Titus Family Department of Clinical Pharmacy, University of Southern, California School of Pharmacy, Los Angeles, CA, United States.
Titus Family Department of Clinical Pharmacy, University of Southern, California School of Pharmacy, Los Angeles, CA, United States.
Alcohol. 2021 Mar;91:1-9. doi: 10.1016/j.alcohol.2020.10.002. Epub 2020 Oct 17.
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.
酒精性肝病（ALD）是由于与酒精（乙醇）消耗和代谢相关的多种因素引起的，是美国最常见的肝脏疾病之一。肝脏是乙醇代谢的主要部位，由于活性氧（ROS）、乙醛和代谢应激的产生，肝脏随后受到损伤。越来越多的证据表明，二氢杨梅素（DHM）是从枳椇子中分离出来的一种生物活性类黄酮，通过维持肝细胞生物能量学、减少氧化应激和激活脂质氧化途径，增强肝脏乙醇代谢，提供肝脏保护作用。本研究通过激活 AMP 激活蛋白激酶（AMPK）/沉默调节蛋白（Sirt）-1/过氧化物酶体增殖物激活受体共激活因子 1（PGC）-1α信号通路，研究 DHM 对肝线粒体生物发生的作用。我们利用强制自由饮酒研究，用 30%乙醇连续喂养雄性 C57BL/6J 小鼠 8 周，诱导 ALD 病理。我们发现，慢性乙醇喂养导致 AMPK 激活和细胞质 Sirt-1 和线粒体 Sirt-3 表达受到抑制，这些作用在每天给予 DHM 治疗（5mg/kg；腹腔内[ip.])时得到逆转。慢性乙醇喂养还导致 PGC-1α的肝乙酰化增加，DHM 治疗及其介导的 Sirt-1 活性增加改善了这种情况。此外，发现乙醇喂养的小鼠线粒体转录因子 A（TFAM）表达增加，线粒体 DNA 与核 DNA 比值评估的线粒体含量减少，肝 ATP 水平显著降低。相比之下，DHM 治疗显著增加了 TFAM 表达、肝 ATP 浓度，并诱导呼吸复合物 III 和 V 的线粒体表达。总的来说，这项工作证明了 DHM 的一种新机制，该机制可改善肝脏生物能量学、代谢信号和线粒体活力，从而为支持 DHM 治疗 ALD 和其他代谢紊乱提供了更多证据。
