内质网膜蛋白seipin基因突变可导致人类脂肪缺失（CGL），并同时伴有严重高甘油三酯血症(HTG)、脂肪肝及胰岛素抵抗。我们自制的seipin基因敲除小鼠表现出和人类CGL相似的表型，也具有脂肪缺失、胰岛素抵抗和脂肪肝；但却无明显HTG。有文献报道，CGL与肥胖相似，可增加动脉粥样硬化(As)风险。.为探讨seipin缺陷小鼠是否会发生HTG，将该小鼠与LDL受体缺陷小鼠杂交生成双基因敲除小鼠(DKO)，发现DKO在喂饲高脂饲料后出现严重ＨＴＧ，且As明显增加。这个结果有重大的转化医学意义，说明通过恰当的基因修饰，可以使小鼠和人类在疾病表型上高度相似。拟通过Cre-LoxP技术分别敲除脂肪和肝脏的seipin基因，分析脂肪和肝脏在HTG中的作用；并对DKO增加As的机理进一步探索，以阐明脂肪缺失时发生严重HTG及其促进As的分子机制，为脂肪缺失病人的HTG及其As高风险提供防控的科学依据

Gene mutations in an ER protein Seipin result in congenital general lipodystrophy (CGL) in human, accompanied with severe hypertriglyceridemiam (HTG), hepatic steatosis and insulin resistance. We have deleted Seipin gene in mice which display similar phenotypes such as lipodystrophy, insulin resistance and steatosis as seen humans. However, these mice do not have hypertriglyceridemia. It has been reported that CGL patients have higher cardiovascular risk as obese patients have. .To study whether Seipin deficient mice will show HTG we crossed these mice with LDL receptor null mice and found that these double knockout mice (DKO) developed severe HTG upon high fat diet feeding and had increased atherosclerosis (As). These data demonstrate that similar phenotypes to human would develop when proper genetic manipulations were applied in mice, making it as a meaningful tool for translational research. We plan to delete Seipin in adipose and liver to further investigate its role in the onset of postprandial HTG and increased atherogenesis in lipodystropy. The proposed research will elucidate the molecular mechanisms of pathogenesis in severe HTG and atherogenesis in lipodystrophy and provide insights and foundation for prevention and treatment to these patients.