Free Cholesterol Accumulation in Hepatic Stellate Cells: Mechanism of Liver Fibrosis Aggravation in Nonalcoholic Steatohepatitis in Mice
Free Cholesterol Accumulation in Hepatic Stellate Cells: Mechanism of Liver Fibrosis Aggravation in Nonalcoholic Steatohepatitis in Mice
复制标题
DOI：
10.1002/hep.26604
复制
发表时间：
2014-01-01
期刊：
影响因子：
13.5
通讯作者：
Hibi, Toshifumi
中科院分区：
文献类型：
--
作者：
Tomita, Kengo;Teratani, Toshiaki;Hibi, Toshifumi
尽管非酒精性脂肪性肝炎(NASH)与高胆固醇血症有关，但这种联系的潜在机制尚未阐明。我们的目的是阐明胆固醇在NASH病理生理学中的确切作用。C57BL/6小鼠分别饲喂对照组、高胆固醇(HC)、蛋氨酸胆碱缺乏(MCD)或MCD+HC饲料12周，或对照组、HC、高脂(HF)或HF+HC饲料24周。在两种小鼠模型中，增加胆固醇摄入量都会加速肝纤维化，而不会影响肝细胞损伤的程度或库普弗细胞的激活。肝纤维化加速的主要原因是游离胆固醇(Fc)在肝星状细胞(HSCs)内积聚，通过抑制TLR4的内酶体-溶酶体降解途径，增加TLR4的水平，从而通过下调骨形态发生蛋白和激活素膜结合抑制物的表达，使细胞对转化生长因子(TGF)诱导的激活敏感。哺乳动物细胞的胆固醇水平是通过由固醇调节元件结合蛋白2(SREBP2)介导的反馈机制来调节的，从而维持细胞胆固醇的稳态。然而，HSC对FC积聚很敏感，因为SREBP裂解激活蛋白(SCAP)与胰岛素诱导基因(INSIG)在细胞内的高表达比率扰乱了SREBP2介导的胆固醇稳态的反馈调节。随后，HSC的激活通过下调Insig-1增强了反馈系统的破坏。此外，在HSC激活的同时抑制过氧化体增殖物激活的受体信号，增强了SREBP2和microRNA-33a信号。因此，Fc在HSCs中的积聚增加，并在恶性循环中进一步敏化这些细胞对转化生长因子诱导的激活，导致NASH肝纤维化的夸大。结论：Fc在肝星状细胞聚集的这些特征机制是治疗包括NASH在内的肝病肝纤维化的潜在靶点。(《肝病》2014；58：154-169)
Although nonalcoholic steatohepatitis (NASH) is associated with hypercholesterolemia, the underlying mechanisms of this association have not been clarified. We aimed to elucidate the precise role of cholesterol in the pathophysiology of NASH. C57BL/6 mice were fed a control, high-cholesterol (HC), methionine-choline-deficient (MCD), or MCD+HC diet for 12 weeks or a control, HC, high-fat (HF), or HF+HC diet for 24 weeks. Increased cholesterol intake accelerated liver fibrosis in both the mouse models without affecting the degree of hepatocellular injury or Kupffer cell activation. The major causes of the accelerated liver fibrosis involved free cholesterol (FC) accumulation in hepatic stellate cells (HSCs), which increased Toll-like receptor 4 protein (TLR4) levels through suppression of the endosomal-lysosomal degradation pathway of TLR4, and thereby sensitized the cells to transforming growth factor (TGF)-induced activation by down-regulating the expression of bone morphogenetic protein and activin membrane-bound inhibitor. Mammalian-cell cholesterol levels are regulated by way of a feedback mechanism mediated by sterol regulatory element-binding protein 2 (SREBP2), maintaining cellular cholesterol homeostasis. Nevertheless, HSCs were sensitive to FC accumulation because the high intracellular expression ratio of SREBP cleavage-activating protein (Scap) to insulin-induced gene (Insig) disrupted the SREBP2-mediated feedback regulation of cholesterol homeostasis in these cells. HSC activation subsequently enhanced the disruption of the feedback system by Insig-1 down-regulation. In addition, the suppression of peroxisome proliferator-activated receptor signaling accompanying HSC activation enhanced both SREBP2 and microRNA-33a signaling. Consequently, FC accumulation in HSCs increased and further sensitized these cells to TGF-induced activation in a vicious cycle, leading to exaggerated liver fibrosis in NASH. Conclusion: These characteristic mechanisms of FC accumulation in HSCs are potential targets to treat liver fibrosis in liver diseases including NASH. (Hepatology 2014;58:154-169)