SREBP1 interaction with prelamin A forms: A pathogenic mechanism for lipodystrophic laminopathies

The understanding of a common complex phenotype such as insulin resistance can be favored by evaluation of monogenic syndromes. Clinical definition, pathogenesis, and therapeutic strategies for the insulin resistance syndrome can thus be improved by the characterization at the molecular genetic level of monogenic forms of lipodystrophies. Among them, the Dunnigan-type familial partial lipodystrophy (FPLD), the mandibuloacral dysplasia (MADA), the syndromes of partial lipodystrophy with cardiomyopathy, the Hutchinson-Gilford progeria (HGPS), and the atypical Werner's syndrome (WS) are due to mutations of the gene coding for the nuclear lamin A/C. FPLD has been shown to associate with altered processing of the lamin A precursor protein, known as prelamin A. The molecular mechanism causing the lipodystrophy phenotype downstream of prelamin A accumulation resides in an anomalous interaction of the nuclear lamina protein with the transcription factor sterol regulatory element binding protein 1 (SREBP1), which slows down the nuclear import of SREBP1. The ultimate effect of sustained prelamin A accumulation in adipocytes is a reduced transcription and possibly activation of the transcription factor peroxisome proliferator-activated receptor (PPARγ) which is involved in differentiation. In the present study, we show that prelamin A accumulates in the nucleus and establishes a strong interaction with SREBP1. We further investigate the interplay between SREBP1 and farnesylated, non-farnesylated or pathogenic prelamin A forms in transfected adipocytes. The obtained results support the view of a major role of prelamin A accumulation in the pathogenesis of LMNA-linked adipose tissue disorders. Furthermore, we found that treatment with the PPARγ ligand troglitazone (TZD) is able to rescue the adipogenic program. Since FPLD recapitulates the essential metabolic abnormalities of the common insulin resistance syndrome, the beneficial effects of TZD on monogenic lipodystrophies might provide a clue as to the future treatment strategies also for the common syndrome of insulin resistance. © 2007 Elsevier Ltd. All rights reserved.