title: Altered mitochondrial and peroxisomal integrity in lipocalin-2-deficient mice with hepatic steatosis.
abstract: Lipocalin-2 (LCN2) is a secreted adipokine that transports small hydrophobic molecules such as fatty acids and steroids. LCN2 limits bacterial growth by sequestering iron-containing siderophores and in mammalian liver protects against inflammation, infection, injury and other stressors. Because LCN2 modulates hepatic fat metabolism and homeostasis, we performed a comparative profiling of proteins and lipids of wild type (WT) and Lcn2-deficient mice fed either standard chow or a methionine- and choline-deficient (MCD) diet. Label-free proteomics and 2D-DIGE protein expression profiling revealed differential expression of BRIT1/MCPH1, FABP5, HMGB1, HBB2, and L-FABP, results confirmed by Western blotting. Gene ontology enrichment analysis identified enrichment for genes associated with mitochondrial membrane permeabilization and metabolic processes involving carboxylic acid. Measurements of mitochondrial membrane potential, mitochondrial chelatable iron pool, intracellular lipid peroxidation, and peroxisome numbers in primary hepatocytes confirmed that LCN2 regulates mitochondrial and peroxisomal integrity. Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight (MALDI-TOF) mass spectrometry imaging identified significant changes to sphingomyelins, triglycerides, and glycerophospholipids in livers of mice fed an MCD diet regardless of LCN2 status. However, two arachidonic acid-containing glycerophospholipids were increased in Lcn2-deficient livers. Thus, LCN2 influences peroxisomal and mitochondrial biology in the liver to maintain triglyceride balance, handle oxidative stress, and control apoptosis.
authors.affiliation: Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Asimakopoulou
authors.affiliation: Applied Research Center in Biomedical Mass Spectrometry (ABIMAS), Instrumental Analysis and Bioanalysis, Mannheim University of Applied Sciences, Mannheim, Germany.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Fülöp
authors.affiliation: Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Erawan
authors.initials: E
authors.lastname: Borkham-Kamphorst
authors.affiliation: Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Eddy Van
authors.initials: EV
authors.lastname: de Leur
authors.affiliation: Institute of Pathology, Braunschweig, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berger
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany; Medizinisches Proteom-Center, Ruhr-University, Bochum, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Beine
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany.
authors.forename: Helmut E
authors.initials: HE
authors.lastname: Meyer
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada; Ontario Cancer Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Applied Research Center in Biomedical Mass Spectrometry (ABIMAS), Instrumental Analysis and Bioanalysis, Mannheim University of Applied Sciences, Mannheim, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Hopf
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany; Medizinisches Proteom-Center, Ruhr-University, Bochum, Germany; Bruker Daltonik GmbH, Bremen.
authors.forename: Corinna
authors.initials: C
authors.lastname: Henkel
authors.affiliation: Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany. Electronic address: rweiskirchen@ukaachen.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
mesh_terms: D000818:Animals; D017209:Apoptosis; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D000071068:Lipocalin-2 / Q000172:deficiency* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000071068:Lipocalin-2; D014280:Triglycerides; C071332:Lcn2 protein, mouse
keywords: Arachidonic acid; Dietary model; Fatty acid binding proteins; GO analysis; Iron pool; Lipidomics; Liver; Mitochondria; Peroxisomes; Phosphoinositide (3,4,5) triphosphate; Proteomics