Expression of human apolipoprotein (apo) A-II in apoE deficient mice reproduces the effects of a major familial combined hyperlipidemia gene

Escolà-Gil, Joan Carles; Julve, Josep; Marzal-Casacuberta, Àfrica; Ordóñez-Llanos, Jordi; González‐Sastre, Francesc; Blanco‐Vaca, Francisco

doi:10.1016/s0021-9150(00)80299-3

Cited by 23 publications

(32 citation statements)

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“…These features are in agreement with the decreased HDL selective lipid uptake we observed, although HDL turnover studies have not been performed in these animals. The finding that increased apoA-II levels are associated with decreased selective lipid uptake is compatible with the model that apoA-II functions in a proatherogenic manner (8,(10)(11)(12) by inhibiting reverse CE transport to the liver. Other potential mechanisms by which apoA-II may retard reverse cholesterol transport include its effect on modulating the interaction of HDL with lipid transfer proteins and enzymes [reviewed in ref.…”

Section: Discussionsupporting

confidence: 85%

“…In contrast to transgenic mice, apoA-II-deficient mice have low HDL levels, increased clearance of triglyceride-rich lipoproteins, and insulin hypersensitivity (9). The majority of studies using human or mouse apoA-II transgenic mice also indicated apoA-II to be proatherogenic (8,(10)(11)(12)(13), although one indicated an antiatherogenic effect (14). Structural differences between human apoA-II (a dimer) and mouse apoA-II (a monomer) may explain many of the observed differences between the biological properties of the two apoA-II species (7).…”

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ApoA-II modulates the association of HDL with class B scavenger receptors SR-BI and CD36

Beer

Castellani

Cai

et al. 2004

Journal of Lipid Research

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The class B scavenger receptors SR-BI and CD36 exhibit a broad ligand binding specificity. SR-BI is well characterized as a HDL receptor that mediates selective cholesteryl ester uptake from HDL. CD36, a receptor for oxidized LDL, also binds HDL and mediates selective cholesteryl ester uptake, although much less efficiently than SR-BI. Apolipoprotein A-II (apoA-II), the second most abundant HDL protein, is considered to be proatherogenic, but the underlying mechanisms are unclear. We previously showed that apoA-II modulates SR-BI-dependent binding and selective uptake of cholesteryl ester from reconstituted HDL. To investigate the effect of apoA-II in naturally occurring HDL on these processes, we compared HDL without apoA-II (from apoA-II null mice) with HDLs containing differing amounts of apoA-II (from C57BL/6 mice and transgenic mice expressing a mouse apoA-II transgene). The level of apoA-II in HDL was inversely correlated with HDL binding and selective cholesteryl ester uptake by both scavenger receptors, particularly CD36. Interestingly, for HDL lacking apoA-II, the efficiency with which CD36 mediated selective uptake reached a level similar to that of SR-BI. These results demonstrate that apoA-II exerts a marked effect on HDL binding and selective lipid uptake by the class B scavenger receptors and establishes a potentially important relationship between apoA-II and CD36.

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Section: Discussionsupporting

confidence: 85%

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confidence: 99%

ApoA-II modulates the association of HDL with class B scavenger receptors SR-BI and CD36

Beer

Castellani

Cai

et al. 2004

Journal of Lipid Research

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“…Results from studies in mice that express a transgene for human apoA-II have shown similarities as well as differences with respect to the effects of apoA-II in the mouse (53). Most (54-61) but not all (62)(63)(64)(65)(66) of these studies have demonstrated that increasing human apoA-II in the mouse resulted in an increase in plasma triglycerides and non-HDL cholesterol, consistent with the effects observed in the present study. However, unlike the transgene for mouse apoA-II, human apoA-II does not increase HDL cholesterol or appear to affect IR or obesity in these mouse models (67).…”

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confidence: 88%

Mechanisms mediating insulin resistance in transgenic mice overexpressing mouse apolipoprotein A-II

Castellani

Gargalovic

Febbraio

et al. 2004

Journal of Lipid Research

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We previously demonstrated that transgenic mice overexpressing mouse apolipoprotein A-II (apoA-II) exhibit several traits associated with the insulin resistance (IR) syndrome, including increased atherosclerosis, hypertriglyceridemia, obesity, and IR. The skeletal muscle appeared to be the insulin-resistant tissue in the apoA-II transgenic mice. We now demonstrate a decrease in FA oxidation in skeletal muscle of apoA-II transgenic mice, consistent with reports that decreased skeletal muscle FA oxidation is associated with increased skeletal muscle triglyceride accumulation, skeletal muscle IR, and obesity. The decrease in FA oxidation is not due to decreased carnitine palmitoyltransferase 1 activity, because oxidation of palmitate and octanoate were similarly decreased. Alterations in both glucose and lipid metabolism are two consistent features of the insulin resistance (IR) syndrome) (1, 2). Several studies have demonstrated that primary changes in FA metabolism can lead to IR (3-8). Although much has been learned about the insulin signaling pathways and the metabolism of both glucose and FAs, the underlying cause of most cases of IRS and type 2 diabetes is unknown (9, 10). Whether primary defects in FA metabolism or glucose metabolism underlie the majority of human cases of IRS and type 2 diabetes remains to be determined.Studies using genetically altered mice have demonstrated that both the scavenger receptor CD36 and the HDL-associated protein apolipoprotein A-II (apoA-II) alter FA metabolism and IR (11-16). Furthermore, HDL is a ligand for the CD36 receptor, which raises the possibility of an HDL-CD36 interaction that affects FA metabolism (15). Mice with a null mutation for apoA-II exhibit increased sensitivity to insulin, with decreased plasma concentrations of triglycerides, FFA, and glucose (11). We previously demonstrated that increasing plasma concentrations of mouse apoA-II in transgenic mice produced several aspects of the IR syndrome including hypertriglyceridemia, obesity, and IR, as well as increased atherosclerotic lesion development (12,(17)(18)(19). The skeletal muscle appeared to be the insulin-resistant tissue in the apoA-II transgenic mice, whereas the liver and adipose tissue in the apoA-II trangenic mice appeared to respond normally (12). Compared with control mice, isolated soleus muscles from the apoA-II transgenic mice exhibited decreased glucose uptake and increased triglyceride accumulation (12). We hypothesize that primary alterations in FA metabolism in skeletal muscle initiate IR and promote the development of obesity. In the present study, we demonstrate that FA oxidation is reduced in the skeletal muscle of apoA-II transgenic mice, which could initiate the metabolic events that lead to skeletal muscle IR. We also placed the apoA-II transgene onto a CD36 knockout background and demonstrated that plasma triglyceride and insulin concentrations are not markedly different in the apoA-II transgenic mice, whether or Abbreviations: apoA-II, apolipoprotein A-II; CPT-1, carnitin...

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“…At greater expression levels of human (12) or murine (15) apoA-II, plasma HDL was increased in mice overexpressing murine apoA-II (14,15) but decreased in mice overexpressing human apoA-II (12,16). Surprisingly, mouse apoA-II overexpression resulted in increased atherosclerotic lesions under standard chow (14), whereas human apoA-II overexpression increased fatty streaks only after long term feeding with an atherogenic diet (13). Two of the above studies reported mildly increased plasma triglyceride (TG), which was associated with the VLDL fraction when mice expressed high levels of human (12) or murine (15) apoA-II.…”

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Overexpression of Human Apolipoprotein A-II in Mice Induces Hypertriglyceridemia Due to Defective Very Low Density Lipoprotein Hydrolysis

Boisfer¹,

Lambert²,

Atger³

et al. 1999

Journal of Biological Chemistry

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Two lines of transgenic mice, hAIItg-␦ and hAIItg-, expressing human apolipoprotein (apo)A-II at 2 and 4 times the normal concentration, respectively, displayed on standard chow postprandial chylomicronemia, large quantities of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) but greatly reduced high density lipoprotein (HDL). Hypertriglyceridemia may result from increased VLDL production, decreased VLDL catabolism, or both. Post-Triton VLDL production was comparable in transgenic and control mice. Postheparin lipoprotein lipase (LPL) and hepatic lipase activities decreased at most by 30% in transgenic mice, whereas adipose tissue and muscle LPL activities were unaffected, indicating normal LPL synthesis. However, VLDL-triglyceride hydrolysis by exogenous LPL was considerably slower in transgenic compared with control mice, with the apparent V max of the reaction decreasing proportionately to human apoA-II expression. Human apoA-II was present in appreciable amounts in the VLDL of transgenic mice, which also carried apoC-II. The addition of purified apoA-II in postheparin plasma from control mice induced a dose-dependent decrease in LPL and hepatic lipase activities. In conclusion, overexpression of human apoA-II in transgenic mice induced the proatherogenic lipoprotein profile of low plasma HDL and postprandial hypertriglyceridemia because of decreased VLDL catabolism by LPL. Low plasma HDL1 levels are negatively correlated with the risk of atherosclerosis. Although a number of metabolic functions of HDL have been identified, no direct link has been established between HDL functions and its antiatherogenic effect (1). In vitro studies have shown that apolipoprotein (apo)A-I, the major HDL apolipoprotein, activates reverse cholesterol transport from extrahepatic tissues to the liver (2). However, conflicting results have been reported concerning the role of apoA-II, the second most abundant HDL apolipoprotein (3, 4). Studies of transgenic mice overexpressing human apoA-I and apoA-II reported that apoA-I protected more against aortic lesions than apoA-II (3). Furthermore, HDL from transgenic mice overexpressing mouse apoA-II lost the ability of HDL to protect against low density lipoprotein (LDL) oxidation (5) and was even proinflammatory (6). Deficiency of either apoA-I (7, 8) or apoA-II (9) obtained by gene targeting technology resulted in very low plasma HDL, showing the critical importance of both apolipoproteins in maintaining the normal structure and metabolism of HDL. At present, apoA-II has been linked with HDL metabolism only, but its exact role remains to be elucidated.Studies of transgenic mice expressing human (10 -13) or murine (14, 15) apoA-II, alone or in combination with human apoA-I, apoC-III, and cholesterol ester transfer protein (16), have provided interesting information. When human apoA-II was expressed at normal levels, overall lipoprotein metabolism was not markedly modified, except for the appearance of a smaller HDL population containing solely human apoA-II (10). At...

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Expression of human apolipoprotein (apo) A-II in apoE deficient mice reproduces the effects of a major familial combined hyperlipidemia gene

Cited by 23 publications

References 0 publications

ApoA-II modulates the association of HDL with class B scavenger receptors SR-BI and CD36

ApoA-II modulates the association of HDL with class B scavenger receptors SR-BI and CD36

Mechanisms mediating insulin resistance in transgenic mice overexpressing mouse apolipoprotein A-II

Overexpression of Human Apolipoprotein A-II in Mice Induces Hypertriglyceridemia Due to Defective Very Low Density Lipoprotein Hydrolysis

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