title: Protective role of macrophage migration inhibitory factor in nonalcoholic steatohepatitis.
abstract: MIF is an inflammatory cytokine but is hepatoprotective in models of hepatotoxin-induced liver fibrosis. Hepatic fibrosis can also develop from metabolic liver disease, such as nonalcoholic fatty liver disease (NASH). We investigated the role of MIF in high-fat or methionine- and choline-deficient diet mouse models of NASH. Mif(-/-) mice showed elevated liver triglyceride levels (WT, 53±14 mg/g liver; Mif(-/-), 103±7 mg/g liver; P<0.05) and a 2-3-fold increased expression of lipogenic genes. Increased fatty degeneration in the livers of Mif(-/-) mice was associated with increased hepatic inflammatory cells (1.6-fold increase in F4/80(+) macrophages) and proinflammatory cytokines (e.g., 2.3-fold increase in Tnf-α and 2-fold increase in Il-6 expression). However, inflammatory cells and cytokines were decreased by 50-90% in white adipose tissue (WAT) of Mif(-/-) mice. Subset analysis showed that macrophage phenotypes in livers of Mif(-/-) mice were skewed toward M2 (e.g., 1.7-fold and 2.5-fold increase in Arg1 and Il-13, respectively, and 2.5-fold decrease in iNos), whereas macrophages were generally reduced in WAT of these mice (70% reduction in mRNA expression of F4/80(+) macrophages). The protective MIF effect was scrutinized in isolated hepatocytes. MIF reversed inflammation-induced triglyceride accumulation in Hepa1-6 cells and primary hepatocytes and also attenuated oleic acid-elicited triglyceride increase in 3T3-L1 adipocytes. Protection from fatty hepatocyte degeneration was paralleled by a 2- to 3-fold 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.
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology and Department of Internal Medicine III, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany; and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Heinrichs
authors.affiliation: Department of Internal Medicine III, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany; and.
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Berres
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology and.
authors.forename: Melanie
authors.initials: M
authors.lastname: Coeuru
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology and.
authors.forename: Meike
authors.initials: M
authors.lastname: Knauel
authors.affiliation: Department of Internal Medicine III, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany; and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Nellen
authors.affiliation: Department of Internal Medicine III, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany; and.
authors.forename: Petra
authors.initials: P
authors.lastname: Fischer
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology and.
authors.forename: Claudia
authors.initials: C
authors.lastname: Philippeit
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.affiliation: Department of Internal Medicine III, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany; and.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Department of Internal Medicine III, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany; and.
authors.forename: Hermann E
authors.initials: HE
authors.lastname: Wasmuth
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology and jbernhagen@ukaachen.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D008263:Macrophage Migration-Inhibitory Factors
keywords: cytokines; fatty liver; hepatic fibrosis; hepatocyte; inflammation