title: Extracellular matrix remodeling and transforming growth factor-β signaling abnormalities induced by lamin A/C variants that cause lipodystrophy.
abstract: Mutations in the lamin A/C gene encoding nuclear lamins A and C (lamin A/C) cause familial partial lipodystrophy type 2 (FPLD2) and related lipodystrophy syndromes. These are mainly characterized by redistribution of adipose tissue associated with insulin resistance. Several reports suggest that alterations in the extracellular matrix of adipose tissue leading to fibrosis play a role in the pathophysiology of lipodystrophy syndromes. However, the extent of extracellular matrix alterations in FPLD2 remains unknown. We show significantly increased fibrosis and altered expression of genes encoding extracellular matrix proteins in cervical subcutaneous adipose tissue from a human subject with FLPD2. Similar extracellular matrix alterations occur in adipose tissue of transgenic mice expressing an FPLD2-causing human lamin A variant and in cultured fibroblasts from human subjects with FPLD2 and related lipodystrophies. These abnormalities are associated with increased transforming growth factor-β signaling and defects in matrix metalloproteinase 9 activity. Our data demonstrate that lamin A/C gene mutations responsible for FPLD2 and related lipodystrophies are associated with transforming growth factor-β activation and an extracellular matrix imbalance in adipose tissue, suggesting that targeting these alterations could be the basis of novel therapies.
authors.affiliation: Departments of Medicine College of Physicians and Surgeons, Columbia University, New York, NY.|Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Caroline
authors.initials: C
authors.lastname: Le Dour
authors.affiliation: Departments of Medicine College of Physicians and Surgeons, Columbia University, New York, NY.|Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Saint-Antoine Research Center, Institute of Cardiometabolism and Nutrition, INSERM UMR, Pierre-and-Marie Curie University, Université Paris, Sorbonne Universités, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Béréziat
authors.affiliation: Saint-Antoine Research Center, Institute of Cardiometabolism and Nutrition, INSERM UMR, Pierre-and-Marie Curie University, Université Paris, Sorbonne Universités, Paris, France.|Department of Biochemistry and Hormonology, Assistance Publique-Hopitaux de Paris, Hôpital Tenon, Paris, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
authors.affiliation: Saint-Antoine Research Center, Institute of Cardiometabolism and Nutrition, INSERM UMR, Pierre-and-Marie Curie University, Université Paris, Sorbonne Universités, Paris, France.|Departments of Molecular Biology and Endocrinology, Assistance Publique-Hopitaux de Paris, Hôpital Saint-Antoine, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Vigouroux
authors.affiliation: Departments of Medicine College of Physicians and Surgeons, Columbia University, New York, NY hjw14@columbia.edu.|Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002460:Cell Line; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D052496:Lipodystrophy, Familial Partial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D034904:Lamin Type A; D016212:Transforming Growth Factor beta; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: adipocytes; adipose tissue; fibrosis; nuclear envelope