title: Nitric oxide, can it be only good? Increasing the antioxidant properties of nitric oxide in hepatocytes by YC-1 compound.
abstract: The aim of the study was to evaluate the effect of Nitric oxide (NO) on redox changes and fat accumulation in hepatocytes. AML-12 hepatocytes were exposed to the NO donor Diethylenetriamine-NONOate (DETA-NO). DETA-NO led to a dose- and time-dependent increase in lipid accumulation in the cells, measured by Nile red fluorescence. Exposure of the cells to 1mM DETA-NO for 24h increased reactive oxygen species production, mainly peroxides. At the same time, NO induced elevation of reduced glutathione (GSH) and a mild activation of the antioxidant transcription factors Hypoxia-inducible factor 1α (HIF1α) and NF-E2 related factor 2 (Nrf-2). We used 100 μM YC-1 to inhibit HIF1α activity and induce activation of soluble Guanylate Cyclase (sGC). YC-1 alone did not affect fat accumulation, and only moderately increased the expression of Nrf-2-targeted genes Heme oxygenase 1 (Hmox1), NAD(P)H dehydrogenase (quinone 1) (Nqo1) and Glutathione S-transferase α1 (Gstα1). However, YC-1 abolished the negative effect of NO on fat accumulation when administered together. Strikingly, YC-1 potentiated the effect of NO on Nrf-2 activation, thus increasing dramatically the antioxidant properties of NO. Moreover, YC-1 intensified the effect of NO on the expression of peroxisome-proliferator-activated receptor-gamma co-activator 1α (PGC1α) and mitochondrial biogenesis markers. This study suggests that YC-1 may shift the deleterious effects of NO into the beneficial ones, and may improve the antioxidant properties of NO.
authors.affiliation: The School of Nutritional Sciences, Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Aharoni-Simon
authors.forename: Sarit
authors.initials: S
authors.lastname: Anavi
authors.forename: Uwe
authors.initials: U
authors.lastname: Beifuss
authors.forename: Zecharia
authors.initials: Z
authors.lastname: Madar
authors.forename: Oren
authors.initials: O
authors.lastname: Tirosh
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009603:Nitroso Compounds / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D007191:Indazoles; D051267:NF-E2-Related Factor 2; D009603:Nitroso Compounds; D016211:Transforming Growth Factor alpha; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009569:Nitric Oxide; D051547:Heme Oxygenase-1; D005978:Glutathione