Acute Elevation of Plasma PLTP Activity Strongly Increases Pre-existing Atherosclerosis

Abstract

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...

Worsening of Diet-Induced Atherosclerosis in a New Model of Transgenic Rabbit Expressing the Human Plasma Phospholipid Transfer Protein

“…In genetically engineered mice, contradictory observations were reported with either no change, a PLTP-mediated increase, or a PLTP-mediated decrease in HDL particle size. 27,[35][36][37][38][39] In contrast, the present rabbit data resemble some human observations in which increased PLTP activity was associated with enlarged HDL. 17,40 It is likely to result from the previously described conversion process involving the fusion of HDL particles of intermediate size.…”

“…Two main points should be considered when addressing the putative molecular mechanism that would account for the more severe hypercholesterolemic trait of cholesterol-fed HuPLTPTg rabbits as compared with cholesterol-fed WT rabbits. First, when PLTP was found to delay the catabolism of apoB-containing lipoproteins in some of the earlier mouse studies, it was accompanied by both the accumulation of triglyceride-rich lipoproteins in plasma 35 and marked alterations in LDL structure and composition. 42 It was not the case in the present study after 8 weeks of dietary manipulation because in cholesterol-fed HuPLTPTg rabbits the plasma triglyceride concentration, as well as the overall structure and composition of circulating apoB-containing particles, remained unchanged despite a 50% increment in LDL particle number as compared with cholesterol-fed WT rabbits.…”

Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis

“…This results in an atherogenic lipoprotein profile with elevated VLDL and reduced HDL, increased plasma cholesterol, and impaired reverse cholesterol transport. Accordingly, hypercholesterolemic mice carrying a PLTP transgene develop accelerated atherosclerosis (36,37), whereas PLTP deficiency protects from disease (38).…”

Impact of Phospholipid Transfer Protein on Nascent High-Density Lipoprotein Formation and Remodeling

“…In apoB-transgenic and apoE-deficient mice, PLTP deficiency markedly decreased atherosclerosis. 11 This concept was supported by results of PLTP over-expression in mice lacking either apoE 12, 13 or the LDL receptor, 14 in which over-expression of PLTP increased atherosclerosis. However, a study has suggested that expression of PLTP in macrophages is atheroprotective in LDLR-deficient mice with systemic PLTP deficiency.…”