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Hepatic fibrosis can also develop from metabolic liver disease, such as nonalcoholic fatty liver disease (NASH). We investigated the role of MIF in high\u2010fat or methionine\u2010 and choline\u2010deficient diet mouse models of NASH.\n                    <jats:italic>Mif<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice showed elevated liver triglyceride levels (WT, 53\u00b114 mg\/g liver;\n                    <jats:italic>Mif<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    , 103\u00b17 mg\/g liver;\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.05) and a 2\u20103\u2010fold increased expression of lipogenic genes. Increased fatty degeneration in the livers of\n                    <jats:italic>Mif<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice was associated with increased hepatic inflammatory cells (1.6\u2010fold increase in F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    macrophages) and proinflammatory cytokines (\n                    <jats:italic>e.g.<\/jats:italic>\n                    , 2.3\u2010fold increase in\n                    <jats:italic>Tnf\u2010\u03b1<\/jats:italic>\n                    and 2\u2010fold increase in\n                    <jats:italic>Il\u20106<\/jats:italic>\n                    expression). However, inflammatory cells and cytokines were decreased by 50\u201090% in white adipose tissue (WAT) of\n                    <jats:italic>Mif<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice. Subset analysis showed that macrophage phenotypes in livers of\n                    <jats:italic>Mif<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice were skewed toward M2 (\n                    <jats:italic>e.g.<\/jats:italic>\n                    , 1.7\u2010fold and 2.5\u2010fold increase in\n                    <jats:italic>Arg1<\/jats:italic>\n                    and\n                    <jats:italic>Il\u201013<\/jats:italic>\n                    , respectively, and 2.5\u2010fold decrease in\n                    <jats:italic>iNos<\/jats:italic>\n                    ), whereas macrophages were generally reduced in WAT of these mice (70% reduction in mRNA expression of F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    macrophages). The protective MIF effect was scrutinized in isolated hepatocytes. MIF reversed inflammation\u2010induced triglyceride accumulation in Hepa1\u20106 cells and primary hepatocytes and also attenuated oleic acid\u2010elicited triglyceride increase in 3T3\u2010L1 adipocytes. Protection from fatty hepatocyte degeneration was paralleled by a 2\u2010 to 3\u2010fold reduction by MIF of hepatocyte proinflammatory cytokine production. Blockade of MIF receptor cluster of differentiation 74 (CD74) but not of CXCR2 or CXCR4 fully reverted the protective effect of MIF, comparable to AMPK inhibition. In summary, we demonstrate that MIF mediates hepatoprotection through the CD74\/AMPK pathway in hepatocytes in metabolic models of liver injury.\u2014Heinrichs, D., Berres, M.\u2010L., Coeuru, M., Knauel, M., Nellen, A., Fischer, P., Philippeit, C., Bucala, R., Trautwein, C., Wasmuth, H. E., Bernhagen, J., Protective role of macrophage migration inhibitory factor in nonalcoholic steatohepatitis. FASEB J. 28, 5136\u20135147 (2014).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.14-256776","type":"journal-article","created":{"date-parts":[[2014,8,14]],"date-time":"2014-08-14T00:11:25Z","timestamp":1407975085000},"page":"5136-5147","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Protective role of macrophage migration inhibitory factor in nonalcoholic steatohepatitis"],"prefix":"10.1096","volume":"28","author":[{"given":"Daniel","family":"Heinrichs","sequence":"first","affiliation":[{"name":"Institute of Biochemistry and Molecular Cell Biology Rheinisch\u2010Westfaelische Technische Hochschule (RWTH) Aachen University Aachen Germany"},{"name":"Department of Internal Medicine III Rheinisch\u2010Westfaelische Technische Hochschule (RWTH) Aachen University Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Luise","family":"Berres","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III Rheinisch\u2010Westfaelische Technische Hochschule (RWTH) Aachen University Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Coeuru","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Cell Biology Rheinisch\u2010Westfaelische Technische Hochschule (RWTH) Aachen University Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meike","family":"Knauel","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Cell Biology Rheinisch\u2010Westfaelische Technische Hochschule (RWTH) Aachen University Aachen 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Yale University School of Medicine New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Trautwein","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III Rheinisch\u2010Westfaelische Technische Hochschule (RWTH) Aachen University Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann E.","family":"Wasmuth","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III Rheinisch\u2010Westfaelische Technische Hochschule (RWTH) Aachen University Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Bernhagen","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Cell Biology Rheinisch\u2010Westfaelische Technische Hochschule (RWTH) Aachen University Aachen 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