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线粒体损伤在非酒精性脂肪性肝病发生发展中的作用

肖卫纯 安威

肖卫纯, 安威. 线粒体损伤在非酒精性脂肪性肝病发生发展中的作用[J]. 临床肝胆病杂志, 2021, 37(7): 1515-1521. DOI: 10.3969/j.issn.1001-5256.2021.07.005
引用本文: 肖卫纯, 安威. 线粒体损伤在非酒精性脂肪性肝病发生发展中的作用[J]. 临床肝胆病杂志, 2021, 37(7): 1515-1521. DOI: 10.3969/j.issn.1001-5256.2021.07.005
XIAO WC, AN W. Role of mitochondrial injury in the development and progression of nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2021, 37(7): 1515-1521. DOI: 10.3969/j.issn.1001-5256.2021.07.005
Citation: XIAO WC, AN W. Role of mitochondrial injury in the development and progression of nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2021, 37(7): 1515-1521. DOI: 10.3969/j.issn.1001-5256.2021.07.005

线粒体损伤在非酒精性脂肪性肝病发生发展中的作用

DOI: 10.3969/j.issn.1001-5256.2021.07.005
详细信息
    通讯作者:

    安威,anwei@ccmu.edu.cn

  • 中图分类号: R575.5

Role of mitochondrial injury in the development and progression of nonalcoholic fatty liver disease

  • 摘要: 线粒体是重要的细胞器,调节细胞脂质代谢、氧化磷酸化和ATP合成。线粒体生物合成障碍、稳态失衡乃至结构破坏都将导致脂质代谢紊乱以及氧化应激。非酒精性脂肪性肝病(NAFLD)是肝细胞脂质堆积为特征的慢性肝病。NAFLD是一个进展性疾病,表现为肝细胞脂肪变、脂肪性肝炎、肝纤维化和肝硬化这一轴向过程。目前认为线粒体在NAFLD发病中发挥着重要作用,NAFLD也被称为“线粒体病”。综述了脂质代谢障碍、氧化应激、线粒体稳态失衡等线粒体损伤与NAFLD发生发展的相关性。

     

  • 图  1  线粒体与脂类代谢

    注:Ⅰ、Ⅱ、Ⅲ和Ⅳ:电子传递链复合物Ⅰ、Ⅱ、Ⅲ和Ⅳ;CytC:细胞色素C。长链脂肪酸通过脂酰CoA合成酶催化为脂酰CoA,由CPT-1催化与肉碱结合为脂酰肉碱进入膜间隙,生成的脂酰肉碱在肉碱-脂酰肉碱转位酶的作用下进入基质,由CPT-2催化重新分解为脂酰CoA和肉碱;脂酰CoA经β-氧化生成乙酰CoA,乙酰CoA经过三羧酸循环彻底氧化。由β-氧化和三羧酸循环产生的氢离子以NADH和FADH2为递氢体,通过ETC传递链传递电子,耦联质子从线粒体基质泵入膜间隙,产生跨内膜的电化学梯度,当质子通过ATP酶复合体中的质子通道进入基质时,ATP合酶利用电化学质子梯度的能量催化ADP与Pi合成ATP,产生H2O。

    图  2  线粒体脂类代谢障碍与脂肪堆积

    注:肝脏所吸收的脂肪主要在肝脏进行代谢。CPT-1是脂肪酸转运的限速酶,催化长链脂肪酸由胞质转入线粒体进行β-氧化。CPT-1表达或活性下降导致脂肪堆积;脂肪酸在线粒体通过β-氧化分解为乙酰CoA, 转运出线粒体,在胞浆中参与脂质从头合成,合成的丙二酰CoA抑制CPT-1的活性,并且受到AMPK的调节; AMPK活性增加,导致ACC磷酸化而活性下降,丙二酰CoA合成减少,CPT-1的活性增加;AMPK活性降低时,SREBP活性增强,脂类合成(ACC, FAS)和胆固醇合成的相关蛋白和酶类增加,促进脂质和胆固醇合成,导致脂质堆积。PGC-1通过NRF1/2、ERR等转录因子调节线粒体电子传递链的生物合成以及FAO和氧化磷酸化所需酶类;活性增高时,促进CPT-1的表达,FAO增多。

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