Functional Analyses of the Crohn's Disease Risk Gene LACC1

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Functional Analyses of the Crohn's Disease Risk Gene LACC1

Assadi, Ghazaleh (author): Karolinska Institutet

Vesterlund, Liselotte (author): Karolinska Institutet

Bonfiglio, Ferdinando (author): Karolinska Institutet

Mazzurana, Luca (author): Karolinska Institutet

Cordeddu, Lina (author): Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

Schepis, Danika (author): Rheumatology unit, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

Mjösberg, Jenny (author): Karolinska Institutet

Ruhrmann, Sabrina (author): Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

Fabbri, Alessia (author): Karolinska Institutet

Vukojevic, Vladana (author): Karolinska Institutet

Percipalle, Piergiorgio (author): Stockholms universitet,Institutionen för molekylär biovetenskap, Wenner-Grens institut,New York University Abu Dhabi, United Arab Emirates

Salomons, Florian A. (author): Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden

Laurencikiene, Jurga (author): Karolinska Institutet

Törkvist, Leif (author): Karolinska Institutet

Halfvarson, Jonas, 1970- (author): Örebro universitet,Institutionen för medicinska vetenskaper,Department of Gastroenterology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden

D'Amato, Mauro (author): Karolinska Institutet

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2016-12-13
2016
English.
In: PLOS ONE. - San Francisco, USA : Public Library of Science. - 1932-6203. ; 11:12

Related links:: https://doi.org/10.1...; show more...; https://journals.plo...; https://urn.kb.se/re...; https://doi.org/10.1...; https://urn.kb.se/re...; http://kipublication...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Gastroenterologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Gastroenterology and Hepatology (hsv//eng)
NATURVETENSKAP -- Biologi (hsv//swe)
NATURAL SCIENCES -- Biological Sciences (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

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By the author/editor: Assadi, Ghazaleh; Vesterlund, Lise ...; Bonfiglio, Ferdi ...; Mazzurana, Luca; Cordeddu, Lina; Schepis, Danika; show more...; Mjösberg, Jenny; Ruhrmann, Sabrin ...; Fabbri, Alessia; Vukojevic, Vlada ...; Percipalle, Pier ...; Salomons, Floria ...; Laurencikiene, J ...; Törkvist, Leif; Halfvarson, Jona ...; D'Amato, Mauro; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Medical Biotechn ...; and Medical Biotechn ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Gastroenterology ...

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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By the university: Örebro University; Stockholm University; Karolinska Institutet

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