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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Vydáno v:Journal of lipid research Ročník 58; číslo 1; s. 151 - 163
Hlavní autoři: Le Dour, Caroline, Wu, Wei, Béréziat, Véronique, Capeau, Jacqueline, Vigouroux, Corinne, Worman, Howard J
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Elsevier 01.01.2017
Témata:
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
adipose tissue
nuclear envelope
fibrosis
adipocytes
ISSN:1539-7262, 0022-2275, 1539-7262
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Shrnutí: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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content type line 23
ISSN:1539-7262
0022-2275
1539-7262
DOI:10.1194/jlr.M071381