Iso-Alpha Acids (IAA) from hops (Humulus lupulus) inhibit hepatic steatosis, inflammation and fibrosis

Chronic alcohol consumption is one of the leading causes of liver disease world-wide. Epidemiological and animal studies indicate that in addition to the amount of alcohol also the type of consumed alcoholic beverages impacts liver injury with beer being less harmful for the liver than intake of spirits. Iso-alpha-acids (IAA), the main bitter acids present in hops, are constituted during wort boiling with hop, thereby providing beer with its typical bitter taste and foam stability.

The aim of this study was to analyze whether IAA beneficially affect the pathogenesis of alcoholic or non-alcoholic (fatty) liver disease.

Methods: IAA were applied to mice in combination with different models of liver injury: (i) high fat, non-alcoholic steatohepatitis (NASH) inducing diet (HFD) in mice, (ii) combined HFD and alcohol application to mice, and (iii) toxic liver injury induced with CCl4 in rats. Furthermore, IAA effects on primary human hepatocytes (PHH) and hepatic stellate cells (HSC) were analyzed in vitro.

Results: IAA significantly reduced HFD or HFD/alcohol induced hepatic steatosis. Reduced expression of PPAR-gamma and key enzymes of lipid synthesis as well as increased expression of PPAR-alpha, indicative for increased lipid combustion, were identified as underlying mechanisms. Analysis of hepatic HMOX1 expression and MDA levels showed reduced oxidative stress in IAA treated mice, which was paralleled by reduced serum transaminase levels, reduced activation of the JNK-pathway and pro-inflammatory gene expression and immune cell infiltration, as well as reduced HSC activation and profibrogenic gene expression. Fitting to this, IAA dose-dependently inhibited cellular lipid accumulation, PPAR-gamma expression and oxidative stress in PHH in an in vitro model of hepatic steatosis. Furthermore, IAA inhibited HSC activation as well as proinflammatory and profibrogenic gene expression in already activated HSC in vitro. Also in the CCl4 model, IAA significantly inhibited cellular damage, oxidative stress, inflammation and fibrosis.

Conclusion: IAA inhibit different pathophysiological steps of disease progression in various models of chronic liver disease. IAA content in beer may explain why it is less harmful for the liver compared to pure alcohol, but certainly, alcohol content in beer surpasses the beneficial IAA effect. However, together with previous studies, which demonstrated the safety of even long term application of IAA in men, our data suggest IAA as promising therapeutic agent for the prevention and treatment of (non)alcoholic (fatty) liver disease.