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Dihydromyricetin improves mitochondrial outcomes in the liver of alcohol-fed mice via the AMPK/Sirt-1/PGC-1α signaling axis
Alcohol ( IF 2.5 ) Pub Date : 2020-10-17 , DOI: 10.1016/j.alcohol.2020.10.002
Joshua Silva 1 , Maximilian H Spatz 1 , Carson Folk 1 , Arnold Chang 1 , Enrique Cadenas 1 , Jing Liang 1 , Daryl L Davies 1
Affiliation  

Alcoholic liver disease (ALD), due to the multifactorial damage associated with alcohol (ethanol) consumption and metabolism, is one of the most prevalent liver diseases in the United States. The liver is the primary site of ethanol metabolism and is subsequently injured due to the production of reactive oxygen species (ROS), acetaldehyde, and metabolic stress. Building evidence suggests that dihydromyricetin (DHM), a bioactive flavonoid isolated from Hovenia dulcis, provides hepatoprotection by enhancing ethanol metabolism in the liver by maintaining hepatocellular bioenergetics, reductions of oxidative stress, and activating lipid oxidation pathways. The present study investigates the utility of DHM on hepatic mitochondrial biogenesis via activation of the AMP-activated protein kinase (AMPK)/Sirtuin (Sirt)-1/PPARG coactivator 1 (PGC)-1α signaling pathway. We utilized a forced drinking ad libitum study that chronically fed 30% ethanol to male C57BL/6J mice over 8 weeks and induced ALD pathology. We found that chronic ethanol feeding resulted in the suppression of AMPK activation and cytoplasmic Sirt-1 and mitochondrial Sirt-3 expression, effects that were reversed with daily DHM administration (5 mg/kg; intraperitoneally [i.p.]). Chronic ethanol feeding also resulted in hepatic hyperacetylation of PGC-1α, which was improved with DHM administration and its mediated increase of Sirt-1 activity. Furthermore, ethanol-fed mice were found to have increased expression of mitochondrial transcription factor A (TFAM), reduced mitochondrial content as assessed by mitochondrial DNA to nuclear DNA ratios, and significantly lower levels of hepatic ATP. In contrast, DHM administration significantly increased TFAM expression, hepatic ATP concentrations, and induced mitochondrial expression of respiratory complex III and V. In total, this work demonstrates a novel mechanism of DHM that improves hepatic bioenergetics, metabolic signaling, and mitochondrial viability, thus adding to the evidence supporting the use of DHM for treatment of ALD and other metabolic disorders.



中文翻译:

二氢杨梅素通过 AMPK/Sirt-1/PGC-1α 信号轴改善酒精喂养小鼠肝脏的线粒体结果

酒精性肝病 (ALD) 是由于与酒精(乙醇)消耗和代谢相关的多因素损害,是美国最普遍的肝病之一。肝脏是乙醇代谢的主要场所,随后由于产生活性氧 (ROS)、乙醛和代谢应激而受到损伤。有证据表明,二氢杨梅素 (DHM) 是一种从枳椇中分离出的具有生物活性的类黄酮,通过维持肝细胞生物能量、减少氧化应激和激活脂质氧化途径来增强肝脏中的乙醇代谢,从而提供肝保护。本研究通过激活 AMP 活化蛋白激酶 (AMPK)/Sirtuin (Sirt)-1/PPARG coactivator 1 (PGC)-1α 信号通路,研究 DHM 在肝线粒体生物合成中的效用。我们使用了强迫饮酒随意研究表明,在 8 周内向雄性 C57BL/6J 小鼠长期喂食 30% 乙醇并诱导 ALD 病理。我们发现慢性乙醇喂养导致 AMPK 活化和细胞质 Sirt-1 和线粒体 Sirt-3 表达的抑制,这些效果通过每日 DHM 给药(5 mg/kg;腹膜内 [ip])逆转。慢性乙醇喂养还导致 PGC-1α 的肝脏过度乙酰化,这随着 DHM 给药及其介导的 Sirt-1 活性增加而得到改善。此外,发现乙醇喂养的小鼠线粒体转录因子 A (TFAM) 的表达增加,通过线粒体 DNA 与核 DNA 比率评估的线粒体含量降低,肝脏 ATP 水平显着降低。相反,DHM 给药显着增加了 TFAM 表达、肝 ATP 浓度、

更新日期:2020-11-15
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