Ldlr Gene Deletion In Mice And Lipid Metabolism, Inflammation And Glucose Metabolism - Related Gene Expression

Atherosclerosis involves a large genetic network, not a simple linear pathway. This network extends to interactions with the many known risk factors for the disease and involves many cell types and organ systems. Arguably the most critical advancement in the elucidation of factors affecting atherogenesis has been the development of mouse models of atherosclerosis. Among available models, the lower density lipoprotein receptor-deficient (LDLR-/-) mouse is particularly popular because of its propensity to spontaneously develop atherosclerotic lesions on a standard chow diet. This review will examine our present understanding of the pathology and progression of plaques in this animal and highlight some of the nutritional, pharmacological, and genetic studies that have enhanced this understanding. There are a variety of theories about the pathogenesis of AS, but the areas that the theories concerned are different respectively, and they reflected the occurrence of AS. Hyperlipidemia is an independent risk factor in the occurrence and the development of AS. Our preliminary experiments show that, the synergies between blood lipid transport, metabolic pathway disorder caused by several abnormal genes related to lipid metabolism and other risk factors play an important role in the occurrence and the development of AS. In order to find the great significant impact factor and discuss the changes in the law of lipid metabolism-related genes, proinflammatory cytokines and glucose metabolism-related genes in the early stage of AS, I used LDLR-/- mice as a model, detected the differential expression of lipid metabolism-related, proinflammatory cytokines and glucose metabolism-related key genes in the liver of LDLR-/- and wild type (WT) mice with RT-PCR method. Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) level as well as aortic morphology were also analyzed.The results showed that: In 14 lipid metabolism-related genes dctected, LDLR-/-mice compared with wild type (WT) mice, the mRNA level of the apolipoprotein A IV (apoA IV), fatty acid translocase (Fat/CD36), carnitine palmitoyl transferase I (CPT I), glucose-regulated protein 78 (GRP78) and scavenger receptor class A (SR-A) changed prominently at the age of 14-days (P<0.05). At 30 days, the mRNA level of apolipoprotein A I (apoA I) was up regulated, but apolipoprotein F (apoF) were down regulated(P<0.05); At 60 days, the mRNA levels of apoA I, CPT I and liver X receptorα(LXRα) were up regulated, but apoA IV was down regulated (P<0.05); At 90 days, the level of the apoA I was higher, but the expression of the apoA IV, apoF and acyl-coenzymeA oxidase 1 (ACOX1) were down regulated (P<0.05), whereas the expression of the apolipoprotein A V (apoA V), apolipoprotein E (apoE), peroxidase proliferator-activated receptorα(PPARα) and angiopoietin-like protein 3 (angptl 3) had no significant changes (P>0.05).LDLR-/-mice compared with wild type (WT) mice, the mRNA expression levels of inflammation-related key genes albumin was higher, but the expression of the janus kinase-1 (JAK-1) were down regulated (P<0.05), whereas the expression of the c-reation protein (CRP) and Mannan-binding lectin (MBL) had no significant changes (P>0.05).The mRNA expression levels of glucose metabolism-related key genes phosphoenolpyruvate carboxykinase (PEPCK) and Protein Kinase B (Akt/PKB)have no significant changes.LDLR-/-mice compared with wild type (WT) mice, the serum levels of TC (P<0.05), TG (P<0.05) and LDLC (P<0.05) in LDLR-/- mice were significantly higher than those in wild type mice with the same age. TC and LDL-C levels were higher than those of age matched WT mice about 4 and 10 folds. TG levels were higher than those of age matched WT mice about 3 folds and HDL-C evels were higher than those of age matched WT mice about 2 folds. Meanwhile, in LDLR-/- mice, with the increase of age, typical early atherosclerotic lesions were observed at sinus and root regions of aorta.The mRNA levels of the apoA I, apoA IV, apoF, FAT/CD36, CPT I, ACOX1, LXRα, albumin and JAK-1 of the LDLR-/- mice were significantly changed compared to the WT mice. These genes may be of some relevance to the complicated lipid metabolism network, and have effect in the early stage of atherogenesis.