Human Molecular Genetics Advance Access originally published online on April 20, 2005
Human Molecular Genetics 2005 14(11):1489-1502; doi:10.1093/hmg/ddi158
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Altered pre-lamin A processing is a common mechanism leading to lipodystrophy
1ITOI, CNR, Unit of Bologna, c/o IOR, Bologna, Italy, 2Laboratory of Cell Biology, Istituti Ortopedici Rizzoli, Bologna, Italy, 3Regeneration and Tissue Engineering Laboratory of the Musculoskeletal Tissue Bank, IOR, Bologna, Italy, 4Centre for Cellular and Molecular Biology, Hyderabad 500 007, India, 5Department of Biopathology and Image Diagnostics, University of Rome Tor Vergata, Rome, Italy and 6Institute of Human Genetics, University of Greifswald, Germany
* To whom correspondence should be addressed at: ITOI, CNR, Unit of Bologna, c/o IOR, Via di Barbiano 1/10, I-40136 Bologna, Italy. Tel: +39 0516366768; Fax: +39 051583593; Email: lattanzi{at}jolly.bo.cnr.it
Received January 20, 2005; Accepted April 8, 2005
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
) 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 and causing impairment of pre-adipocyte differentiation. This defect can be rescued by treatment with troglitazone, a known PPAR ligand activating the adipogenic program.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. M. Wojtanik, K. Edgemon, S. Viswanadha, B. Lindsey, M. Haluzik, W. Chen, G. Poy, M. Reitman, and C. Londos The role of LMNA in adipose: a novel mouse model of lipodystrophy based on the Dunnigan-type familial partial lipodystrophy mutation J. Lipid Res., June 1, 2009; 50(6): 1068 - 1079. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Tilgner, K. Wojciechowicz, C. Jahoda, C. Hutchison, and E. Markiewicz Dynamic complexes of A-type lamins and emerin influence adipogenic capacity of the cell via nucleocytoplasmic distribution of {beta}-catenin J. Cell Sci., February 1, 2009; 122(3): 401 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. N. Malhas, C. F. Lee, and D. J. Vaux Lamin B1 controls oxidative stress responses via Oct-1 J. Cell Biol., January 12, 2009; 184(1): 45 - 55. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Araujo-Vilar, G Lattanzi, B Gonzalez-Mendez, A T Costa-Freitas, D Prieto, M Columbaro, E Mattioli, B Victoria, N Martinez-Sanchez, A Ramazanova, et al. Site-dependent differences in both prelamin A and adipogenic genes in subcutaneous adipose tissue of patients with type 2 familial partial lipodystrophy J. Med. Genet., January 1, 2009; 46(1): 40 - 48. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Gambineri, R K Semple, G Forlani, S Genghini, I Grassi, C S S Hyden, U Pagotto, S O'Rahilly, and R Pasquali Monogenic polycystic ovary syndrome due to a mutation in the lamin A/C gene is sensitive to thiazolidinediones but not to metformin Eur. J. Endocrinol., September 1, 2008; 159(3): 347 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Stewart, K. J. Roux, and B. Burke Blurring the Boundary: The Nuclear Envelope Extends Its Reach Science, November 30, 2007; 318(5855): 1408 - 1412. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Wilkie and E. C. Schirmer Guilt by Association: The Nuclear Envelope Proteome and Disease Mol. Cell. Proteomics, October 1, 2006; 5(10): 1865 - 1875. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. L.R.M. Verstraeten, J. L.V. Broers, M. A.M. van Steensel, S. Zinn-Justin, F. C.S. Ramaekers, P. M. Steijlen, M. Kamps, H. J.H. Kuijpers, D. Merckx, H. J.M. Smeets, et al. Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation Hum. Mol. Genet., August 15, 2006; 15(16): 2509 - 2522. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. V. Broers, F. C. S. Ramaekers, G. Bonne, R. B. Yaou, and C. J. Hutchison Nuclear lamins: laminopathies and their role in premature ageing. Physiol Rev, July 1, 2006; 86(3): 967 - 1008. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Manju, B. Muralikrishna, and V. K Parnaik Expression of disease-causing lamin A mutants impairs the formation of DNA repair foci J. Cell Sci., July 1, 2006; 119(13): 2704 - 2714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Boguslavsky, C. L. Stewart, and H. J. Worman Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy Hum. Mol. Genet., February 15, 2006; 15(4): 653 - 663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Young, L. G. Fong, and S. Michaelis Thematic Review Series: Lipid Posttranslational Modifications. Prelamin A, Zmpste24, misshapen cell nuclei, and progeria--new evidence suggesting that protein farnesylation could be important for disease pathogenesis J. Lipid Res., December 1, 2005; 46(12): 2531 - 2558. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Liang and B. Ventura Physiological genomics in PG and beyond: July to September 2005 Physiol Genomics, October 17, 2005; 23(2): 119 - 124. [Full Text] [PDF]
|
|
|
|
|
|
I. Filesi, F. Gullotta, G. Lattanzi, M. R. D'Apice, C. Capanni, A. M. Nardone, M. Columbaro, G. Scarano, E. Mattioli, P. Sabatelli, et al. Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy Physiol Genomics, October 17, 2005; 23(2): 150 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. I. Toth, S. H. Yang, X. Qiao, A. P. Beigneux, M. H. Gelb, C. L. Moulson, J. H. Miner, S. G. Young, and L. G. Fong Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes PNAS, September 6, 2005; 102(36): 12873 - 12878. [Abstract] [Full Text] [PDF]
|
|