title: Hop bitter acids exhibit anti-fibrogenic effects on hepatic stellate cells in vitro.
abstract: Female inflorescences of the hop plant Humulus lupulus L. contain a variety of secondary metabolites with bitter acids (BA) as quantitatively dominating secondary metabolites. The use of hops in beer brewing has a long history due to the antibacterial effects of the BA and their typical bitter taste. Furthermore, hop cones are used in traditional medicine and for pharmaceutical purposes. Recent studies indicate that BA may affect activity of the transcription factor NFκB. NFκB plays a key role in the activation process of hepatic stellate cells (HSC), which is the key event of hepatic fibrosis. The aim of this study was to investigate the effect of BA on HSC (activation) and their potential to inhibit molecular processes involved in the pathogenesis of hepatic fibrosis. HSC were isolated from murine and human liver tissue and incubated with a characterized fraction of bitter acids purified from a CO(2) hop extract. At a concentration of 25μg/ml BA started to induce LDH leakage. Already at lower concentrations BA lead to a dose dependent inhibition of HSC proliferation and inhibited IκB-α-phosphorylation, nuclear p65 translocation and binding activity in a dose dependent way (up to 10μg/ml). Accordingly, the same BA-doses inhibited the expression of pro-inflammatory and NFκB regulated genes as MCP-1 and RANTES, but did not affect expression of genes not related to NFκB signaling. In addition to the effect on activated HSC, BA inhibited the in vitro activation process of freshly isolated HSC as evidenced by delayed expression of collagen I and α-SMA mRNA and protein. Together, these findings indicate that BA inhibit NFκB activation, and herewith the activation and development of profibrogenic phenotype of HSC. Thus, bitter acids appear as potential functional nutrients for the prevention or treatment hepatic fibrosis in chronic liver disease.
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Saugspier
authors.forename: Christoph
authors.initials: C
authors.lastname: Dorn
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
authors.forename: Manfred
authors.initials: M
authors.lastname: Gehrig
authors.forename: Jörg
authors.initials: J
authors.lastname: Heilmann
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
mesh_terms: D000143:Acids / Q000494:pharmacology*; D000199:Actins / Q000096:biosynthesis; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D024042:Collagen Type I / Q000096:biosynthesis; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D006801:Humans; D027582:Humulus / Q000737:chemistry* / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C541116:ACTA2 protein, human; D000143:Acids; D000199:Actins; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D024042:Collagen Type I; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C544013:alpha-smooth muscle actin, mouse; D000072000:NF-KappaB Inhibitor alpha