Towards a mechanistic understanding of lipodystrophy and seipin functions

Abstract

CGL (Congenital generalized lipodystrophy) is a genetic disorder characterized by near complete loss of adipose tissue along with increased ectopic fat storage in other organs including liver and muscle. Of the four CGL types, BSCL2 (Berardinelli–Seip Congenital lipodystrophy type 2), resulting from mutations in the BSCL2/seipin gene, exhibits the most severe lipodystrophic phenotype with loss of both metabolic and mechanical adipose depots. The majority of Seipin mutations cause C-terminal truncations, along with a handful of point mutations. Seipin localizes to the ER and is composed of a conserved region including a luminal loop and two transmembrane domains, plus cytosolic N- and C-termini. Animal models deficient in seipin recapitulate the human lipodystrophic phenotype. Cells isolated from seipin knockout mouse models also exhibit impaired adipogenesis. Mechanistically, seipin appears to function as a scaffolding protein to bring together interacting partners essential for lipid metabolism and LD (lipid droplet) formation during adipocyte development. Moreover, cell line and genetic studies indicate that seipin functions in a cell-autonomous manner. Here we will provide a brief overview of the genetic association of the CGLs, and focus on the current understanding of differential contributions of distinct seipin domains to lipid storage and adipogenesis. We will also discuss the roles of seipin-interacting partners, including lipin 1 and 14-3-3β, in mediating seipin-dependent regulation of cellular pathways such as actin cytoskeletal remodelling.

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

“…The lead SNP of the other novel locus, GANAB, rs7949030, showed some evidence of association with WHRadjBMI in the latest GIANT GWAS ( P value=3.3 × 10 −6 ) and was reported to be an eQTL for several other genes21: In monocytes, regulation of MIR3654 , EEF1G , EML3 , BSCL2 , HNRNPUL2-BSCL2 , LRRN4CL was found293031. BSCL2 is of interest, as it is a known candidate gene for the most severe lipodystrophy phenotype32. In blood rs7949030 was found to be an eQTL of HNRNPUL2-BSCL2 , AHNAK , LRRN4CL and INTS5 (refs 33, 34), while in skin and adipocytes it was found as an eQTL for EML3 (refs 30, 31, 35).…”

Congenital generalized lipodystrophies—new insights into metabolic dysfunction

“…13 Type 2 CGL has also been reported in patients various ethnicities of including individuals originating from Europe, Mediterranean and Middle Eastern Arabs and Japanese. 102 Patients with type 2 CGL have an almost total lack of body fat with both metabolically active and mechani cal adipose tissue being absent (Figure 1b,g,h, Table 1). 90 These patients have an increased prevalence of cardio myopathy and mild mental retardation, 13,15 and have lower median serum levels of leptin (0.01 ng/ml) and adipo nectin (3.3 μg/ml) than healthy individuals (who had median serum levels of 4.6 ng/ml and 7.8 μg/ml for Nature Reviews | Endocrinology CIDEC and seipin might be involved in the fusion of lipid droplets to form a larger droplet, whereas perilipin 1 is essential for lipid storage and hormone-mediated lipolysis.…”

Metreleptin and generalized lipodystrophy and evolving therapeutic perspectives

“…Seipin is a protein involved in stabilizing the lipid droplet structure during adipogenesis and adipocyte differentiation [93] CGL3 CAV1 Caveolin-1 is a protein found in caveolate. It translocates Fas to the surface membrane to form larger lipid droplets [94] CGL4 PTRF Cavin is a protein that regulates expression of Caveolins 1 and 2 and is a critical component to caveolae formation [95] Partial, congenital Familial partial lipodystrophy, Type 1 (FPLD1) [96] Unknown Unknown…”