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Iso-alpha acids from hops (Humulus lupulus) inhibit hepatic steatosis, inflammation, and fibrosis

Laboratory Investigationvolume 98pages16141626 (2018) | Download Citation


Non-alcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of the metabolic syndrome. Iso-alpha acids (IAAs), hop-derived bitter compounds in beer, have been shown to beneficially affect different components of the metabolic syndrome such as insulin resistance and dyslipidemia. However, IAAs have not yet been studied in the context of chronic liver disease. Here we analyzed the effect of IAA on the pathogenesis of NAFLD. Once, we applied IAA to mice in combination with a NAFLD-inducing Western-type diet (WTD), and observed that IAA significantly inhibited WTD-induced body weight gain, glucose intolerance, and hepatic steatosis. Fitting to this, IAA dose-dependently inhibited cellular lipid accumulation in primary human hepatocytes (PHH) in vitro. 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 of reduced hepatocellular steatosis in vitro and in vivo. Analysis of hepatic HMOX1 expression indicated reduced oxidative stress in IAA-treated mice, which was paralleled by reduced activation of the JNK pathway and pro-inflammatory gene expression and immune cell infiltration. Furthermore, IAA reduced hepatic stellate cell (HSC) activation and pro-fibrogenic gene expression. Similarly, IAA also dose-dependently reduced oxidative stress and JNK activation in steatotic PHH, inhibited HSC activation, and reduced proliferation and pro-fibrogenic gene expression in already activated HSC in vitro. In conclusion, IAAs inhibit different pathophysiological steps of disease progression in NAFLD. Together with previous studies, which demonstrated the safety of even long-term application of IAA in humans, our data suggest IAA as promising therapeutic agent for the prevention and treatment of (non)alcoholic (fatty) liver disease.

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This work was supported by a grant from the “Wissenschaftsförderung der Deutschen Brauwirtschaft e.V.” (Berlin, Germany) (Project No R437) to CH. CH and AB are supported by the German Research Foundation (FOR 2127 and KFO262). We want to thank Rudolf Jung for excellent technical assistance. We acknowledge the Human Tissue and Cell Research (HTCR) Foundation for making human tissue available for research and Hepacult GmbH (Regensburg, Germany) for providing PHH for in vitro studies.

Author contributions

AM and CH designed the study. AM, AK and KM performed the experiments. TS, WET, CS and AB provided material. IB and AB provided technical support. AM and CH wrote the manuscript.

Author information


  1. Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany

    • Abdo Mahli
    • , Andreas Koch
    • , Kim Fresse
    • , Anja Bosserhoff
    •  & Claus Hellerbrand
  2. Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany

    • Abdo Mahli
    • , Andreas Koch
    •  & Claus Hellerbrand
  3. Biobank o.b. HTCR, Department of General Visceral and Transplantation Surgery, Ludwig-Maximilians-University Munich, Munich, Germany

    • Tobias Schiergens
    •  & Wolfgang Erwin Thasler
  4. Joh Barth & Sohn GmbH & Co. KG, Nürnberg, Germany

    • Christina Schönberger
  5. Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria

    • Ina Bergheim


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Conflict of interest

CH was consultant of Joh. Barth & Sohn GmbH, and AM, AK, and KF are working in the laboratory of CH. CS is employee of the Joh. Barth & Sohn GmbH. IB received funding for a research project from Yakult Ltd. All authors had complete and independent control over the study design, analysis and interpretation of data, report writing, and publication, regardless of results.

Corresponding author

Correspondence to Claus Hellerbrand.

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