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

• Published in: Stem cells translational medicine Vol. 1; no. 4; pp. 309 - 321
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States AlphaMed Press 01.04.2012; Oxford University Press
• Subjects: Adipocytes; Adipogenesis; Adipogenesis - physiology; Adipose tissue; Adipose Tissue - cytology; Adipose Tissue - metabolism; Body fat; Cell adhesion & migration; Cell cycle; Cell differentiation; Cell Differentiation - physiology; Differentiation; Experimental models; Extracellular matrix; Extracellular Matrix - genetics; Extracellular Matrix - metabolism; Gene expression; Gene Expression Regulation - genetics; Grants; HIV; Homeostasis; Human immunodeficiency virus; Humans; Lamin Type A; Lipid Metabolism - physiology; Lipids; Lipodystrophy; Lipodystrophy - genetics; Lipodystrophy - metabolism; Lipodystrophy - pathology; Mesenchymal stem cells; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - metabolism; Mesenchyme; Metabolic disorders; Microscopy; Mutation; Nuclear Proteins - biosynthesis; Nuclear Proteins - genetics; Original and Reviews; Phenotypes; Physiology; Protein Precursors - biosynthesis; Protein Precursors - genetics; Proteinase inhibitors; Secretory Vesicles - genetics; Secretory Vesicles - metabolism; Sp1 protein; Sp1 Transcription Factor - genetics; Sp1 Transcription Factor - metabolism; Stem cells; Transcription factor; Transcription factors; Triglycerides; Spain
• ISSN: 2157-6564; 2157-6580
• DOI: 10.5966/sctm.2011-0010

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. A lamin A (LMNA)‐linked lipodystrophy human mesenchymal stem cell experimental model has been developed, which indicates a crucial role for LMNA in the mechanism of these syndromes. It is reported 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. This study shows a novel, essential, and finely tuned role for Sp1 in adipose lineage differentiation in human mesenchymal stem cells.