Triglyceride-rich lipoprotein metabolism in unique VLDL receptor, LDL receptor, and LRP triple-deficient mice

Leiden University, Leyden, South Holland, Netherlands
The Journal of Lipid Research (Impact Factor: 4.42). 07/2005; 46(6):1097-102. DOI: 10.1194/jlr.C500007-JLR200
Source: PubMed


The very low density lipoprotein receptor (VLDLR), low density lipoprotein receptor (LDLR), and low density lipoprotein receptor-related protein (LRP) are the three main apolipoprotein E-recognizing endocytic receptors involved in the clearance of triglyceride (TG)-rich lipoproteins from plasma. Whereas LDLR deficiency in mice results in the accumulation of plasma LDL-sized lipoproteins, VLDLR or LRP deficiency alone only minimally affects plasma lipoproteins. To investigate the combined effect of the absence of these receptors on TG-rich lipoprotein levels, we have generated unique VLDLR, LDLR, and LRP triple-deficient mice. Compared with wild-type mice, these mice markedly accumulated plasma lipids and lipases. These mice did not show aggravated hyperlipidemia compared with LDLR and LRP double-deficient mice, but plasma TG was increased after high-fat diet feeding. In addition, these mice showed a severely decreased postprandial TG clearance typical of VLDLR-deficient (VLDLR-/-) mice. Collectively, although VLDLR deficiency in LRP- and LDLR-/- mice does not aggravate hyperlipidemia, these triple-deficient mice represent a unique model of markedly delayed TG clearance on a hyperlipidemic background.

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Available from: Patrick C.N. Rensen
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    • "LRP1 is normally associated with macrophages and vascular smooth muscle cells and is upregulated in lipid-enriched plaques in atherosclerotic lesions [88], [92], [93]. In addition, lipid peroxidation of low and very low density lipoproteins has been implicated in early stages of heart diseases through multiple potential pathways [94], [95]. Overexpression of LRP1 in our experimentally HIV infected cells exemplifies its multiple roles in enhancing the quantity of fatty acids (p = 0.02), increasing free fatty acids (p = 0.005), removal of lipids (p = 0.0002) and clearance of triacylglcerol (p = 0.0005) (Table 2). "
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    • "mice by intraperitoneal injection of polyinosinic:polycytidylic ribonucleic acid (pI: pC, Sigma, St. Louis, MO, USA), which results in the complete absence of LRP protein in liver membrane extracts [19]. Experiments were performed after 4 h of fasting at 12:00 pm with food withdrawn at 8:00 am. "
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    ABSTRACT: We have recently shown that the predominant hypertriglyceridemia in human apolipoprotein C1 (APOC1) transgenic mice is mainly explained by apoCI-mediated inhibition of the lipoprotein lipase (LPL)-dependent triglyceride (TG)-hydrolysis pathway. Since the very-low-density lipoprotein receptor (VLDLr) and apoCIII are potent modifiers of LPL activity, our current aim was to study whether the lipolysis-inhibiting action of apoCI would be dependent on the presence of the VLDLr and apoCIII in vivo. Hereto, we employed liver-specific expression of human apoCI by using a novel recombinant adenovirus (AdAPOC1). In wild-type mice, moderate apoCI expression leading to plasma human apoCI levels of 12-33 mg/dl dose-dependently and specifically increased plasma TG (up to 6.6-fold, P < 0.001), yielding the same hypertriglyceridemic phenotype as observed in human APOC1 transgenic mice. AdAPOC1 still increased plasma TG in vldlr(-/-) mice (4.1-fold, P < 0.001) and in apoc3(-/-) mice (6.8-fold, P < 0.001) that were also deficient for the low-density lipoprotein receptor (LDLr) and LDLr-related protein (LRP) or apoE, respectively. Thus, irrespective of receptor-mediated remnant clearance by the liver, liver-specific expression of human apoCI causes hypertriglyceridemia in the absence of the VLDLr and apoCIII. We conclude that apoCI is a powerful and direct inhibitor of LPL activity independent of the VLDLr and apoCIII.
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