Objective-A transgenic mouse model was generated that allows conditional expression of human PLTP, based on the tetracycline-responsive gene system, to study the effects of an acute increase in plasma PLTP activity as may occur in inflammation. Methods and Results-The effects of an acute elevation of plasma PLTP activity on the metabolism of apolipoprotein B-containing lipoproteins and on diet-induced pre-existing atherosclerosis were determined in mice displaying a humanized lipoprotein profile (low-density lipoprotein receptor knockout background). Induced expression of PLTP strongly increases plasma VLDL levels in LDL receptor knockout mice, whereas VLDL secretion is not affected. The elevation in plasma triglyceride levels is explained by a PLTP-dependent inhibition of VLDL catabolism, which is caused, at least partly, by a decreased lipoprotein lipase activity. Together with the decreased plasma HDL levels, the acutely increased PLTP expression results in a highly atherogenic lipoprotein profile. Induction of PLTP expression leads to a further increase in size of pre-existing atherosclerotic lesions, even on a chow diet. In addition, the lesions contain more macrophages and less collagen relative to controls, suggesting a less stable lesion phenotype. Key Words: atherosclerosis Ⅲ lipoproteins Ⅲ phospholipid transfer protein Ⅲ transgenic mouse models Ⅲ triglycerides S tudies in various atherosclerosis-prone mouse models have demonstrated that expression of human phospholipid transfer protein (PLTP) stimulates the development of atherosclerosis. [1][2][3] This can be explained by effects of PLTP activity on lipoprotein composition and metabolism. PLTP increases hepatic VLDL secretion 4 -7 and decreases plasma HDL levels, resulting in a more atherogenic lipoprotein profile. [7][8][9] Furthermore, PLTP unfavorably affects the antiinflammatory and antioxidative properties of HDL particles. 6,10 -12 Recently we developed a transgenic mouse model that allows conditional expression of human PLTP. 13 We hypothesize that the physiological effect of an acute increase in plasma PLTP activity differs significantly from the effects seen in mice overexpressing human PLTP innately and life-long and which may have developed compensatory mechanisms. We tested this hypothesis in transgenic mice that conditionally overexpress human PLTP and that are deficient for the LDL receptor. The first objective was to test the effects of acute elevation of plasma PLTP activity on lipoprotein metabolism. The second objective was to study the effect of the acute expression of human PLTP on diet-induced pre-existing atherosclerosis.
Conclusion-In
Materials and Methods
AnimalsThe generation of inducible human PLTP transgenic mice is described in detail elsewhere. 13 Briefly, 2 constructs were used to generate transgenic mice that allow inducible expression of PLTP: (1) hnRNP-rtTA-SV40, which consists of an improved version of the tetracycline-controlled transactivator rtTA2S-M2 under the control of an hnRNP A2 coding sequence, resulting in r...