2. Academic Validation
  3. Functional Analyses of the Crohn's Disease Risk Gene LACC1

Functional Analyses of the Crohn's Disease Risk Gene LACC1

  • PLoS One. 2016 Dec 13;11(12):e0168276. doi: 10.1371/journal.pone.0168276.
Ghazaleh Assadi 1,  Liselotte Vesterlund 1,  Ferdinando Bonfiglio 1,  Luca Mazzurana 2,  Lina Cordeddu 1,  Danika Schepis 3,  Jenny Mjösberg 2,  Sabrina Ruhrmann 4,  Alessia Fabbri 5,  Vladana Vukojevic 4,  Piergiorgio Percipalle 6 7,  Florian A Salomons 8,  Jurga Laurencikiene 9,  Leif Törkvist 10,  Jonas Halfvarson 11,  Mauro D'Amato 1 12
Affiliations

Affiliations

  • 1 Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
  • 2 Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
  • 3 Rheumatology unit, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
  • 4 Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
  • 5 Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
  • 6 Biology Program, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
  • 7 Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
  • 8 Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
  • 9 Lipid laboratory, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
  • 10 Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.
  • 11 Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
  • 12 BioDonostia Health Research Institute, San Sebastian and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
PMID: 27959965 DOI: 10.1371/journal.pone.0168276
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.

Conclusion: 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.

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