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.
Highlights
Mutations in the lamin A/C gene encoding nuclear lamins A and C cause familial partial lipodystrophy type 2 (FPLD2) and related lipodystrophy syndromes
We examined anterior cervical subcutaneous adipose tissue from one patient with FPLD2 caused by the lamin A/C gene (LMNA) p.R482W mutation and from unaffected controls
We examined in cervical adipose tissue of the patient and five unaffected controls the expression of mRNAs for three different extracellular matrix (ECM) proteins: fibronectin, which binds type I collagen and is involved in the maintenance of adipocyte shape [33]; elastin, a major component of elastic fibers providing strength and flexibility to connective tissue [34]; and decorin, which binds to type I collagen and functions in matrix assembly [35]
Summary
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. 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- signaling and defects in matrix metalloproteinase 9 activity.
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