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 (PPAR gamma) 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 PPAR gamma and causing impairment of pre-adipocyte differentiation. This defect can be rescued by treatment with troglitazone, a known PPAR gamma ligand activating the adipogenic program.

Capanni, C., Mattioli, E., Columbaro, M., Lucarelli, E., Parnaik, V.k., Novelli, G., et al. (2005). Altered pre-lamin A processing is a common mechanism leading to lipodystrophy. HUMAN MOLECULAR GENETICS, 14(11), 1489-1502 [10.1093/hmg/ddi158].

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

NOVELLI, GIUSEPPE;
2005

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 (PPAR gamma) 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 PPAR gamma and causing impairment of pre-adipocyte differentiation. This defect can be rescued by treatment with troglitazone, a known PPAR gamma ligand activating the adipogenic program.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/03 - Genetica Medica
English
Con Impact Factor ISI
lamin A; lamin C; mevinolin; n [[5 [(2 amino 3 mercaptopropyl)amino][1,1' biphenyl] 2 yl]carbonyl]methionine methyl ester; peroxisome proliferator activated receptor gamma; prelamin A; protein inhibitor; protein precursor; sterol regulatory element binding protein 1; troglitazone; unclassified drug; adipocyte; animal cell; article; bone dysplasia; cell differentiation; controlled study; familial disease; fibroblast; human; human cell; insulin resistance; lipid metabolism; lipodystrophy; mouse; nonhuman; phenotype; priority journal; protein localization; protein modification; protein processing; protein protein interaction; Werner syndrome; 3T3-L1 Cells; Adipocytes; Animals; Blotting, Western; Cell Differentiation; Cell Nucleus; Fibroblasts; Fluorescent Antibody Technique; Humans; Immunoprecipitation; Lipodystrophy; Mice; Nuclear Proteins; Protein Binding; Protein Precursors; Protein Processing, Post-Translational
Capanni, C., Mattioli, E., Columbaro, M., Lucarelli, E., Parnaik, V.k., Novelli, G., et al. (2005). Altered pre-lamin A processing is a common mechanism leading to lipodystrophy. HUMAN MOLECULAR GENETICS, 14(11), 1489-1502 [10.1093/hmg/ddi158].
Capanni, C; Mattioli, E; Columbaro, M; Lucarelli, E; Parnaik, V; Novelli, G; Wehnert, M; Cenni, V; Maraldi, N; Squarzoni, S; Lattanzi, G
Articolo su rivista
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/30265
Citazioni
  • ???jsp.display-item.citation.pmc??? 64
  • Scopus 176
  • ???jsp.display-item.citation.isi??? 164
social impact