@article{RaselliHearnWyssetal.2019,
  author    = {Raselli, Tina and Hearn, Tom and Wyss, Annika and Atrott, Kirstin and Peter, Alain and Frey-Wagner, Isabelle and Spalinger, Marianne R. and Maggio, Ewerton M. and Sailer, Andreas W. and Schmitt, Johannes and Schreiner, Philipp and Moncsek, Anja and Mertens, Joachim and Scharl, Michael and Griffiths, William J. and Bueter, Marco and Geier, Andreas and Rogler, Gerhard and Wang, Yuqin and Misselwitz, Benjamin},
  title     = {Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis},
  series = {Journal of Lipid Research},
  volume    = {60},
  journal   = {Journal of Lipid Research},
  number    = {7},
  doi       = {10.1194/jlr.M093229},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225004},
  pages     = {1270-1283},
  year      = {2019},
  abstract  = {Nonalcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2) and its oxysterol ligand 7 alpha,25-dihydroxycholesterol (7 alpha,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in the livers of NASH patients by LC-MS and tested the role of the EBI2-7 alpha,25-diHC system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared with controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype-related differences were observed in Ebi2(-/-) mice and mice with defects in the 7 alpha,25-diHC synthesizing enzymes CH25H and CYP7B1 compared with wild-type littermate controls, arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by the enhanced level of 7 alpha-hydroxycholest-4-en-3-one and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.},
  language  = {en}
}
@article{RobertsonHsiehForsteretal.2016,
  author    = {Robertson, Kevin A. and Hsieh, Wei Yuan and Forster, Thorsten and Blanc, Mathieu and Lu, Hongjin and Crick, Peter J. and Yutuc, Eylan and Watterson, Steven and Martin, Kimberly and Griffiths, Samantha J. and Enright, Anton J. and Yamamoto, Mami and Pradeepa, Madapura M. and Lennox, Kimberly A. and Behlke, Mark A. and Talbot, Simon and Haas, J{\"u}rgen and D{\"o}lken, Lars and Griffiths, William J. and Wang, Yuqin and Angulo, Ana and Ghazal, Peter},
  title     = {An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway},
  series = {PLoS Biology},
  volume    = {14},
  journal   = {PLoS Biology},
  number    = {3},
  doi       = {10.1371/journal.pbio.1002364},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166666},
  pages     = {e1002364},
  year      = {2016},
  abstract  = {In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of newly transcribed RNA and pri/pre-miRNA in IFN-activated macrophages, we identify a new post-transcriptional viral defense mechanism mediated by miR-342-5p. On the basis of ChIP and site-directed promoter mutagenesis experiments, we find the synthesis of miR-342-5p is coupled to the antiviral IFN response via the IFN-induced transcription factor, IRF1. Strikingly, we find miR-342-5p targets mevalonate-sterol biosynthesis using a multihit mechanism suppressing the pathway at different functional levels: transcriptionally via SREBF2, post-transcriptionally via miR-33, and enzymatically via IDI1 and SC4MOL. Mass spectrometry-based lipidomics and enzymatic assays demonstrate the targeting mechanisms reduce intermediate sterol pathway metabolites and total cholesterol in macrophages. These results reveal a previously unrecognized mechanism by which IFN regulates the sterol pathway. The sterol pathway is known to be an integral part of the macrophage IFN antiviral response, and we show that miR-342-5p exerts broad antiviral effects against multiple, unrelated pathogenic viruses such Cytomegalovirus and Influenza A (H1N1). Metabolic rescue experiments confirm the specificity of these effects and demonstrate that unrelated viruses have differential mevalonate and sterol pathway requirements for their replication. This study, therefore, advances the general concept of broad antiviral defense through multihit targeting of a single host pathway.},
  language  = {en}
}