Protective effects of Iso-Alpha Acids (IAA) on hepatic steatosis, inflammation and fibrosis

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. Recent studies showed that IAA exhibit beneficial effects on glucose and lipid levels in diabetic mice and obese subjects with pre-diabetes. Non-alcoholic fatty liver disease (NAFLD) is considered is the hepatic manifestation of the metabolic syndrome and related metabolic disorders. It starts with hepatocellular lipid accumulation, i.e. steatosis, and a significant number of patients also develops hepatocellular damage and inflammation, i.e. non-alcoholic steatohepatitis (NASH) and progressive fibrosis. The activation of hepatic stellate cells (HSCs) is the key event of hepatic fibrosis, since these cells are the cellular source of excessive extracellular matrix deposition in chronic liver disease including NASH.

The aim of this study was to establish an in vitro models to assess the effect of IAA on lipid accumulation in primary human hepatocytes (PHH) and on primary human HSCs.

Methods and Results: Initially, we determined a dose range in which IAA exhibited no toxic effects on PHH and HSCs (up to 50 µg/ml) as assessed by measurement of XTT activity and LDH in the cell supernatants. Next, to assessed the effect of IAA on hepatocelluar lipid accumulation. For that, PHH were incubated with oleate (up to 0.3 mM) for 24h leading to significant accumulation of cellular free fatty acids (FAA) and triglyceride (TG) levels. The hepatocellular lipid accumulation in PHH was inhibited by IAA in dose-dependent manner. Furthermore, IAA inhibited ROS-formation and pro-inflammatory gene expression (IL-8) induced by cellular lipid accumulation in PHH. Next, we assessed the effects of IAA on HSCs and observed a dose dependant inhibition of the expression of pro-inflammatory (MCP-1 and RANTES) and pro-fibrogenic (TGF-beta, Collagen-I) genes.

Conclusion: Our data indicate a beneficial effect of IAA on hepatic steatosis, inflammation and fibrosis. Together, with previous studies, which revealed a positive influence on further components of the metabolic syndrome and demonstrated the safety of even long term application of IAA in men, our data suggest IAA as promising therapeutic agents for the prevention and treatment of NAFLD since IAA affect different pathological factors of the disease cascade.