title: Melatonin protects hepatocytes against bile acid-induced mitochondrial oxidative stress via the AMPK-SIRT3-SOD2 pathway.
abstract: Mitochondrial oxidative damage is hypothesized to contribute to the pathogenesis of chronic cholestatic liver diseases. Melatonin, an indolamine synthesized in the pineal gland, shows a wide range of physiological functions, and is under clinical investigation for expanded applications. Melatonin has demonstrated efficient protective effects against various types of oxidative damage in the liver system. This study investigates the protective effects of melatonin pretreatment on glycochenodeoxycholic acid (GCDCA)-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. Melatonin markedly decreased mitochondrial ROS (mROS) production in L02 cells treated with 100 μM GCDCA, and inhibited GCDCA-stimulated cytotoxicity. Notably, melatonin exerted its hepatoprotective effects by upregulating sirtuin 3 (SIRT3) activity and its expression level, thus regulating superoxide dismutase 2 (SOD2) acetylation and inhibiting the production of mROS induced by GCDCA. Moreover, siRNA targeting SIRT3 blocked the melatonin-mediated elevation in mitochondrial function by inhibiting SIRT3/SOD2 signaling. Importantly, melatonin-activated SIRT3 activity was completely abolished by AMP-activated, alpha 1 catalytic subunit (AMPK) siRNA transfection. Similar results were obtained in rat with bile duct ligation or BDL. In summary, our findings indicate that melatonin is a novel hepatoprotective small molecule that functions by elevating SIRT3, stimulating SOD2 activity, and suppressing mitochondrial oxidative stress at least through AMPK, and that SIRT3 may be of therapeutic value in liver cell protection for GCDCA-induced hepatotoxicity.
authors.affiliation: a Department of Hepatobiliary Surgery , Fuzhou General Hospital , Fuzhou , China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: W
authors.initials: W
authors.lastname: Qing
authors.forename: M
authors.initials: M
authors.lastname: Sun
authors.forename: L
authors.initials: L
authors.lastname: Lv
authors.forename: D
authors.initials: D
authors.lastname: Guo
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000107:Acetylation; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005999:Glycochenodeoxycholic Acid / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D056566:Sirtuin 3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013482:Superoxide Dismutase / Q000502:physiology*; D000099156:Superoxide Dismutase 2
chemical_list: D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate; D005999:Glycochenodeoxycholic Acid; D008550:Melatonin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D056566:Sirtuin 3; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C466093:SIRT3 protein, human
keywords: AMPK; GCDCA; SIRT3; SOD2; hepatotoxicity; mitochondrial ROS