Open AccessSp1 Transcription Factor Interaction with Accumulated Prelamin A Impairs Adipose Lineage Differentiation in Human Mesenchymal Stem Cells: Essential Role of Sp1 in the Integrity of Lipid Vesicles
Author(s) -
Ruiz de Eguino Garbiñe,
Infante Arantza,
Schlangen Karin,
Aransay Ana M.,
Fullaondo Ane,
Soriano Mario,
García-Verdugo José Manuel,
Martín Ángel G.,
Rodríguez Clara I.
Publication year - 2012
Publication title -
stem cells translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.781
H-Index - 71
eISSN - 2157-6580
pISSN - 2157-6564
DOI - 10.5966/sctm.2011-0010
Subject(s) - lmna , lamin , mesenchymal stem cell , adipogenesis , adipose tissue , lipodystrophy , biology , transcription factor , microbiology and biotechnology , cancer research , phenotype , genetics , endocrinology , immunology , gene , antiretroviral therapy , human immunodeficiency virus (hiv) , nucleus , viral load
Lamin A ( LMNA )‐linked lipodystrophies may be either genetic (associated with LMNA mutations) or acquired (associated with the use of human immunodeficiency virus protease inhibitors [PIs]), and in both cases they share clinical features such as anomalous distribution of body fat or generalized loss of adipose tissue, metabolic alterations, and early cardiovascular complications. Both LMNA ‐linked lipodystrophies are characterized by the accumulation of the lamin A precursor prelamin A. The pathological mechanism by which prelamin A accumulation induces the lipodystrophy associated phenotypes remains unclear. Since the affected tissues in these disorders are of mesenchymal origin, we have generated an LMNA ‐linked experimental model using human mesenchymal stem cells treated with a PI, which recapitulates the phenotypes observed in patient biopsies. This model has been demonstrated to be a useful tool to unravel the pathological mechanism of the LMNA ‐linked lipodystrophies, providing an ideal system to identify potential targets to generate new therapies for drug discovery screening. We report for the first time that impaired adipogenesis is a consequence of the interaction between accumulated prelamin A and Sp1 transcription factor, sequestration of which results in altered extracellular matrix gene expression. In fact, our study shows a novel, essential, and finely tuned role for Sp1 in adipose lineage differentiation in human mesenchymal stem cells. These findings define a new physiological experimental model to elucidate the pathological mechanisms LMNA ‐linked lipodystrophies, creating new opportunities for research and treatment not only of LMNA ‐linked lipodystrophies but also of other adipogenesis‐associated metabolic diseases.