Dihydromyricetin Improves Mitochondrial Biogenesis in the Liver of Alcohol Fed Mice via the AMPK/Sirt-1/PGC-1α Signaling Axis.

Alcoholic liver disease (ALD), due to the multifactorial damage associated with alcohol (ethanol/EtOH) consumption and metabolism, is one of the most prevalent liver diseases in the United States. The liver is the primary site of EtOH 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 EtOH 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% EtOH to male C57BL/6J mice over 8 weeks and induced ALD pathology. We found that chronic EtOH feeding resulted in the suppression of AMPK activation and cytoplasmic Sirt1 and mitochondrial Sirt3 expression, effects that were reversed with daily DHM administration (5 mg/kg; i.p.). Chronic EtOH feeding also resulted in hepatic hyperacetylation of PGC-1α, which was improved with DHM administration and its mediated increase of Sirt-1 activity. Furthermore, EtOH-fed mice were found to have increased expression of mitochondrial transcription factor A (TFAM), reduced mitochondrial biogenesis as assessed by mitochondrial DNA to nuclear DNA ratios, and significantly lower levels of hepatic ATP. In contrast, DHM administration significantly increased TFAM expression relative to water and EtOH-fed mice, increased hepatic ATP concentrations, and induced mitochondrial biogenesis. In total, this work demonstrates a novel mechanism of DHM that improves hepatic bioenergetics, metabolic signaling, and mitochondrial biogenesis that supports its utility for treatment of ALD and other metabolic disorders.