Human Molecular Genetics Advance Access published online on April 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi158
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1 ITOI, CNR, Unit of Bologna, c/o IOR, Bologna, Italy
* To whom correspondence should be addressed. Lipodystrophies are a heterogeneous group of human disorders characterised 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, while at the molecular level they have been linked to mutations of lamin A/C, PPAR
Received January 20, 2005
Revised April 8, 2005
Accepted April 8, 2005
Article
Altered pre-lamin A processing is a common mechanism leading to lipodystrophy
2 Laboratory of Cell Biology, Istituti Ortopedici Rizzoli, Bologna, Italy
3 Regeneration and Tissue Engineering Laboratory of the Musculoskeletal Tissue Bank, IOR, Bologna, Italy
4 Centre for Cellular and Molecular Biology, Hyderabad 500 007, India
5 Department of Biopathology and Image Diagnostics, University of Rome Tor Vergata, Rome, Italy
6 Institute of Human Genetics, University of Greifswald, Germany.
7 ITOI, CNR, Unit of Bologna, c/o IOR, Bologna, Italy; Laboratory of Cell Biology, Istituti Ortopedici Rizzoli, Bologna, Italy
8 ITOI, CNR, Unit of Bologna, c/o IOR, Via di Barbiano 1/10, I-40136, Bologna, Italy
Giovanna Lattanzi, E-mail: lattanzi{at}jolly.bo.cnr.it
Abstract 
and other seemingly unrelated proteins. In this study, we examined lamin A/C processing in three laminopathies characterised by lipodystrophic phenotypes: Dunnigan type familial partial lipodystrophy, mandibuloacral dysplasia and atypical Werner 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-localised with the adipocyte transcription factor SREBP1. By 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. On the contrary, 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 PPAR and causing impairment of pre-adipocyte differentiation. This defect can be rescued by treatment with troglitazone, a known PPAR ligand activating the adipogenic program.
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