Laboratory of Lipid Metabolism, Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei 050017, China; Laboratory Department of Hebei General Hospital, Shijiazhuang, Hebei 050051, China.
Laboratory of Lipid Metabolism, Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei 050017, China; Department of General Surgery, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050031, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Jan;1870(1):166850. doi: 10.1016/j.bbadis.2023.166850. Epub 2023 Aug 15.
Dysfunction of adipose tissue increases the risk of cardiovascular disease. It was well established that obesity aggravates atherosclerosis, but the effect of adipose tissue loss on atherosclerosis has been less studied. AGPAT2 is the first causative gene of congenital generalized lipodystrophy (CGL), but the role of AGPAT2 on atherosclerosis has not been reported. Hypertriglyceridemia is one of the clinical manifestations of CGL patients, but it is usually absent in CGL mouse model on a normal diet. This study will investigate the effect of Agpat2 on hyperlipidemia and atherosclerosis.
In this study, Agpat2 knockout (Agpat2) mice were generated using CRISPR/Cas system, which showed severe loss of adipose tissue and fatty liver, consistent with previous reports. Agpat2 mice were then crossed with hypercholesterolemic and atherosclerotic prone LDL receptor knockout (Ldlr) mice to obtain double knockout mouse model (Agpat2Ldlr). Plasma lipid profile, insulin resistance, fatty liver, and atherosclerotic lesions were observed after 12 weeks of the atherogenic high-fat diet (HFD) feeding. We found that compared with Ldlr mice, Agpat2Ldlr mice showed significantly higher plasma total cholesterol and triglycerides after HFD feeding. Agpat2Ldlr mice also developed hyperglycemia and hyperinsulinemia, with increased pancreatic islet area. The liver weight of Agpat2Ldlr mice was about 4 times higher than that of Ldlr mice. The liver lipid deposition was severe and Sirius red staining showed liver fibrosis. In addition, in Agpat2Ldlr mice, the area of atherosclerotic lesions in aortic arch and aortic root was significantly increased.
Our results show that Agpat2 deficiency led to more severe hyperlipidemia, liver fibrosis and aggravation of atherosclerosis in Ldlr mice. This study provided additional insights into the role of adipose tissue in hyperlipidemia and atherosclerosis.
脂肪组织功能障碍会增加心血管疾病的风险。众所周知，肥胖会加重动脉粥样硬化，但脂肪组织减少对动脉粥样硬化的影响研究较少。AGPAT2 是先天性全身性脂肪营养不良（CGL）的第一个致病基因，但 AGPAT2 对动脉粥样硬化的作用尚未报道。高甘油三酯血症是 CGL 患者的临床表现之一，但在正常饮食的 CGL 小鼠模型中通常不存在。本研究将探讨 Agpat2 对高脂血症和动脉粥样硬化的影响。
在这项研究中，使用 CRISPR/Cas 系统生成了 Agpat2 基因敲除（Agpat2）小鼠，这些小鼠表现出严重的脂肪组织和脂肪肝缺失，与之前的报道一致。然后，将 Agpat2 小鼠与高胆固醇血症和易患动脉粥样硬化的 LDL 受体敲除（Ldlr）小鼠杂交，以获得双敲除小鼠模型（Agpat2Ldlr）。在致动脉粥样硬化的高脂肪饮食（HFD）喂养 12 周后，观察血浆脂质谱、胰岛素抵抗、脂肪肝和动脉粥样硬化病变。与 Ldlr 小鼠相比，Agpat2Ldlr 小鼠在 HFD 喂养后血浆总胆固醇和甘油三酯明显升高。Agpat2Ldlr 小鼠还出现了高血糖和高胰岛素血症，胰岛面积增加。Agpat2Ldlr 小鼠的肝重约为 Ldlr 小鼠的 4 倍。肝脂质沉积严重，天狼星红染色显示肝纤维化。此外，在 Agpat2Ldlr 小鼠中，主动脉弓和主动脉根部的动脉粥样硬化病变面积明显增加。
我们的结果表明，Agpat2 缺乏导致 Ldlr 小鼠的高脂血症、肝纤维化和动脉粥样硬化加重。本研究为脂肪组织在高脂血症和动脉粥样硬化中的作用提供了更多的见解。
