Lipodystrophic gene Agpat2 deficiency aggravates hyperlipidemia and atherosclerosis in Ldlr −/− mice

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 ( Agpat2 −/− Ldlr −/− ). 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, Agpat2 −/− Ldlr −/− mice showed significantly higher plasma total cholesterol and triglycerides after HFD feeding. Agpat2 −/− Ldlr −/− mice also developed hyperglycemia and hyperinsulinemia, with increased pancreatic islet area. The liver weight of Agpat2 −/− Ldlr −/− 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 Agpat2 −/− Ldlr −/− 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.