Dihydromyricetin improves mitochondrial outcomes in the liver of alcohol-fed mice via the AMPK/Sirt-1/PGC-1α signaling axis.

Abstract

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 (5mg/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.