Lipid Metabolism-related Gene Mutation Mouse Model Of Atherosclerosis Mechanism

Atherosclerosis is a complex multifactorial disease. Due to its high incidence, it has attracted people's considerable attention to study its mechanisms. At the present study, young apoE~/7LDLR"/YLeprdb/dbtreble-gene mutant mice were established and used for study the mechanisms of polygenetic dysfunction in dyslipidemia as well as atherogenesis. The relationship between treble-genetic mutation and hyperlipidemia, following atherosclerotic lesion and the differentially expressed genes in liver were discussed. The influence of high fat high cholesterol diet induction on the development of hyperlipidemia and atherosclerosis was also studied.The results showed that no manner with regular chow and high fat high cholesterol diet, plasma TC and TG levels of all mutant mice were significantly elevated compared with that of wild type mice at all stage of age, except that db mice had only slight elevations. Plasma levels of TC of treble-gene mutants at 5w of age was 19.88 +1.94mM, only slightly higher than that of double knockout mice, while when fed with high fat high cholesterol diet, it was 137.92 +30.62mM, dramatically elevated than that of any other mice. From 7w of age on, TC levels of treble-gene mutants were all significantly higher than that of double knockout mice and other mutant mice at the condition of either regular chow and high fat high cholesterol diet. The TG levels were increased with age, and when at 15w old, were significantly higher compared with that of other mutant mice. High fat high cholesterol diet promoted the development of hyperlipidemia. Concentrations of TC with regular chow diet was persistently elevated with age, while went up sharply at 5w of age, and then slightly got down at later till 15w when with high fat high cholesterol diet. TG levels were steadily increased with age in the treble mutant mice no manner under condition of regular chow or high fat high cholesterol diet.Treble-gene mutant mice had atherogenetic lesions even at 5w of age, and also more severe atherosclerotic lesions later. Their extent of intima lesions were significantly than that of other mutants at all stages of age and fed with both two diets. High fat high cholesterol diet accelerated the process of the onset anddevelopment of atherosclerosis.Among the 4000 target genes, 92 genes up-regulated and 105 gene down-regulated in the regular chow feeding treble-gene mutants compared with wild-type control. And 78 and 114 genes up- and down-regulated, respectively, under high fat high cholesterol diet feeding condition, in treble-gene mutants compared with that of regular chow littermates. The quite differently altered genes were involved with genes such as lipid and carbohydrate metabolism, cell skeleton, immune and inflammation related, which may reflect the physiological and pathological condition of these mutants. My data suggested treble-genetic mutation, especially the genes fatty metabolism related contributed to hyperlipidemia and atherogenetic lesion in these young mutants. Atherogenic diet stimulation could promote hyperlipidemia, aggravate pathological changes of aorta, and even develop atherosclerosis in the treble-genetic mutants. As my knowledge, this is a first report that established a treble-gene mutant mouse model that related with hyperlipidemia and atherosclerosis and have been used for liver gene expression profile using cDNA microarray. Further more detail and long term study using molecular and pathological analysis is underway.