions (complex formation), receptor localization to membrane microdomains, endocytosis, proteolytic modification (shedding), exosome transfer, and downstream TGF-β signaling via Smad and non-Smad pathways.(ii) Cholesterol levels and homeostasis are altered in NAFLD/NASH progression and may modulate the response to TGF-β stimuli at the aforementioned steps from receptor binding to transcriptional control.(iii) Cholesterol/TGF-β signaling co-regulation and interaction contribute to hepatocellular fate decisions towards cellular stress, cell death and autophagy, thus inducing liver damage, or survival and epithelial-to-mesenchymal transition (EMT) to mediate carcinogenesis.