Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Melatonin protects against lipid-induced mitochondrial
dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice
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| Creator |
Das, Nabanita
Mandala, Ashok Naaz, Shamreen Giri, Suresh Jain, Mukul Bandyopadhyay, Debasish Reiter, Russel J Roy, Sib Sankar |
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| Subject |
Cell Biology & Physiology
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| Description |
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 lipidmediated 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
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| Publisher |
Blackwell Publishing
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| Date |
2017-05-09
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2634/1/Das_et_al%2D2017%2DJournal_of_Pineal_Research.pdf
Das, Nabanita and Mandala, Ashok and Naaz, Shamreen and Giri, Suresh and Jain, Mukul and Bandyopadhyay, Debasish and Reiter, Russel J and Roy, Sib Sankar (2017) Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice. Journal Of Pineal Research, 62 (4). 01p.-21p.. |
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| Relation |
https://doi.org/10.1111/jpi.12404
http://www.eprints.iicb.res.in/2634/ |
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