title: Functional Analyses of the Crohn's Disease Risk Gene LACC1.
abstract: BACKGROUND
  Genetic variation in the Laccase (multicopper oxidoreductase) domain-containing 1 (LACC1) gene has been shown to affect the risk of Crohn's disease, leprosy and, more recently, ulcerative colitis and juvenile idiopathic arthritis. LACC1 function appears to promote fatty-acid oxidation, with concomitant inflammasome activation, reactive oxygen species production, and anti-bacterial responses in macrophages. We sought to contribute to elucidating LACC1 biological function by extensive characterization of its expression in human tissues and cells, and through preliminary analyses of the regulatory mechanisms driving such expression.
  
  
  METHODS
  We implemented Western blot, quantitative real-time PCR, immunofluorescence microscopy, and flow cytometry analyses to investigate fatty acid metabolism-immune nexus (FAMIN; the LACC1 encoded protein) expression in subcellular compartments, cell lines and relevant human tissues. Gene-set enrichment analyses were performed to initially investigate modulatory mechanisms of LACC1 expression. A small-interference RNA knockdown in vitro model system was used to study the effect of FAMIN depletion on peroxisome function.
  
  
  RESULTS
  FAMIN expression was detected in macrophage-differentiated THP-1 cells and several human tissues, being highest in neutrophils, monocytes/macrophages, myeloid and plasmacytoid dendritic cells among peripheral blood cells. Subcellular co-localization was exclusively confined to peroxisomes, with some additional positivity for organelle endomembrane structures. LACC1 co-expression signatures were enriched for genes involved in peroxisome proliferator-activated receptors (PPAR) signaling pathways, and PPAR ligands downregulated FAMIN expression in in vitro model systems.
  
  
  CONCLUSIONS
  FAMIN is a peroxisome-associated protein with primary role(s) in macrophages and other immune cells, where its metabolic functions may be modulated by PPAR signaling events. However, the precise molecular mechanisms through which FAMIN exerts its biological effects in immune cells remain to be elucidated.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ghazaleh
authors.identifier: http://orcid.org/0000-0002-3723-9141
authors.initials: G
authors.lastname: Assadi
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Liselotte
authors.initials: L
authors.lastname: Vesterlund
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Bonfiglio
authors.affiliation: Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Luca
authors.initials: L
authors.lastname: Mazzurana
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lina
authors.initials: L
authors.lastname: Cordeddu
authors.affiliation: Rheumatology unit, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Danika
authors.initials: D
authors.lastname: Schepis
authors.affiliation: Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Mjösberg
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ruhrmann
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fabbri
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vladana
authors.initials: V
authors.lastname: Vukojevic
authors.affiliation: Biology Program, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.|Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Percipalle
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Florian A
authors.initials: FA
authors.lastname: Salomons
authors.affiliation: Lipid laboratory, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jurga
authors.initials: J
authors.lastname: Laurencikiene
authors.affiliation: Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Törkvist
authors.affiliation: Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Halfvarson
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.|BioDonostia Health Research Institute, San Sebastian and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003424:Crohn Disease / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry; D011506:Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D005227:Fatty Acids; D058847:Inflammasomes; D047908:Intracellular Signaling Peptides and Proteins; C000614085:LACC1 protein, human; D008024:Ligands; D011506:Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D010100:Oxygen