The hop constituent xanthohumol exhibits hepatoprotective effects against acute alcohol-induced liver injury

Xanthohumol is the principal prenylated flavonoid of the female inflorescences of the hop plant. It has been shown that XN exhibits beneficial effects in models of non-alcoholic fatty liver disease. Moreover, XN holds promise as a therapeutic agent for treating obesity and diabetes, known to be risk factors for the progression of alcoholic liver disease (ALD). However, XN has not yet been studied in the context of ALD.

The aim of this study was to analyze the effect of XN on acute alcohol mediated hepatocellular injury.

Methods and Results:

For in vitro analysis we treated primary human hepatocytes (PHH) with alcohol concentrations (up to 400 mM) that did not exhibit toxic effect in the presence or absence of XN (5 and 10 µM) for 24h. In this experimental setting, XN dose-dependently inhibited alcohol-induced hepatocellular lipid accumulation. This was accompanied by reduced carnitine palmitoyltransferase I (CPT-1) and acylcoenzyme A oxidase-1 (ACOX1) expression, indicative for reduced mitochondrial and peroxisomal beta-oxidation, which is known to cause reactive oxygen species (ROS) formation. Fitting to this we found that XN also inhibited alcohol induced ROS-formation, HMOX-expression (a marker for oxidative stress), as well as pro-inflammatory (IL-8 and ICAM-1) and pro-fibrogenic (PAI-1) gene expression. Furthermore, XN reduced basal as well as alcohol induced expression of key enzymes of de novo lipogenesis (fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1)) and triglyceride synthesis (diacylglycerol acyltransferase (DGTA2)), which could be an explanation for inhibitory effect on alcohol induced steatosis. Next, we analyzed the effect of a single dose of XN (20 mg/kg BW per gavage) in a mouse model of acute alcohol induced liver injury (6 g alcohol/kg BW per gavage). Analysis of liver tissues 12h after alcohol application revealed that XN significantly inhibited alcohol induced steatosis and inflammation accompanied by reduced CPT-1, ACOX1, HMOX1, FASN and DGTA2 expression.

Conclusion:

Our in vitro and in vivo models indicate the potential of xanthohumol to prevent alcohol induced hepatocellular injury and suggest modulating effects on hepatic lipid metabolisms as potential underlying mechanisms. Together, with previous studies showing the safety of XN-applications in men suggest XN-application as a promising therapeutic strategy, to inhibit the development as well as the progression of ALD particularly in obese drinkers.