期刊
NUCLEUS
卷 9, 期 1, 页码 235-248出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/19491034.2018.1456217
关键词
Lamin A/C; lipodystrophy; adipose tissue; differentiation; senescence; extracellular matrix; anticipation; epigenetics; induced pluripotent stem cells; metreleptin
类别
资金
- Sorbonne Universite
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Institute of CardioMetabolism (ICAN)
- ANRS (France REcherche Nord&Sud Sida-hiv Hepatites)
- Region Ile-de-France STEM-Pole
- Association Francaise d'Etude et de Recherche sur l'Obesite (AFERO)
- Fondation de France
- Fondation pour la Recherche Medicale
- Societe Francophone du Diabete (SFD)
Mutations in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and premature ageing syndromes. LMNA mutations have been shown to alter nuclear structure and stiffness, binding to partners at the nuclear envelope or within the nucleoplasm, gene expression and/or prelamin A maturation. LMNA-associated lipodystrophic features, combining generalized or partial fat atrophy and metabolic alterations associated with insulin resistance, could result from altered adipocyte differentiation or from altered fat structure.Recent studies shed some light on how pathogenic A-type lamin variants could trigger lipodystrophy, metabolic complications, and precocious cardiovascular events. Alterations in adipose tissue extracellular matrix and TGF-beta signaling could initiate metabolic inflexibility. Premature senescence of vascular cells could contribute to cardiovascular complications. In affected families, metabolic alterations occur at an earlier age across generations, which could result from epigenetic deregulation induced by LMNA mutations. Novel cellular models recapitulating adipogenic developmental pathways provide scalable tools for disease modeling and therapeutic screening.
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