Division of Gastroenterology, Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA; Division of Gastroenterology, Department of Internal Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hepatology. 2014 Feb;59(2):483-95. doi: 10.1002/hep.26698. Epub 2013 Dec 18.
Transforming growth factor beta (TGF-β) signaling activates Smad- and TGF-β-activated kinase 1 (TAK1)-dependent signaling to regulate cell survival, proliferation, fibrosis, and tumorigenesis. The effects of TGF-β signaling on metabolic syndrome, including nonalcoholic fatty liver disease, remain elusive. Wild-type (WT) and hepatocyte-specific TGF-β receptor type II-deficient (Tgfbr2ΔHEP) mice were fed a choline-deficient amino acid (CDAA)-defined diet for 22 weeks to induce NASH. WT mice fed a CDAA diet displayed increased activation of Smad2/3 and had marked lipid accumulation, inflammatory cell infiltration, hepatocyte death, and fibrosis; in comparison, Tgfbr2ΔHEP mice fed a CDAA diet had suppressed liver steatosis, inflammation, and fibrosis. Both palmitate-induced steatotic hepatocytes and hepatocytes isolated from WT mice fed a CDAA diet had increased susceptibility to TGF-β-mediated death. TGF-β-mediated death in steatotic hepatocytes was inhibited by silencing Smad2 or blocking reactive oxygen species (ROS) production and was enhanced by inhibiting TAK1 or nuclear factor kappa B. Increased hepatic steatosis in WT mice fed a CDAA diet was associated with the increased expression of lipogenesis genes (Dgat1 and Srebp1c), whereas the decreased steatosis in Tgfbr2ΔHEP mice was accompanied by the increased expression of genes involved in β-oxidation (Cpt1 and Acox1). In combination with palmitate treatment, TGF-β signaling promoted lipid accumulation with induction of lipogenesis-related genes and suppression of β-oxidation-related genes in hepatocytes. Silencing Smad2 decreased TGF-β-mediated lipid accumulation and corrected altered gene expression related to lipid metabolism in hepatocytes. Finally, we confirmed that livers from patients with nonalcoholic steatohepatitis (NASH) displayed phosphorylation and nuclear translocation of Smad2/3.
TGF-β signaling in hepatocytes contributes to hepatocyte death and lipid accumulation through Smad signaling and ROS production that promote the development of NASH.
转化生长因子β（TGF-β）信号转导激活 Smad 和 TGF-β激活激酶 1（TAK1）依赖性信号转导，调节细胞存活、增殖、纤维化和肿瘤发生。TGF-β信号转导对代谢综合征（包括非酒精性脂肪性肝病）的影响仍不清楚。野生型（WT）和肝细胞特异性 TGF-β受体 II 缺陷型（Tgfbr2ΔHEP）小鼠喂食胆碱缺乏氨基酸（CDAA）定义的饮食 22 周以诱导 NASH。喂食 CDAA 饮食的 WT 小鼠显示 Smad2/3 的活性增加，并伴有明显的脂质堆积、炎症细胞浸润、肝细胞死亡和纤维化；相比之下，喂食 CDAA 饮食的 Tgfbr2ΔHEP 小鼠则抑制肝脂肪变性、炎症和纤维化。棕榈酸诱导的脂肪变性肝细胞和喂食 CDAA 饮食的 WT 小鼠分离的肝细胞对 TGF-β介导的死亡具有更高的敏感性。TGF-β 介导的脂肪变性肝细胞死亡可通过沉默 Smad2 或阻断活性氧（ROS）产生来抑制，通过抑制 TAK1 或核因子 kappa B 来增强。喂食 CDAA 饮食的 WT 小鼠肝脂肪变性增加与脂生成基因（Dgat1 和 Srebp1c）的表达增加有关，而 Tgfbr2ΔHEP 小鼠脂肪变性减少与参与β-氧化的基因（Cpt1 和 Acox1）的表达增加有关。与棕榈酸处理相结合，TGF-β 信号转导通过诱导肝细胞中与脂生成相关基因的表达和抑制与 β-氧化相关基因的表达来促进脂质积累。沉默 Smad2 可减少 TGF-β 介导的脂质积累并纠正肝细胞中与脂质代谢相关的改变的基因表达。最后，我们证实非酒精性脂肪性肝炎（NASH）患者的肝脏显示 Smad2/3 的磷酸化和核转位。
肝细胞中的 TGF-β 信号转导通过 Smad 信号转导和 ROS 产生促进 NASH 的发展，导致肝细胞死亡和脂质积累。
