Protection of nicotinic acid against oxidative stress-induced cell death in hepatocytes contributes to its beneficial effect on alcohol-induced liver injury in mice.
Protection of nicotinic acid against oxidative stress-induced cell death in hepatocytes contributes to its beneficial effect on alcohol-induced liver injury in mice.
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DOI：
10.1016/j.jnutbio.2012.12.012
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发表时间：
2013-08
期刊：
影响因子：
--
通讯作者：
Song Z
中科院分区：
文献类型：
--
作者：
Dou X;Shen C;Wang Z;Li S;Zhang X;Song Z
氧化应激在酒精性肝病的发展中起着病理作用。在这项研究中，我们研究了烟酸（NA）补充对H2O2诱导的肝细胞死亡和酒精诱导的小鼠肝损伤的影响。用NA（0 - 100 µ M）预处理2小时后，将肝细胞暴露于H2O2（0 - 0.4 mM）16小时。测定细胞活力、细胞内谷胱甘肽和总NAD含量。在动物实验中，雄性C57 BL/6小鼠暴露于Lieber-De Carli液体饮食（+/−乙醇，含/不含NA补充剂（0.5%，w/v））4周。烟酸磷酸核糖转移酶（NaPRT）是参与NA代谢的第一个酶，将NA转化为烟酸单核苷酸（NaMN）。在NaPRT表达的Hep3B细胞中，NA可减弱H2O2诱导的细胞死亡，而在NaPRT缺失的HepG2细胞中，只有NaMN具有保护作用，这表明NA代谢是其对H2O2的保护作用所必需的。在Hep3B细胞中，NA补充防止H2O2诱导的细胞内总NAD和GSH/GSSG比率的下降。进一步的机制研究表明，Akt活性的保护有助于NA对H2O2诱导的细胞死亡的保护作用。在酒精喂养的小鼠中，补充NA可减轻慢性酒精暴露引起的肝损伤，这与减轻肝脏脂质过氧化和增加肝脏GSH浓度有关。总之，我们的研究结果表明，外源性NA补充可能是一个理想的选择，用于治疗肝脏疾病涉及氧化应激。
Oxidative stress plays a pathological role in the development of alcoholic liver disease. In this study, we investigated the effects of nicotinic acid (NA) supplementation on H2O2-induced cell death in hepatocytes and alcohol-induced liver injury in mice. Hepatocytes were exposed to H2O2 (0–0.4 mM) for 16 hours after a 2-hour pretreatment with NA (0–100 µM). Cell viability, intracellular glutathione and total NAD contents were determined. In animal experiments, male C57 BL/6 mice were exposed to Lieber-De Carli liquid diet (+/− ethanol with/without NA supplementation (0.5%, w/v) for 4 weeks. Nicotinic acid phosphoribosyltransferase (NaPRT) is the first enzyme participated in the NA metabolism, converting NA to nicotinic acid mononucleotide (NaMN). In NaPRT-expressing Hep3B cells, H2O2-induced cell death was attenuated by NA, whereas in NaPRT-lost HepG2 cells, only NaMN conferred protective effect, suggesting that NA metabolism is required for its protective action against H2O2. In Hep3B cells, NA supplementation prevented H2O2-inudced declines in intracellular total NAD and GSH/GSSG ratios. Further mechanistic investigations revealed that conservation of Akt activity contributed to NA’s protective effect against H2O2-inudced cell death. In alcohol-fed mice, NA supplementation attenuated liver injury induced by chronic alcohol exposure, which was associated with alleviated hepatic lipid peroxidation and increased liver GSH concentrations. In conclusion, our findings indicate that exogenous NA supplementation may be an ideal choice for the treatment of liver diseases involved oxidative stress.