Sp1 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.

Abstract

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.

• Authors: Garbiñe Ruiz de Eguino, Arantza Infante, Karin Schlangen, Ana M Aransay, Ane Fullaondo, Mario Soriano, José Manuel García-Verdugo, Angel G Martín, Clara I Rodríguez
• Journal: Stem cells translational medicine (Stem Cells Transl Med) Vol. 1 Issue 4 Pg. 309-21 (Apr 2012) ISSN: 2157-6564 [Print] England
• PMID: 23197810 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lamin Type A
• Nuclear Proteins
• Protein Precursors
• Sp1 Transcription Factor
• prelamin A

Topics

• Adipogenesis (physiology)
• Adipose Tissue (cytology, metabolism)
• Cell Differentiation (physiology)
• Extracellular Matrix (genetics, metabolism)
• Gene Expression Regulation (genetics)
• Humans
• Lamin Type A
• Lipid Metabolism (physiology)
• Lipodystrophy (genetics, metabolism, pathology)
• Mesenchymal Stem Cells (cytology, metabolism)
• Mutation
• Nuclear Proteins (biosynthesis, genetics)
• Protein Precursors (biosynthesis, genetics)
• Secretory Vesicles (genetics, metabolism)
• Sp1 Transcription Factor (genetics, metabolism)