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The interaction of <jats:styled-content style=\"fixed-case\">SIRT<\/jats:styled-content>1\/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\u2010mediated mitochondrial <jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content> generation. Lipotoxicity induces disruption of <jats:styled-content style=\"fixed-case\">SIRT<\/jats:styled-content>1 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\u2010mediated dysfunctions. These impaired mitochondrial dynamics also enhances the cellular glycolytic flux and reduces mitochondrial oxygen consumption rate that potentiates <jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content> production. High glycolytic flux generates metabolically unfavorable milieu in hepatocytes leading to inflammation, which is abrogated by melatonin. The melatonin\u2010mediated protection against mitochondrial dysfunction was also observed in high\u2010fat diet (<jats:styled-content style=\"fixed-case\">HFD<\/jats:styled-content>)\u2010fed mice through restoration of enzymatic activities associated with respiratory chain and <jats:styled-content style=\"fixed-case\">TCA<\/jats:styled-content> cycle. Subsequently, melatonin reduces hepatic fat deposition and inflammation in <jats:styled-content style=\"fixed-case\">HFD<\/jats:styled-content>\u2010fed mice. Thus,\u00a0melatonin 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\u2010mediated hepatic stellate cell activation and prevent the fibrosis progression.<\/jats:p>","DOI":"10.1111\/jpi.12404","type":"journal-article","created":{"date-parts":[[2017,3,1]],"date-time":"2017-03-01T07:23:44Z","timestamp":1488353024000},"source":"Crossref","is-referenced-by-count":134,"title":["Melatonin protects against lipid\u2010induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice"],"prefix":"10.1111","volume":"62","author":[{"given":"Nabanita","family":"Das","sequence":"first","affiliation":[{"name":"Cell Biology and Physiology Division CSIR\u2010Indian Institute of Chemical Biology  Kolkata India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok","family":"Mandala","sequence":"additional","affiliation":[{"name":"Cell Biology and Physiology 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