Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice
Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice
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DOI：
10.1111/jpi.12404
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发表时间：
2017-05-01
影响因子：
10.3
通讯作者：
Roy, Sib Sankar
中科院分区：
文献类型：
--
作者：
Das, Nabanita;Mandala, Ashok;Roy, Sib Sankar
线粒体分裂导致脂质产生活性氧（ROS），随后炎症传播肝纤维化。 SIRT1/Mitofusin2 的相互作用对于维持线粒体完整性和功能至关重要，在脂肪性肝炎进展过程中，线粒体完整性和功能会因过量脂质浸润而受到破坏。肝星状细胞和脂肪肝细胞之间复杂的相互作用受到细胞外因素的严格调节，包括纤维形成过程中循环游离脂肪酸的增加。褪黑激素是一种有效的抗氧化剂，可防止脂质介导的线粒体 ROS 生成。脂毒性会导致 SIRT1 和 Mitofusin2 相互作用的破坏，导致肝细胞中线粒体形态的崩解。此外，碎片化的线粒体导致线粒体通透性转换孔开放、细胞周期停滞和细胞凋亡，而褪黑激素可以防止所有这些脂毒性介导的功能障碍。这些受损的线粒体动力学还增强了细胞糖酵解通量并降低了线粒体耗氧率，从而增强了 ROS 的产生。高糖酵解通量会在肝细胞中产生不利的代谢环境，导致炎症，而褪黑激素可消除炎症。通过恢复与呼吸链和 TCA 循环相关的酶活性，在高脂饮食 (HFD) 喂养的小鼠中也观察到褪黑素介导的针对线粒体功能障碍的保护作用。随后，褪黑激素减少了高脂饮食小鼠的肝脏脂肪沉积和炎症。因此，褪黑激素破坏脂肪肝细胞和星状细胞之间的相互作用，导致后者被激活，从而消除胶原沉积。总而言之，当前研究的结果表明，低剂量褪黑激素的药理学干预可以消除脂毒性介导的肝星状细胞活化并防止纤维化进展。
Lipid generates reactive oxygen species (ROS) in consequence to mitochondrial fission followed by inflammation in propagating hepatic fibrosis. The interaction of SIRT1/Mitofusin2 is critical for maintaining mitochondrial integrity and functioning, which is disrupted upon excess lipid infiltration during the progression of steatohepatitis. The complex interplay between hepatic stellate cells and steatotic hepatocytes is critically regulated by extracellular factors including increased circulating free fatty acids during fibrogenesis. Melatonin, a potent antioxidant, protects against lipid-mediated mitochondrial ROS generation. Lipotoxicity induces disruption of SIRT1 and Mitofusin2 interaction leading to mitochondrial morphological disintegration in hepatocytes. Further, fragmented mitochondria leads to mitochondrial permeability transition pore opening, cell cycle arrest and apoptosis and melatonin protects against all these lipotoxicity-mediated dysfunctions. These impaired mitochondrial dynamics also enhances the cellular glycolytic flux and reduces mitochondrial oxygen consumption rate that potentiates ROS production. High glycolytic flux generates metabolically unfavorable milieu in hepatocytes leading to inflammation, which is abrogated by melatonin. The melatonin-mediated protection against mitochondrial dysfunction was also observed in high-fat diet (HFD)-fed mice through restoration of enzymatic activities associated with respiratory chain and TCA cycle. Subsequently, melatonin reduces hepatic fat deposition and inflammation in HFD-fed mice. Thus, melatonin disrupts the interaction between steatotic hepatocyte and stellate cells, leading to the activation of the latter to abrogate collagen deposition. Altogether, the results of the current study document that the pharmacological intervention with low dose of melatonin could abrogate lipotoxicity-mediated hepatic stellate cell activation and prevent the fibrosis progression.