Mitigation of autophagy ameliorates hepatocellular damage following ischemia-reperfusion injury in murine steatotic liver
Mitigation of autophagy ameliorates hepatocellular damage following ischemia-reperfusion injury in murine steatotic liver
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DOI：
10.1152/ajpgi.00210.2014
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发表时间：
2014-12-01
影响因子：
4.5
通讯作者：
Kirk, Allan D.
中科院分区：
文献类型：
--
作者：
Gupta, Nitika A.;Kolachala, Vasantha L.;Kirk, Allan D.
缺血再灌注损伤（IRI）是肝脏手术、心源性休克和肝移植的常见临床后果。脂肪变性的肝脏特别容易受到IRI的影响，其反应是广泛的肝细胞损伤。自噬是一种平衡细胞存活和细胞死亡的溶酶体途径，参与了IRI，尽管其在脂肪变性肝脏IRI中的作用尚不清楚。在高脂饮食（HFD）喂养的小鼠体内暴露于IRI和脂肪变性肝细胞暴露于缺氧IRI（HIRI）体外研究自噬的作用。自噬的两种抑制剂，3-甲基腺嘌呤和巴弗洛霉素A1，保护脂肪变性肝细胞HIRI。Exendin 4（Ex 4）是一种胰高血糖素样肽1类似物，也可抑制自噬，表现为自噬相关蛋白[微管相关蛋白1A/1B-轻链3（LC 3）II、p62、高迁移率族蛋白B1、beclin-1和自噬相关蛋白7]减少，肝细胞损伤减少，暴露于IRI的HFD喂养小鼠的线粒体结构和功能改善。在HFD喂养的小鼠中，IRI后LC 3的点状模式的逆转和自噬通量的降低进一步证明了自噬的减少。在相同条件下，Ex 4的作用被竞争性拮抗剂exendin 9-39逆转。本研究表明，在肝脂肪变性的IRI中，用Ex 4处理肝细胞减轻自噬，改善肝细胞损伤，并保持线粒体完整性。这些数据表明，靶向自噬的疗法，特别是通过Ex 4治疗，可以改善IRI在高度流行的脂肪变性肝脏中的作用。
Ischemia-reperfusion injury (IRI) is a common clinical consequence of hepatic surgery, cardiogenic shock, and liver transplantation. A steatotic liver is particularly vulnerable to IRI, responding with extensive hepatocellular injury. Autophagy, a lysosomal pathway balancing cell survival and cell death, is engaged in IRI, although its role in IRI of a steatotic liver is unclear. The role of autophagy was investigated in high-fat diet (HFD)-fed mice exposed to IRI in vivo and in steatotic hepatocytes exposed to hypoxic IRI (HIRI) in vitro. Two inhibitors of autophagy, 3-methyladenine and bafilomycin A1, protected the steatotic hepatocytes from HIRI. Exendin 4 (Ex4), a glucagon-like peptide 1 analog, also led to suppression of autophagy, as evidenced by decreased autophagy-associated proteins [microtubule-associated protein 1A/1B-light chain 3 (LC3) II, p62, high-mobility group protein B1, beclin-1, and autophagy-related protein 7], reduced hepatocellular damage, and improved mitochondrial structure and function in HFD-fed mice exposed to IRI. Decreased autophagy was further demonstrated by reversal of a punctate pattern of LC3 and decreased autophagic flux after IRI in HFD-fed mice. Under the same conditions, the effects of Ex4 were reversed by the competitive antagonist exendin 9-39. The present study suggests that, in IRI of hepatic steatosis, treatment of hepatocytes with Ex4 mitigates autophagy, ameliorates hepatocellular injury, and preserves mitochondrial integrity. These data suggest that therapies targeting autophagy, by Ex4 treatment in particular, may ameliorate the effects of IRI in highly prevalent steatotic liver.