Nuclear envelope-related lipodystrophies.

Several alterations in nuclear envelope proteins building up the lamina meshwork beneath the inner nuclear membrane (mutations in lamins A/C, alterations of prelamin-A maturation, lamin B mutations or deregulation) have been shown to be responsible for or associated to human lipodystrophic syndromes. Lipodystrophic syndromes are rare and heterogeneous diseases, either genetic or acquired, characterized by generalized or partial fat atrophy associated with metabolic complications comprising insulin-resistant diabetes, dyslipidemia, and non-alcoholic fatty liver disease. Recent advances in the molecular genetics of different types of lipodystrophies generally pointed to primary adipocyte alterations leading to impaired adipogenesis and/or deregulation of the adipocyte lipid droplet. However, the precise mechanisms linking nuclear envelope abnormalities to lipodystrophies remain largely unknown. The phenotype of nuclear envelope-linked lipodystrophies ranges from the typical familial partial lipodystrophy of the Dunnigan type (FPLD2), due to heterozygous substitutions of the 482nd arginine of lamins A/C, to complex diseases that can combine lipodystrophy, metabolic complications, muscular or cardiac alterations and/or signs of accelerated aging. In this review we present the clinical, tissular and cellular characteristics of the nuclear envelope-linked lipodystrophies, as well as their hypothetical pathophysiological mechanisms.

Guénantin AC ，Briand N ，Bidault G ，Afonso P ，Béréziat V ，Vatier C ，Lascols O ，Caron-Debarle M ，Capeau J ，Vigouroux C ... -  《-》

LMNA-linked lipodystrophies: from altered fat distribution to cellular alterations.

Bidault G ，Vatier C ，Capeau J ，Vigouroux C ，Béréziat V ... -  《-》

Lipodystrophy-linked LMNA p.R482W mutation induces clinical early atherosclerosis and in vitro endothelial dysfunction.

Bidault G ，Garcia M ，Vantyghem MC ，Ducluzeau PH ，Morichon R ，Thiyagarajah K ，Moritz S ，Capeau J ，Vigouroux C ，Béréziat V ... -  《-》

A homozygous mutation of prelamin-A preventing its farnesylation and maturation leads to a severe lipodystrophic phenotype: new insights into the pathogenicity of nonfarnesylated prelamin-A.

Le Dour C ，Schneebeli S ，Bakiri F ，Darcel F ，Jacquemont ML ，Maubert MA ，Auclair M ，Jeziorowska D ，Reznik Y ，Béréziat V ，Capeau J ，Lascols O ，Vigouroux C ... -  《-》

Molecular mechanisms of human lipodystrophies: from adipocyte lipid droplet to oxidative stress and lipotoxicity.

Adipose tissue is now recognized for its major role in the control of energy metabolism and insulin sensitivity. We review here the human lipodystrophies, that are rare conditions in which total or partial fat loss is associated with severe lipid and glucose abnormalities leading to diabetes with early cardiovascular and hepatic complications. The genetic origin of a number of human lipodystrophies has been recently unraveled, emphasizing the importance of proteins of previously unknown or unexpected functions. Major adipose functions were also illuminated when studying acquired forms of lipodystrophies linked to human immunodeficiency virus-antiretrovirals. Overall, most of the proteins or functions affected by mutations or antiretrovirals result in altered adipogenesis and insulin sensitivity, triglyceride storage and formation of the unique adipocyte lipid droplet, oxidative stress and fat remodeling. Some mutations or antiretrovirals could affect directly (peroxisome proliferator-activated receptor-γ, Akt2) or indirectly (lamin A/C, human immunodeficiency virus-protease inhibitors) adipogenesis, through the transcription factors peroxisome proliferator-activated receptor gamma-γ or sterol regulatory element binding protein 1c, and insulin signaling through Akt2 that controls adipocyte lipolysis. A number of proteins mutated in genetic lipodystrophies are involved in the control of triglyceride synthesis towards the lipid droplet (1-acylglycerol-3-phosphate-O-acyltransferase 2), or its functions (seipin, cell death-inducing DFF45-like effector C, perilipin, caveolin-1, cavin-1). Decreased triglyceride storage leads to adipocyte lipotoxicity, mitochondrial dysfunction and increased oxidative stress, which could also be induced by some thymidine analogue antiretrovirals. This results in production of inflammatory mediators and deregulated release of free fatty acids. Thus, the impaired ability of adipose tissue to safely store triglycerides inside the lipid droplet results in impaired insulin sensitivity and adverted liver, muscles and heart functions leading to early complications.

Vigouroux C ，Caron-Debarle M ，Le Dour C ，Magré J ，Capeau J ... -  《-》