The sterol regulatory element binding protein 1c (SREBP1c) isoform, whose amino terminus shares sequence identity with adipocyte determination and differentiation factor 1 (ADD1), is part of a transcriptional network of control of adipogenesis.
SREBP1c/ADD1 can activate peroxisome proliferator activated receptor γ (PPARγ ou PPARG) by inducing its expression, and by promoting the production of an endogenous PPARγ ligand.
PPARγ (PPARG) then forms a heterodimer with retinoic acid X receptor (RXR), which targets peroxisome proliferator response elements (PPRE) to regulate expression of genes involved in adipocyte differentiation and insulin sensitivity.
SREBP1 is synthesized as a 125-kD precursor that interacts with the nuclear envelope at an undefined site.
Lipodystrophy and Dunnigan-type familial partial lipodystrophy (FPLD)
It is possible that SREBP1c/ADD1 interacts with lamin A during its translocation into the nucleus, as indicated by the 15-point stars.
A possible mechanism by which mutations in lamin A can affect adipocytes is through abnormal interaction with transcription factors that regulate adipogenesis. The nuclear envelope comprises the nuclear membranes, the pore complexes and the nuclear lamina, which contains lamin A.
LMNA mutations in Dunnigan-type familial partial lipodystrophy (FPLD) could specify points of interaction of lamin A with SREBP1c/ADD1. The abnormal interaction could alter the delivery of the transcription factor to the nucleoplasm.
This, in turn, could have downstream consequences with respect to the activation of PPARγ and of genes with PPRE that affect adipocyte differentiation and insulin sensitivity.
Interestingly, the abnormal regulation of SREBP1c/ADD1 seen in the SREBP1c transgenic mouse is also associated with lipodystrophy and insulin resistance.
See also
References
Hegele RA. Molecular basis of partial lipodystrophy and prospects for therapy. Trends Mol Med. 2001 Mar;7(3):121-6. PMID: 11286783