Dyslipidemia, steatohepatitis and atherogenesis in lipodystrophic apoE deficient mice with Seipin deletion.

SEIPIN is an integral membrane protein located in the endoplasmic reticulum, regulating adipocytes differentiation and lipolysis. Deficiency of Seipin in mice causes severe general lipodystrophy, accompanied by insulin resistance, postprandial hypertriglyceridemia and steatohepatitis. In atherosclerosis-prone Ldlr null (Ldlr-/-) mice, lipodystrophy caused by Seipin deletion even led to severe hypercholesteremia and accelerated atherogenesis, when challenged with an atherogenic diet. However, whether the phenotypes observed in Seipin-/-Ldlr-/- mice were a common consequence due to lipodystrophy, rather than genetic background restricted or diet dependent, was unknown. Herein we explored the lipodystrophy-related dyslipidemia, steatohepatitis and atherogenesis in another atherosclerosis-prone murine model, apolipoprotein E null (apoE-/-) mice. Besides, we also compared phenotypes between sexes in apoE-/- mice with Seipin deletion (Seipin-/-apoE-/-). We found that compared with apoE-/- controls, Seipin-/-apoE-/- mice also developed severe general lipodystrophy with hyperlipidemia, steatohepatitis and increased atherogenesis. Although the severity of adipose loss in female and male Seipin-/-apoE-/- mice were similar, hyperlipidemia, steatohepatitis and atherosclerosis were less severe in females than in males. Therefore, we demonstrated that lipodystrophy-related metabolic disorders, caused by Seipin deletion, were independent of genetic background and experimental diet, as seen in Ldlr-/- and apoE-/- mice. However, gender factor affected the disease progression, with females more resistant to developing lipodystrophy-related metabolic consequences.