title: 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.affiliation: Stem Cells and Cell Therapy Laboratory, BioCruces, Hospital Universitario Cruces, Barakaldo, Spain.
authors.forename: Garbiñe
authors.initials: G
authors.lastname: Ruiz de Eguino
authors.forename: Arantza
authors.initials: A
authors.lastname: Infante
authors.forename: Karin
authors.initials: K
authors.lastname: Schlangen
authors.forename: Ana M
authors.initials: AM
authors.lastname: Aransay
authors.forename: Ane
authors.initials: A
authors.lastname: Fullaondo
authors.forename: Mario
authors.initials: M
authors.lastname: Soriano
authors.forename: José Manuel
authors.initials: JM
authors.lastname: García-Verdugo
authors.forename: Angel G
authors.initials: AG
authors.lastname: Martín
authors.forename: Clara I
authors.initials: CI
authors.lastname: Rodríguez
mesh_terms: D050156:Adipogenesis / Q000502:physiology; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D034904:Lamin Type A; D050356:Lipid Metabolism / Q000502:physiology*; D008060:Lipodystrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D011498:Protein Precursors / Q000096:biosynthesis* / Q000235:genetics; D022142:Secretory Vesicles / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; D016329:Sp1 Transcription Factor; C090764:prelamin A