Altered pre-lamin A processing is a common mechanism leading to lipodystrophy

Cristina Capanni, Elisabetta Mattioli, Marta Columbaro, Enrico Lucarelli, Veena K. Parnaik, Giuseppe Novelli, Manfred Wehnert, Vittoria Cenni, Nadir M. Maraldi, Stefano Squarzoni, Giovanna Lattanzi

Research output: Contribution to journalArticle

166 Scopus citations

Abstract

Lipodystrophies are a heterogeneous group of human disorders characterized by the anomalous distribution of body fat associated with insulin resistance and altered lipid metabolism. The pathogenetic mechanism of inherited lipodystrophies is not yet clear; at the molecular level they have been linked to mutations of lamin A/C, peroxisome proliferator-activated receptor (PPARγ) and other seemingly unrelated proteins. In this study, we examined lamin A/C processing in three laminopathies characterized by lipodystrophic phenotypes: Dunnigan type familial partial lipodystrophy, mandibuloacral dysplasia and atypical Werner's syndrome. We found that the lamin A precursor was specifically accumulated in lipodystrophy cells. Pre-lamin A was located at the nuclear envelope and co-localized with the adipocyte transcription factor sterol regulatory element binding protein 1 (SREBP1). Using co-immunoprecipitation experiments, we obtained the first demonstration of an in vivo interaction between SREBP1 and pre-lamin A. Binding of SREBP1 to the lamin A precursor was detected in patient fibroblasts as well as in control fibroblasts forced to accumulate pre-lamin A by farnesylation inhibitors. In contrast, SREBP1 did not interact in vivo with mature lamin A or C in cultured fibroblasts. To gain insights into the effect of pre-lamin A accumulation in adipose tissue, we inhibited lamin A precursor processing in 3T3-L1 pre-adipocytes. Our results show that pre-lamin A sequesters SREBP1 at the nuclear rim, thus decreasing the pool of active SREBP1 that normally activates PPARγ and causing impairment of pre-adipocyte differentiation. This defect can be rescued by treatment with troglitazone, a known PPARγ ligand activating the adipogenic program.

Original languageEnglish (US)
Pages (from-to)1489-1502
Number of pages14
JournalHuman Molecular Genetics
Volume14
Issue number11
DOIs
StatePublished - Jun 1 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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