The critical role played by endotoxin-induced liver autophagy in the maintenance of lipid metabolism during sepsis
The critical role played by endotoxin-induced liver autophagy in the maintenance of lipid metabolism during sepsis
复制标题
内毒素诱导的肝自噬在脓毒症期间维持脂质代谢中的关键作用
DOI：
10.1080/15548627.2017.1319040
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发表时间：
2017-01-01
期刊：
影响因子：
13.3
通讯作者：
Chung, Hae Young
中科院分区：
文献类型：
--
作者：
Chung, Ki Wung;Kim, Kyung Mok;Chung, Hae Young
自噬是维持细胞完整性和稳态的重要机制，内毒素诱导的自噬在先天免疫中起重要作用。虽然由脂多糖（LPS）介导的TLR 4刺激也上调肝细胞和肝脏中的自噬，但其生理作用仍然难以捉摸。本研究的目的是确定LPS诱导的自噬在肝脏脂质代谢调节中的作用。LPS处理（5 mg/kg）增加自噬，如通过C57 BL 6小鼠肝脏中的LC 3转化和透射电子显微镜（TEM）分析所检测的。AC 2F肝细胞在LPS处理（1 μ g/ml）后也显示出增加的自噬通量。为了进一步研究LPS诱导的自噬的作用，比较了LPS处理的小鼠和禁食对照的肝脏脂质代谢变化。有趣的是，LPS处理的小鼠显示肝脏中的脂质积聚比禁食小鼠少，尽管脂肪酸摄取和脂质合成相关基因增加。使用AC 2F肝细胞的体外分析表明，LPS诱导的自噬影响脂滴的降解。使用巴弗洛霉素A（1）或Atg 7敲低抑制LPS诱导的自噬显著增加了AC 2F肝细胞中的脂质蓄积。此外，氯喹预处理加重LPS诱导的C57 BL 6小鼠肝脏脂质蓄积和炎症。在LPS处理的年轻和老年大鼠中证实了自噬的生理重要性。LPS处理的老年大鼠自噬反应减弱，脓毒症时脂代谢受损，表明自噬反应在内毒素攻击后调节脂代谢中是重要的。我们的研究结果表明，内毒素诱导的自噬是重要的调节脂质代谢，并建议自噬有助于维持脂质代谢稳态在脓毒症。
Macroautophagy/autophagy is a central mechanism by which cells maintain integrity and homeostasis, and endotoxin-induced autophagy plays important roles in innate immunity. Although TLR4 stimulation mediated by lipopolysaccharide (LPS) also upregulates autophagy in hepatocytes and liver, its physiological role remains elusive. The objective of this study was to determine the role of LPS-induced autophagy in the regulation of liver lipid metabolism. LPS treatment (5 mg/kg) increased autophagy, as detected by LC3 conversion and transmission electron microscopy (TEM) analysis in C57BL6 mouse livers. AC2F hepatocytes also showed increased autophagic flux after LPS treatment (1 mu g/ml). To investigate the role of LPS-induced autophagy further, liver lipid metabolism changes in LPS-treated mice and fasted controls were compared. Interestingly, LPS-treated mice showed less lipid accumulation in liver than fasted mice despite increased fatty acid uptake and lipid synthesis-associated genes. In vitro analysis using AC2F hepatocytes demonstrated LPS-induced autophagy influenced the degradation of lipid droplets. Inhibition of LPS-induced autophagy using bafilomycin A(1) or Atg7 knockdown significantly increased lipid accumulation in AC2F hepatocytes. In addition, pretreatment with chloroquine aggravated LPS-induced lipid accumulation and inflammation in C57BL6 mouse livers. The physiological importance of autophagy was verified in LPS-treated young and aged rats. Autophagic response was diminished in LPS-treated aged rats and lipid metabolism was impaired during sepsis, indicating autophagy response is important for regulating lipid metabolism after endotoxin challenge. Our findings demonstrate endotoxin-induced autophagy is important for the regulation of lipid metabolism, and suggest that autophagy helps maintain lipid metabolism homeostasis during sepsis.