title: Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice.
abstract: 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.
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Nabanita
authors.initials: N
authors.lastname: Das
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.|Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Ashok
authors.initials: A
authors.lastname: Mandala
authors.affiliation: Department of Physiology, Oxidative Stress and Free Radical Biology Laboratory, University of Calcutta, University College of Science and Technology, Kolkata, India.
authors.forename: Shamreen
authors.initials: S
authors.lastname: Naaz
authors.affiliation: Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Giri
authors.affiliation: Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India.
authors.forename: Mukul
authors.initials: M
authors.lastname: Jain
authors.affiliation: Department of Physiology, Oxidative Stress and Free Radical Biology Laboratory, University of Calcutta, University College of Science and Technology, Kolkata, India.
authors.forename: Debasish
authors.initials: D
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Centre, San Antonio, TX, USA.
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.|Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Sib Sankar
authors.identifier: http://orcid.org/0000-0002-6117-1546
authors.initials: SS
authors.lastname: Roy
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D059305:Diet, High-Fat / Q000009:adverse effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008550:Melatonin / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000473:pathology*; D017382:Reactive Oxygen Species
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D008550:Melatonin
keywords: fibrogenesis; hepatic steatosis; hepatic stellate cells; hepatocytes; melatonin; mitochondria; palmitate