Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury
Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury
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DOI：
10.1111/liv.14425
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发表时间：
2020-03-20
影响因子：
6.7
通讯作者：
Buitrago-Molina, Laura Elisa
中科院分区：
文献类型：
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作者：
Roemermann, Dorothee;Ansari, Nadiea;Buitrago-Molina, Laura Elisa
背景与目的自噬是细胞存活和维持体内平衡的关键过程。然而，实施的治疗方法的基础上的自噬机制肝损伤后仍然是challenging.Methods我们使用了一个肝特异性Atg 7缺陷小鼠模型来解决这个问题。一方面，Atg 7缺陷型肝细胞表现出稳态过度增殖。另一方面，外部触发因素如部分肝切除术（PHx）或细胞移植并不诱导肝细胞增殖或肝脏再生。PHx后，肝细胞增殖强烈下降，伴随着高死亡率。这种死亡率的增加可以通过药理学mTOR抑制来克服。根据损伤后肝细胞增殖低下，Atg 7缺陷肝细胞未能在肝损伤模型中重新填充肝脏。Atg 7缺陷小鼠表现出肝脏肥大、一过性细胞肥大和转氨酶水平升高，随后随着年龄的增长出现强烈的窦周/细胞周纤维化。他们升高的改良肝活动指数（mHAI）几乎完全是由于细胞凋亡而没有任何炎症。这些参数与PHx后甘油三酯含量的变化和受损的脂滴形成相关。机制上，我们还观察到了HGF，PAK 4，NOTCH 3和YES 1的调节，这些蛋白参与细胞周期的调控。结论我们证明了自噬在肝细胞再生能力中的重要作用。我们显示了自噬和甘油三酯之间的因果关系，这对促进肝脏恢复至关重要。最后，药理学mTOR抑制克服了肝损伤后自噬缺陷的影响，并预防了死亡率。
Background and aims Autophagy is a critical process in cell survival and the maintenance of homeostasis. However, the implementation of therapeutic approaches based on autophagy mechanisms after liver damage is still challenging.Methods We used a hepatospecific Atg7-deficient murine model to address this question.Results We showed that the proliferation and regeneration capacity of Atg7-deficient hepatocytes was impaired. On the one hand, Atg7-deficient hepatocytes showed steady-state hyperproliferation. On the other hand, external triggers such as partial hepatectomy (PHx) or cell transplantation did not induce hepatocellular proliferation or liver repopulation. After PHx, hepatocyte proliferation was strongly decreased, accompanied by high mortality. This increase in mortality could be overcome by pharmacological mTOR inhibition. In accordance with hepatocyte hypoproliferation after damage, Atg7-deficient hepatocytes failed to repopulate the liver in a hepatic injury model. Atg7-deficient mice showed hepatic hypertrophy, transient cellular hypertrophy, and high transaminase levels followed by strong perisinusoidal/pericellular fibrosis with age. Their elevated modified hepatic activity index (mHAI) was almost exclusively due to apoptosis without any inflammation. These parameters were associated with variations in the triglyceride content and compromised lipid droplet formation after PHx. Mechanistically, we also observed a modulation of HGF, PAK4, NOTCH3 and YES1, which are proteins involved in cell cycle regulation.Conclusion We demonstrated the important role of autophagy in the regeneration capacity of hepatocytes. We showed the causative relationship between autophagy and triglycerides that is essential for promoting liver recovery. Finally, pharmacological mTOR inhibition overcame the impact of autophagy deficiency after liver damage and prevented mortality.