Many diseases such as cardiovascular disease, obesity, and diabetes are related with multi gene mutation. Multi gene interaction also plays a key role in the development of hyperlipidemia and atherosclerosis. Apolipoprotein E (apoE), a high affinity ligand of low density lipoprotein receptor (LDLR), mediates the clearance of the lipoprotein in vivo. OB R is the receptor of leptin, which can regulate the expenditure of energy and food intake. It has five spliced isoforms, the common two of which is the long form, OB Rb and the short form, OB Ra, the long receptor OB Rb has the capacity of signal transduction. The focus of the present study is to construct a multi gene mutation mouse model to characterize the mechanism of hyperlipidemia and atherosclerosis development based on the above three single gene mutation models (apoE -/- ,LDLR -/- ,and db/db mice). The results show that when with normal diet single mutation and multi gene mutation mice have a greatly elevated cholesterol and triglyceride level with progress of time, Plasma glucose level is significantly increased in the multi gene mutation mice and OB Rdb mice, While others have no distinct increase compared with wild type mice, and when with high fat diet, all the three plasma levels in the mutation mouse models especially in the multi gene mutation mice are improved remarkably in time of only two weeks, thereafter the intima of the aorta appears with typical pathological plaques. Take together, our data suggested such multi gene mutation were highly correlated with hyperlipidemia and even the process of atherosclerosis. The multi gene mutation mouse model also provides a more resemble human disease studying model, which can be very helpful to further study of pharmaceutical and gene mediated therapy. Multi-gene interaction also plays a key role in the development of hyperlipidemia and atherosclerosis. Apolipoprotein E (apoE), a high affinity ligand of low density lipoprotein receptor ( LDRR), mediates the clearance of the lipoprotein in vivo. OB R is the receptor of leptin, which can regulate the expenditure of energy and food intake. The common two of which is the long form, OB Rb and the short form, OB Ra, the long receptor OB Rb has the capacity of signal transduction. The focus of the present study is to construct a multi gene mutation mouse model to characterize the mechanism of hyperlipidemia and atherosclerosis development based on the above three single gene mutation patterns (apoE - / -, LDLR - / -, and db / db mice). The results show that when with normal diet single mutation and multi gene mutation mice have a significant elevated cho lesterol and triglyceride level with progress of time, Plasma glucose level is significantly increased in the multi gene mutation mice and OB Rdb mice, While others have no distinct increase compared with wild type mice, and when with high fat diet, all the three plasma levels in the mutation mouse models especially in the multi gene mutation mice are improved remarkably in time of only two weeks, thereafter the intima of the aorta appears with typical pathological plaques. Take together, our data suggested such multi-gene mutation were highly correlated with hyperlipidemia and even the process of atherosclerosis. The multi gene mutation mouse model also provides a more resemble human disease studying model, which can be very helpful to further study of pharmaceutical and gene mediated therapy.