Dihydromyricetin (DHM) Increases Lipid Clearance and Mitochondrial Function in Mice Exposed to Long-Term Ethanol Consumption

Alcohol-associated liver disease (ALD) is one of the most prevalent liver diseases in the United States and is caused by long-term, heavy alcohol consumption. ALD is characterized by three major stages, progressing from steatosis to steatohepatitis/fibrosis, to finally cirrhosis, an end-stage liver disease. Unfortunately, there are no effective treatments for ALD besides abstinence, or in extreme cases, a liver transplant. Corticosteroids can be used to treat hepatic inflammation associated with steatohepatitis, but long-term use is associated with adverse side effects and risk of infection. The lack of effective ALD pharmacotherapies necessitates the need for novel therapeutics. Dihydromyricetin (DHM) is a bioactive flavonoid derived from a variety of plants, particularly Holvenia dulcis, that has demonstrated anti-alcohol effects. Chronic alcohol consumption has been shown to induce dyslipidemia and impair mitochondrial health. Promising evidence has shown that DHM produces hepatoprotective effects. In this study, we demonstrate the effect of DHM on lipid droplet accumulation and mitochondrial function. Mitochondrial proliferation and increased activity of critical enzymes involved in mitophagy can regulate healthy mitochondria function. Using an established ALD mouse model, the Lieber DeCarli diet, we measured the effect of DHM supplementation on mitochondrial health and lipid clearance. We observed and quantified the changes in lipid size and concentration and found that DHM supplementation led to an increase in lipid droplet clearance and heterogeneity. In addition, we looked at mitochondrial health and proteins associated with mitophagy. With this evidence, we determined that DHM supplementation improved mitochondrial metabolic function, with data suggesting an increase in mitophagy. Taken together, this data demonstrates that DHM can increase lipid clearance and mitochondrial efficiency as demonstrated by a decrease in lipid count and improved metabolic function and health. This evidence will support future research investigating DHM as a promising therapeutic to treat ALD by providing insight into DHM’s role in mitigating mitochondrial damage and hepatic lipid accumulation.