Exploiting the Vascular Protective Effects of High-Density Lipoprotein and Its Apolipoproteins

Shah, Prediman K.; Kaul, Sanjay; Nilsson, Jan; Cercek, Bojan

doi:10.1161/hc4401.098467

Cited by 217 publications

(106 citation statements)

References 169 publications

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“…So, the lower HDL-cholesterol level observed both in the proband and in his brother may be related to a less efficient reverse cholesterol transport, which facilitates the accumulation of cholesterol in spleen macrophages and the development of splenomegaly. 6,7 Finally, it has also been shown that type III hyperlipidemia was much more common in men and tends to occur earlier in men than in women. 5 In conclusion, this report gives further emphasis that, besides to storage disease, the 149 variant of apoE appears as a cause of splenomegaly with sea-blue histiocytes, when associated to hypertriglyceridemia, thrombocytopenia.…”

Section: Discussionmentioning

confidence: 99%

Variable expressivity of the clinical and biochemical phenotype associated with the apolipoprotein E p.Leu149del mutation

et al. 2005

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Splenomegaly with sea-blue histiocytes, thrombocytopenia and hypertriglyceridemia is a very rare association that has been described in only one report to date. The molecular defect in the two reported patients consists in a deletion of a leucine at position 149 in the receptor-binding region of the apoE molecule. Here, we report on another family in whom the proband and his brother were diagnosed with splenomegaly, thrombocytopenia and hypertriglyceridemia. An apoE p.Leu149del mutation was found in both subjects. A large b band in the VLDL fraction and elevated VLDL cholesterol-to-plasma triglyceride ratio was observed in the proband only. Their mother, presenting with isolated hypertriglyceridemia, also carried the same p.Leu149del mutation. The coexistence of factors facilitating the development of hypertriglyceridemia and/or low HDL-cholesterol level could explain why the proband and his brother developed a splenomegaly with thrombocytopenia, whereas the mother did not. Moreover, the presence of an apoE2 allele in the proband likely explains the more severe phenotype we observed in this subject. In conclusion, the apoE p.Leu149del mutation results in a very striking phenotype including one or all symptoms among splenomegaly, thrombocytopenia and hypertriglyceridemia, and should be considered as a differential diagnosis of storage disorders in the causes of splenomegaly with sea-blue histiocytes.

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Section: Discussionmentioning

confidence: 99%

Variable expressivity of the clinical and biochemical phenotype associated with the apolipoprotein E p.Leu149del mutation

et al. 2005

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“…The underlying molecular mechanism of the atheroprotective effect of HDL is complex because HDL has multiple functions that contribute to this relationship. These include a key role in reverse cholesterol transport, antioxidant effects via proteins associated with HDL like paraoxonase, and anti-inflammatory properties of HDL (4,(33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

Increased Risk of Atherosclerosis by Elevated Plasma Levels of Phospholipid Transfer Protein

Haperen¹,

Tol²,

Gent³

et al. 2002

Journal of Biological Chemistry

118

122

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Plasma phospholipid transfer protein (PLTP) is thought to be involved in the remodeling of high density lipoproteins (HDL), which are atheroprotective. It is also involved in the metabolism of very low density lipoproteins (VLDL). Hence, PLTP is thought to be an important factor in lipoprotein metabolism and the development of atherosclerosis. We have overexpressed PLTP in mice heterozygous for the low density lipoprotein (LDL) receptor, a model for atherosclerosis. We show that increased PLTP activity results in a dose-dependent decrease in HDL, and a moderate stimulation of VLDL secretion (<1.5-fold). The mice were given a high fat, high cholesterol diet, which resulted in hypercholesterolemia in all animals. HDL concentrations were dramatically reduced in PLTP-overexpressing animals when compared with LDL receptor controls, whereas VLDL ؉ LDL cholesterol levels were identical. Susceptibility to atherosclerosis was increased in a PLTP doseresponsive manner. We conclude that PLTP increases susceptibility to atherosclerosis by lowering HDL concentrations, and therefore we suggest that an increase in PLTP is a novel, long term risk factor for atherosclerosis in humans. High density lipoproteins (HDL)1 are believed to be protective against the development of atherosclerosis because they mediate reverse cholesterol transport, i.e. the transfer of cholesterol from peripheral tissues to the liver (1, 2). However, our understanding of the molecular details and key regulatory proteins involved is incomplete (3-5). One effector of this process is the ATP-binding cassette ABCA1, which is functionally deficient in Tangier disease (reviewed in Ref. 6). The high incidence of coronary artery disease in Tangier patients suggests an essential, protective role of HDL-mediated reverse cholesterol transport in the development of atherosclerosis (7).However, recent results suggest that the contribution of ABCA1 to overall reverse cholesterol transport and its role in atherogenesis are primarily related to its function in macrophages (8 -10). Therefore, other potential key proteins in reverse cholesterol transport are of interest, including PLTP (11-13).Previously, we generated transgenic mice overexpressing human PLTP and showed that plasma from these animals is more effective in preventing accumulation of cholesterol by cultured macrophages (14). We and others therefore suggested an antiatherogenic effect for PLTP (14 -16). On the other hand, overexpression of PLTP results in a decrease of plasma HDL levels (14, 17, 18), which could be an atherogenic effect. Thus, it is unclear whether the net effect of high PLTP activity levels would be atherogenic or anti-atherogenic. The complete absence of PLTP activity in PLTP knockout mice inhibits HDL maturation, which results in reduced levels of plasma HDL caused by accelerated decay (19,20). Still, PLTP knockout mice showed decreased atherosclerosis (21). This could be partly explained by the discovery of a novel, intracellular function of PLTP in hepatocytes; it was found that PLTP def...

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“…Recent work demonstrates that vascular inflammation can be limited by anti-inflammatory counter-regulatory agents, including HDL and exchangeable apolipoproteins, such as apoA-I (45,46). It has been reported that HDL and exchangeable apolipoproteins neutralize LPS pro-inflammatory activity and prevent LDL oxidation (47).…”

Section: ␣-Helical Peptides Block Pro-inflammatory Responsesmentioning

confidence: 99%

Targeting of Scavenger Receptor Class B Type I by Synthetic Amphipathic α-Helical-containing Peptides Blocks Lipopolysaccharide (LPS) Uptake and LPS-induced Pro-inflammatory Cytokine Responses in THP-1 Monocyte Cells

Bocharov

Baranova

Vishnyakova³

et al. 2004

Journal of Biological Chemistry

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Exploiting the Vascular Protective Effects of High-Density Lipoprotein and Its Apolipoproteins

Cited by 217 publications

References 169 publications

Variable expressivity of the clinical and biochemical phenotype associated with the apolipoprotein E p.Leu149del mutation

Variable expressivity of the clinical and biochemical phenotype associated with the apolipoprotein E p.Leu149del mutation

Increased Risk of Atherosclerosis by Elevated Plasma Levels of Phospholipid Transfer Protein

Targeting of Scavenger Receptor Class B Type I by Synthetic Amphipathic α-Helical-containing Peptides Blocks Lipopolysaccharide (LPS) Uptake and LPS-induced Pro-inflammatory Cytokine Responses in THP-1 Monocyte Cells

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