Extracellular matrix remodeling and transforming growth factor-β signaling abnormalities induced by lamin A/C variants that cause lipodystrophy
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 alt...
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| Veröffentlicht in: | Journal of lipid research Jg. 58; H. 1; S. 151 - 163 |
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Elsevier
01.01.2017
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| 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. |
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| AbstractList | 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. 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.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. 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 |
| Author | Wu, Wei Vigouroux, Corinne Capeau, Jacqueline Le Dour, Caroline Worman, Howard J Béréziat, Véronique |
| Author_xml | – sequence: 1 givenname: Caroline surname: Le Dour fullname: Le Dour, Caroline organization: Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY – sequence: 2 givenname: Wei surname: Wu fullname: Wu, Wei organization: Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY – sequence: 3 givenname: Véronique surname: Béréziat fullname: Béréziat, Véronique organization: Saint-Antoine Research Center, Institute of Cardiometabolism and Nutrition, INSERM UMR, Pierre-and-Marie Curie University, Université Paris, Sorbonne Universités, Paris, France – sequence: 4 givenname: Jacqueline surname: Capeau fullname: Capeau, Jacqueline organization: Department of Biochemistry and Hormonology, Assistance Publique-Hopitaux de Paris, Hôpital Tenon, Paris, France – sequence: 5 givenname: Corinne surname: Vigouroux fullname: Vigouroux, Corinne organization: Departments of Molecular Biology and Endocrinology, Assistance Publique-Hopitaux de Paris, Hôpital Saint-Antoine, Paris, France – sequence: 6 givenname: Howard J surname: Worman fullname: Worman, Howard J email: hjw14@columbia.edu organization: Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY |
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| SubjectTerms | adipocytes adipose tissue Adipose Tissue - metabolism Adipose Tissue - pathology Aged Aged, 80 and over Animals Cell Line Extracellular Matrix - genetics Extracellular Matrix - metabolism fibrosis Gene Expression Regulation Humans Lamin Type A - genetics Lipodystrophy, Familial Partial - genetics Lipodystrophy, Familial Partial - metabolism Lipodystrophy, Familial Partial - pathology Male Matrix Metalloproteinase 9 - biosynthesis Matrix Metalloproteinase 9 - genetics Mice Mice, Knockout Middle Aged Mutation nuclear envelope Transforming Growth Factor beta - biosynthesis Transforming Growth Factor beta - genetics |
| Title | Extracellular matrix remodeling and transforming growth factor-β signaling abnormalities induced by lamin A/C variants that cause lipodystrophy |
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