{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T04:14:46Z","timestamp":1791000886182,"version":"4.1.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","license":[{"start":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T00:00:00Z","timestamp":1595980800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatol. Commun."],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:p>Myeloperoxidase (MPO) activity has been associated with the metabolic syndrome, cardiovascular and liver disease. Here, we evaluate the therapeutic potential of MPO inhibition on nonalcoholic steatohepatitis (NASH) and NASH\u2010induced fibrosis, the main determinant of outcomes. MPO plasma levels were elevated in patients with nonalcoholic fatty liver disease (NAFLD) compared with healthy controls. In a second cohort, hepatic <jats:italic toggle=\"yes\">MPO<\/jats:italic> messenger RNA expression correlated with higher body mass index and hemoglobin A1c, both being risk factors for NAFLD. We could establish by immunohistochemistry that MPO\u2010positive cells were recruited to the liver in various mouse models of fibrogenic liver injury, including bile duct ligation, carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>) treatment, spontaneous liver fibrogenesis in multidrug resistance 2 knockout (MDR2 KO) mice, and NASH\u2010inducing diet. Comparison of MPO\u2010deficient mice and their wild\u2010type littermates exposed to a high\u2010caloric diet revealed that MPO deficiency protects against NASH\u2010related liver injury and fibrosis. In line with this, hepatic gene expression analysis demonstrated a MPO\u2010dependent activation of pathways relevant for wound healing, inflammation, and cell death in NASH. MPO deficiency did not affect NAFLD\u2010independent liver injury and fibrosis in MDR2 KO or CCl<jats:sub>4<\/jats:sub>\u2010treated mice. Finally, we treated wild\u2010type mice exposed to NASH\u2010inducing diet with an oral MPO inhibitor. Pharmacological MPO inhibition not only reduced markers of MPO\u2010mediated liver damage, serum alanine aminotransferase levels, and hepatic steatosis, but also significantly decreased NASH\u2010induced liver fibrosis. MPO inhibitor treatment, but not MPO deficiency, significantly altered gut microbiota including a significant expansion of <jats:italic toggle=\"yes\">Akkermansia muciniphila<\/jats:italic>. <jats:italic toggle=\"yes\">Conclusions:<\/jats:italic> MPO specifically promotes NASH\u2010induced liver fibrosis. Pharmacological MPO inhibition attenuates NASH progression and NASH\u2010induced liver fibrosis in mice and is associated with beneficial changes of intestinal microbiota.<\/jats:p>","DOI":"10.1002\/hep4.1566","type":"journal-article","created":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T18:36:57Z","timestamp":1596047817000},"page":"1441-1458","source":"Crossref","is-referenced-by-count":48,"title":["Therapeutic Targeting of Myeloperoxidase Attenuates NASH in Mice"],"prefix":"10.1097","volume":"4","author":[{"given":"Anja Christina","family":"Koop","sequence":"first","affiliation":[{"name":"1st Department of Medicine,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina Doreen","family":"Thiele","sequence":"additional","affiliation":[{"name":"1st Department of Medicine,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Steins","sequence":"additional","affiliation":[{"name":"1st Department of Medicine,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Micha\u00eblsson","sequence":"additional","affiliation":[{"name":"Bioscience Cardiovascular, Research and Early Development,Cardiovascular, Renal and Metabolism,BioPharmaceuticals R&D,AstraZeneca,Gothenburg,Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Wehmeyer","sequence":"additional","affiliation":[{"name":"1st Department of Medicine,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludger","family":"Scheja","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Cell Biology,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Babett","family":"Steglich","sequence":"additional","affiliation":[{"name":"1st Department of Medicine,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"},{"name":"Department of General, Internal and Thoracic Surgery,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Huber","sequence":"additional","affiliation":[{"name":"1st Department of Medicine,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Schulze zur Wiesch","sequence":"additional","affiliation":[{"name":"1st Department of Medicine,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ansgar W.","family":"Lohse","sequence":"additional","affiliation":[{"name":"1st Department of Medicine,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Heeren","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Cell Biology,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Kluwe","sequence":"additional","affiliation":[{"name":"1st Department of Medicine,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2020,7,29]]},"reference":[{"key":"hep41566-bib-0001-20240114","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic 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