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Functional Analyses of the Crohn's Disease Risk Gene LACC1
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden .
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, e0168276Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
San Francisco, USA: Public Library of Science , 2016. Vol. 11, no 12, e0168276
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:oru:diva-54101DOI: 10.1371/journal.pone.0168276ISI: 000392753900054PubMedID: 27959965ScopusID: 2-s2.0-85005949720OAI: oai:DiVA.org:oru-54101DiVA: diva2:1058532
Funder
Swedish Research Council
Note

Funding Agency:

Karolinska Institutet KID PhD fellowship

Available from: 2016-12-21 Created: 2016-12-20 Last updated: 2017-03-07Bibliographically approved

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