@article{ZimnyKoobLietal.2022,
  author    = {Zimny, Sebastian and Koob, Dennis and Li, Jingguo and Wimmer, Ralf and Schiergens, Tobias and Nagel, Jutta and Reiter, Florian Paul and Denk, Gerald and Hohenester, Simon},
  title     = {Hydrophobic bile salts induce pro-fibrogenic proliferation of hepatic stellate cells through PI3K p110 alpha signaling},
  series = {Cells},
  volume    = {11},
  journal   = {Cells},
  number    = {15},
  issn      = {2073-4409},
  doi       = {10.3390/cells11152344},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281806},
  year      = {2022},
  abstract  = {Bile salts accumulating during cholestatic liver disease are believed to promote liver fibrosis. We have recently shown that chenodeoxycholate (CDC) induces expansion of hepatic stellate cells (HSCs) in vivo, thereby promoting liver fibrosis. Mechanisms underlying bile salt-induced fibrogenesis remain elusive. We aimed to characterize the effects of different bile salts on HSC biology and investigated underlying signaling pathways. Murine HSCs (mHSCs) were stimulated with hydrophilic and hydrophobic bile salts. Proliferation, cell mass, collagen deposition, and activation of signaling pathways were determined. Activation of the human HSC cell line LX 2 was assessed by quantification of α-smooth muscle actin (αSMA) expression. Phosphatidyl-inositol-3-kinase (PI3K)-dependent signaling was inhibited both pharmacologically and by siRNA. CDC, the most abundant bile salt accumulating in human cholestasis, but no other bile salt tested, induced Protein kinase B (PKB) phosphorylation and promoted HSC proliferation and subsequent collagen deposition. Pharmacological inhibition of the upstream target PI3K-inhibited activation of PKB and pro-fibrogenic proliferation of HSCs. The PI3K p110α-specific inhibitor Alpelisib and siRNA-mediated knockdown of p110α ameliorated pro-fibrogenic activation of mHSC and LX 2 cells, respectively. In summary, pro-fibrogenic signaling in mHSCs is selectively induced by CDC. PI3K p110α may be a potential therapeutic target for the inhibition of bile salt-induced fibrogenesis in cholestasis.},
  language  = {en}
}
@article{HohenesterKanitzSchiergensetal.2020,
  author    = {Hohenester, Simon and Kanitz, Veronika and Schiergens, Tobias and Einer, Claudia and Nagel, Jutta and Wimmer, Ralf and Reiter, Florian P. and Gerbes, Alexander L. and De Toni, Enrico N. and Bauer, Christian and Holdt, Lesca and Mayr, Doris and Rust, Christian and Schnurr, Max and Zischka, Hans and Geier, Andreas and Denk, Gerald},
  title     = {IL-18 but not IL-1 signaling is pivotal for the initiation of liver injury in murine non-alcoholic fatty liver disease},
  series = {International Journal of Molecular Sciences},
  volume    = {21},
  journal   = {International Journal of Molecular Sciences},
  number    = {22},
  issn      = {1422-0067},
  doi       = {10.3390/ijms21228602},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285221},
  year      = {2020},
  abstract  = {Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life "American lifestyle-induced obesity syndrome" (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r\(^{-/-}\)- but not Il-1r\(^{-/-}\) mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.},
  language  = {en}
}