Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
Gastroenterology. 2012 Apr;142(4):938-46. doi: 10.1053/j.gastro.2011.12.044. Epub 2012 Jan 10.
BACKGROUND & AIMS: The pathogenesis of liver fibrosis involves activation of hepatic stellate cells, which is associated with depletion of intracellular lipid droplets. When hepatocytes undergo autophagy, intracellular lipids are degraded in lysosomes. We investigated whether autophagy also promotes loss of lipids in hepatic stellate cells to provide energy for their activation and extended these findings to other fibrogenic cells.
We analyzed hepatic stellate cells from C57BL/6 wild-type, Atg7(F/F), and Atg7(F/F)-GFAP-Cre mice, as well as the mouse stellate cell line JS1. Fibrosis was induced in mice using CCl(4) or thioacetamide (TAA); liver tissues and stellate cells were analyzed. Autophagy was blocked in fibrogenic cells from liver and other tissues using small interfering RNAs against Atg5 or Atg7 and chemical antagonists. Human pulmonary fibroblasts were isolated from samples of lung tissue from patients with idiopathic pulmonary fibrosis or from healthy donors.
In mice, induction of liver injury with CCl(4) or TAA increased levels of autophagy. We also observed features of autophagy in activated stellate cells within injured human liver tissue. Loss of autophagic function in cultured mouse stellate cells and in mice following injury reduced fibrogenesis and matrix accumulation; this effect was partially overcome by providing oleic acid as an energy substrate. Autophagy also regulated expression of fibrogenic genes in embryonic, lung, and renal fibroblasts.
Autophagy of activated stellate cells is required for hepatic fibrogenesis in mice. Selective reduction of autophagic activity in fibrogenic cells in liver and other tissues might be used to treat patients with fibrotic diseases.
肝纤维化的发病机制涉及肝星状细胞的激活，这与细胞内脂质滴的耗竭有关。当肝细胞发生自噬时，细胞内的脂质在溶酶体中降解。我们研究了自噬是否也促进肝星状细胞中脂质的丢失，以为其激活提供能量，并将这些发现扩展到其他纤维生成细胞。
我们分析了 C57BL/6 野生型、Atg7(F/F)和 Atg7(F/F)-GFAP-Cre 小鼠的肝星状细胞以及小鼠星状细胞系 JS1。用 CCl(4)或硫代乙酰胺 (TAA)在小鼠中诱导纤维化；分析肝组织和星状细胞。用针对 Atg5 或 Atg7 的小干扰 RNA 和化学拮抗剂在肝和其他组织的纤维生成细胞中阻断自噬。从特发性肺纤维化患者或健康供体的肺组织样本中分离出人肺成纤维细胞。
用 CCl(4)或 TAA 诱导肝损伤，增加了自噬水平。我们还观察到损伤人肝组织中活化的星状细胞中自噬的特征。在培养的小鼠星状细胞和损伤后的小鼠中，自噬功能的丧失减少了纤维化和基质积累；这种效应部分被提供油酸作为能量底物所克服。自噬还调节胚胎、肺和肾成纤维细胞中纤维生成基因的表达。
激活的星状细胞的自噬是小鼠肝纤维化所必需的。在肝和其他组织中的纤维生成细胞中选择性地降低自噬活性可能用于治疗纤维性疾病患者。
