Altered pre-lamin A processing is a common mechanism leading to lipodystrophy

Abstract

Lipodystrophies are a heterogeneous group of human disorders characterized by the anomalous distribution of body fat associated with insulin resistance and altered lipid metabolism. The pathogenetic mechanism of inherited lipodystrophies is not yet clear; at the molecular level they have been linked to mutations of lamin A/C, peroxisome proliferator-activated receptor (PPARgamma) and other seemingly unrelated proteins. In this study, we examined lamin A/C processing in three laminopathies characterized by lipodystrophic phenotypes: Dunnigan type familial partial lipodystrophy, mandibuloacral dysplasia and atypical Werner's syndrome. We found that the lamin A precursor was specifically accumulated in lipodystrophy cells. Pre-lamin A was located at the nuclear envelope and co-localized with the adipocyte transcription factor sterol regulatory element binding protein 1 (SREBP1). Using co-immunoprecipitation experiments, we obtained the first demonstration of an in vivo interaction between SREBP1 and pre-lamin A. Binding of SREBP1 to the lamin A precursor was detected in patient fibroblasts as well as in control fibroblasts forced to accumulate pre-lamin A by farnesylation inhibitors. In contrast, SREBP1 did not interact in vivo with mature lamin A or C in cultured fibroblasts. To gain insights into the effect of pre-lamin A accumulation in adipose tissue, we inhibited lamin A precursor processing in 3T3-L1 pre-adipocytes. Our results show that pre-lamin A sequesters SREBP1 at the nuclear rim, thus decreasing the pool of active SREBP1 that normally activates PPARgamma and causing impairment of pre-adipocyte differentiation. This defect can be rescued by treatment with troglitazone, a known PPARgamma ligand activating the adipogenic program.

Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence

“…4,5,8,11 The increased amount of prelamin A in adipose tissue samples from lipodystrophic patients bearing LMNA mutations or treated with PIs indicates that prelamin A accumulation is occuring in vivo. Moreover, lipodystrophy itself could result from defective prelamin A processing, as sterol-regulatory element-binding protein-1, which contributes to adipogenesis, is sequestrated at the nuclear rim in cells with other LMNA mutations 7 and in preadipocytes chronically treated with PIs, 21 thereby impairing adipocyte differentiation. However, the role of lamin A in adipocyte differentiation is unclear.…”

“…LMNA-linked lipodystrophies and progeroid syndromes form a clinical continuum of related phenotypes. [2][3][4][5][6][7][8] Otherwise, HIV-infected patients receiving antiretroviral therapy frequently develop a lipodystrophy syndrome associated with a high risk of metabolic and cardiovascular complications. 9 These patients also face a growing number of other agerelated comorbidities, such as neurodegeneration, osteopenia and malignancies.…”

Mouse models of the laminopathies

“…It has been proposed that since they are both located on the outside of the carboxyl-terminal globular domain, they might perturb interactions between the A-type lamins and other nuclear proteins [1], such as the adipogenic factor SREBP1, rather than disrupting the structure and/ or assembly of the lamins, as has been suggested for the striated muscle laminopathies [42]. Intriguingly, human cells carrying either an FPLD, MAD, or one of the mutations responsible for atypical Werner's syndrome have been reported to have increased levels of prelamin A [43].…”

Obesity and polymorphisms in genes regulating human adipose tissue

“…Mutation in this gene leading to accumulation of LMNA precursor is one cause of partial lipodystrophy, indicating a role in human adipogenesis. 37 The LMNA precursor interacts with SREBP1, thereby decreasing the pool of active SREBP-1c that normally promotes pre-adipocyte differentiation. 37 A silent allele, 1908T, in LMNA is associated with obesity in two populations.…”

“…37 The LMNA precursor interacts with SREBP1, thereby decreasing the pool of active SREBP-1c that normally promotes pre-adipocyte differentiation. 37 A silent allele, 1908T, in LMNA is associated with obesity in two populations. 38,39 Recently, other genes that infer with adipocyte differentiation have emerged as candidates for obesity.…”