Loss of phospholipase PLAAT3 causes a mixed ...
Document type :
Article dans une revue scientifique: Article original
PMID :
Permalink :
Title :
Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling
Author(s) :
Schuermans, Nika [Auteur]
El Chehadeh, Salima [Auteur]
Hemelsoet, Dimitri [Auteur]
Gautheron, Jérémie [Auteur]
Vantyghem, Marie-Christine [Auteur]
Service Endocrinologie, diabétologie, maladies métaboliques et nutrition [LILLE - Endocrino]
Recherche translationnelle sur le diabète (RTD) - U1190
Nouioua, Sonia [Auteur]
Tazir, Meriem [Auteur]
Vigouroux, Corinne [Auteur]
Auclair, Martine [Auteur]
Bogaert, Elke [Auteur]
Dufour, Sara [Auteur]
Okawa, Fumiya [Auteur]
Hilbert, Pascale [Auteur]
Van Doninck, Nike [Auteur]
Taquet, Marie-Caroline [Auteur]
Rosseel, Toon [Auteur]
De Clercq, Griet [Auteur]
Debackere, Elke [Auteur]
Van Haverbeke, Carole [Auteur]
Cherif, Ferroudja Ramdane [Auteur]
Urtizberea, Jon Andoni [Auteur]
Chanson, Jean-Baptiste [Auteur]
Funalot, Benoit [Auteur]
Authier, François-Jérôme [Auteur]
Kaya, Sabine [Auteur]
Terryn, Wim [Auteur]
Callens, Steven [Auteur]
Depypere, Bernard [Auteur]
Van Dorpe, Jo [Auteur]
Poppe, Bruce [Auteur]
Impens, Francis [Auteur]
Mizushima, Noboru [Auteur]
Depienne, Christel [Auteur]
Jéru, Isabelle [Auteur]
Dermaut, Bart [Auteur]
Universiteit Gent = Ghent University = Université de Gand [UGENT]
El Chehadeh, Salima [Auteur]
Hemelsoet, Dimitri [Auteur]
Gautheron, Jérémie [Auteur]
Vantyghem, Marie-Christine [Auteur]

Service Endocrinologie, diabétologie, maladies métaboliques et nutrition [LILLE - Endocrino]
Recherche translationnelle sur le diabète (RTD) - U1190
Nouioua, Sonia [Auteur]
Tazir, Meriem [Auteur]
Vigouroux, Corinne [Auteur]
Auclair, Martine [Auteur]
Bogaert, Elke [Auteur]
Dufour, Sara [Auteur]
Okawa, Fumiya [Auteur]
Hilbert, Pascale [Auteur]
Van Doninck, Nike [Auteur]
Taquet, Marie-Caroline [Auteur]
Rosseel, Toon [Auteur]
De Clercq, Griet [Auteur]
Debackere, Elke [Auteur]
Van Haverbeke, Carole [Auteur]
Cherif, Ferroudja Ramdane [Auteur]
Urtizberea, Jon Andoni [Auteur]
Chanson, Jean-Baptiste [Auteur]
Funalot, Benoit [Auteur]
Authier, François-Jérôme [Auteur]
Kaya, Sabine [Auteur]
Terryn, Wim [Auteur]
Callens, Steven [Auteur]
Depypere, Bernard [Auteur]
Van Dorpe, Jo [Auteur]
Poppe, Bruce [Auteur]
Impens, Francis [Auteur]
Mizushima, Noboru [Auteur]
Depienne, Christel [Auteur]
Jéru, Isabelle [Auteur]
Dermaut, Bart [Auteur]
Universiteit Gent = Ghent University = Université de Gand [UGENT]
Journal title :
Nature Genetics
Abbreviated title :
Nat Genet
Volume number :
55
Pages :
1929–1940
Publisher :
Nature Publishing Group
Publication date :
2023-11-02
ISSN :
1546-1718
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
Phospholipase A/acyltransferase 3 (PLAAT3) is a phospholipid-modifying enzyme predominantly expressed in neural and white adipose tissue (WAT). It is a potential drug target for metabolic syndrome, as Plaat3 deficiency in ...
Show more >Phospholipase A/acyltransferase 3 (PLAAT3) is a phospholipid-modifying enzyme predominantly expressed in neural and white adipose tissue (WAT). It is a potential drug target for metabolic syndrome, as Plaat3 deficiency in mice protects against diet-induced obesity. We identified seven patients from four unrelated consanguineous families, with homozygous loss-of-function variants in PLAAT3, who presented with a lipodystrophy syndrome with loss of fat varying from partial to generalized and associated with metabolic complications, as well as variable neurological features including demyelinating neuropathy and intellectual disability. Multi-omics analysis of mouse Plaat3−/− and patient-derived WAT showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in the signaling of peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipocyte differentiation. Accordingly, CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. These findings establish PLAAT3 deficiency as a hereditary lipodystrophy syndrome with neurological manifestations, caused by a PPARγ-dependent defect in WAT differentiation and function.Show less >
Show more >Phospholipase A/acyltransferase 3 (PLAAT3) is a phospholipid-modifying enzyme predominantly expressed in neural and white adipose tissue (WAT). It is a potential drug target for metabolic syndrome, as Plaat3 deficiency in mice protects against diet-induced obesity. We identified seven patients from four unrelated consanguineous families, with homozygous loss-of-function variants in PLAAT3, who presented with a lipodystrophy syndrome with loss of fat varying from partial to generalized and associated with metabolic complications, as well as variable neurological features including demyelinating neuropathy and intellectual disability. Multi-omics analysis of mouse Plaat3−/− and patient-derived WAT showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in the signaling of peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipocyte differentiation. Accordingly, CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. These findings establish PLAAT3 deficiency as a hereditary lipodystrophy syndrome with neurological manifestations, caused by a PPARγ-dependent defect in WAT differentiation and function.Show less >
Language :
Anglais
Peer reviewed article :
Oui
Audience :
Internationale
Popular science :
Non
ANR Project :
Administrative institution(s) :
Université de Lille
Inserm
CHU Lille
Inserm
CHU Lille
Collections :
Submission date :
2024-01-19T22:12:03Z
2024-09-24T09:36:27Z
2024-09-24T09:36:27Z
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