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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    • "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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    ABSTRACT: HIV-infected patients develop multiple metabolic abnormalities including insulin resistance, lipodystrophy and dyslipidemia. Although progression of these disorders has been associated with the use of various protease inhibitors and other antiretroviral drugs, HIV-infected individuals who have not received these treatments also develop lipid abnormalities albeit to a lesser extent. How HIV alters lipid metabolism in an infected cell and what molecular changes are affected through protein interaction pathways are not well-understood. Since many genetic, epigenetic, dietary and other factors influence lipid metabolism in vivo, we have chosen to study genome-wide changes in the proteomes of a human T-cell line before and after HIV infection in order to circumvent computational problems associated with multiple variables. Four separate experiments were conducted including one that compared 14 different time points over a period of >3 months. By subtractive analyses of protein profiles overtime, several hundred differentially expressed proteins were identified in HIV-infected cells by mass spectrometry and each protein was scrutinized for its biological functions by using various bioinformatics programs. Herein, we report 18 HIV-modulated proteins and their interaction pathways that enhance fatty acid synthesis, increase low density lipoproteins (triglycerides), dysregulate lipid transport, oxidize lipids, and alter cellular lipid metabolism. We conclude that HIV replication alone (i.e. without any influence of antiviral drugs, or other human genetic factors), can induce novel cellular enzymes and proteins that are significantly associated with biologically relevant processes involved in lipid synthesis, transport and metabolism (p = <0.0002-0.01). Translational and clinical studies on the newly discovered proteins may now shed light on how some of these proteins may be useful for early diagnosis of individuals who might be at high risk for developing lipid-related disorders. The target proteins could then be used for future studies in the development of inhibitors for preventing lipid-metabolic anomalies. This is the first direct evidence that HIV-modulates production of proteins that are significantly involved in disrupting the normal lipid-metabolic pathways.
    PLoS ONE 02/2008; 3(8):e3003. DOI:10.1371/journal.pone.0003003 · 3.23 Impact Factor
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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.
    Biochimica et Biophysica Acta 03/2006; 1761(2):213-20. DOI:10.1016/j.bbalip.2006.01.002 · 4.66 Impact Factor
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    ABSTRACT: LPL activity plays an important role in preceding the VLDL remnant clearance via the three major apolipo- protein E (apoE)-recognizing receptors: the LDL receptor (LDLr), LDL receptor-related protein (LRP), and VLDL re- ceptor (VLDLr). The aim of this study was to determine whether LPL activity is also important for VLDL remnant clearance irrespective of these receptors and to determine the mechanisms involved in the hepatic remnant uptake. Ad- ministration of an adenovirus expressing LPL (AdLPL) into lrp2ldlr2/2vldlr2/2 mice reduced both VLDL-triglyceride (TG) and VLDL-total cholesterol (TC) levels. Conversely, in- hibition of LPL by AdAPOC1 increased plasma VLDL-TG and VLDL-TC levels. Metabolic studies with radiolabeled VLDL-like emulsion particles showed that the clearance and hepatic association of their remnants positively corre- lated with LPL activity. This hepatic association was inde- pendent of the bridging function of LPL and HL, since heparin did not reduce the liver association. In vitro studies demonstrated that VLDL-like emulsion particles avidly bound to the cell surface of primary hepatocytes from lrp2ldlr2/2vldlr2/2 mice, followed by slow internalization, and involved heparin-releaseable cell surface proteins as well as scavenger receptor class B type I (SR-BI). Collec- tively, we conclude that hepatic VLDL remnant uptake in the absence of the three classical apoE-recognizing recep- tors is regulated by LPL activity and involves heparan sulfate proteoglycans and SR-BI.—Hu, L., C. C. van der Hoogt, S. M. S. Espirito Santo, R. Out, K. E. Kypreos, B. J. M. van Vlijmen, T. J. C. Van Berkel, J. A. Romijn, L. M. Havekes, K. Willems van Dijk, and P. C. N. Rensen. The hepatic uptake of VLDL in lrp2ldlr2/2vldlr2/2 mice is regulated by LPL activity and involves proteoglycans and SR-BI. J. Lipid Res. 2008. 49: 1553-1561.
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