A Mouse Model with Features of Familial Combined Hyperlipidemia

Masucci-Magoulas, L.; Goldberg, Ira J.; Bisgaier, Charles L.; Serajuddin, Humaira; Francone, Omar L.; Breslow, Jan L.; Tall, Alan R.

doi:10.1126/science.275.5298.391

Cited by 126 publications

(76 citation statements)

References 28 publications

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“…First, Tall's laboratory has demonstrated that LDL-receptor deficient mice get large aortic root lesions when fed the Westerntype diet for three months [75],whilst this diet is not known to lead to atherosclerosis in the susceptible C57BL/6 strain. Secondly, this model is currently being used by many laboratories to study atherosclerosis in a context of hyperlipidaemia that is somewhat less extreme, and more human-like in the elevation of LDL, than that observed in the apoE-deficient mice.…”

Section: Ldl Receptor Deficiency-induced Atherosclerosismentioning

confidence: 99%

“…Secondly, this model is currently being used by many laboratories to study atherosclerosis in a context of hyperlipidaemia that is somewhat less extreme, and more human-like in the elevation of LDL, than that observed in the apoE-deficient mice. The LDL receptor-deficient mice on the Western-type diet have total cholesterol levels of approximately 400 mg dL Ϫ1 , which is largely in the LDL ϩ IDL size factions [75]. Overexpression of apoCIII in the LDL-receptor deficient context, by breeding in an apoCIII transgene, led to a marked and synergistic increase in plasma triglycerides, VLDL ϩ LDL cholesterol, and aortic root lesion area [75].…”

Section: Ldl Receptor Deficiency-induced Atherosclerosismentioning

confidence: 99%

“…The LDL receptor-deficient mice on the Western-type diet have total cholesterol levels of approximately 400 mg dL Ϫ1 , which is largely in the LDL ϩ IDL size factions [75]. Overexpression of apoCIII in the LDL-receptor deficient context, by breeding in an apoCIII transgene, led to a marked and synergistic increase in plasma triglycerides, VLDL ϩ LDL cholesterol, and aortic root lesion area [75]. In addition, by adding the human CETP gene to the above combination, HDL levels were decreased, thus creating a mouse model for human familial combined hyperlipidaemia with increased triglycerides, increased VLDL ϩ LDL cholesterol levels, and decreased HDL cholesterol [75].…”

Section: Ldl Receptor Deficiency-induced Atherosclerosismentioning

confidence: 99%

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The emergence of mouse models of atherosclerosis and their relevance to clinical research

Smith

Breslow

1997

Journal of Internal Medicine

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Due to the ability to introduce or mutate genes, the mouse has become the most common experimental animal model for atherosclerosis research. Wildtype mice on a chow diet do not get atherosclerosis. Three ways to induce atherosclerosis in mice are discussed: diet-induced, apoE deficiency-induced, and LDL receptor-deficiency induced. The atherosclerotic lesions in apoE-deficient mice have been well characterized, and they resemble human lesions in their sites of predilection and progression to the fibroproliferative stage. These mouse models of atherosclerosis are being used to identify genes which modify atherosclerosis susceptibility and in the development of antiatherogenic therapies.

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Section: Ldl Receptor Deficiency-induced Atherosclerosismentioning

confidence: 99%

Section: Ldl Receptor Deficiency-induced Atherosclerosismentioning

confidence: 99%

Section: Ldl Receptor Deficiency-induced Atherosclerosismentioning

confidence: 99%

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The emergence of mouse models of atherosclerosis and their relevance to clinical research

Smith

Breslow

1997

Journal of Internal Medicine

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“…LDL receptor-deficient mice expressing a human apoCIII transgene (LDLr0/CIII) were derived as described by Masucci-Magoulas et al (35).…”

Section: Methodsmentioning

confidence: 99%

Secretory Sphingomyelinase, a Product of the Acid Sphingomyelinase Gene, Can Hydrolyze Atherogenic Lipoproteins at Neutral pH

Schissel¹,

Jiang²,

Tweedie-Hardman³

et al. 1998

Journal of Biological Chemistry

302

263

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The subendothelial aggregation and retention of low density lipoprotein (LDL) are key events in atherogenesis, but the mechanisms in vivo are not known. Previous studies have shown that treatment of LDL with bacterial sphingomyelinase (SMase) in vitro leads to the formation of lesion-like LDL aggregates that become retained on extracellular matrix and stimulate macrophage foam cell formation. In addition, aggregated human lesional LDL, but not unaggregated lesional LDL or plasma LDL, shows evidence of hydrolysis by an arterial wall SMase in vivo, and several arterial wall cell types secrete a SMase (S-SMase). S-SMase, however, has a sharp acid pH optimum using a standard in vitro SMmicelle assay. Thus, a critical issue regarding the potential role of S-SMase in atherogenesis is whether the enzyme can hydrolyze lipoprotein-SM, particularly at neutral pH. We now show that S-SMase can hydrolyze and aggregate native plasma LDL at pH 5.5 but not at pH 7.4. Remarkably, LDL modified by oxidation, treatment with phospholipase A 2 , or enrichment with apolipoprotein CIII, which are modifications associated with increased atherogenesis, is hydrolyzed readily by S-SMase at pH 7.4. In addition, lipoproteins from the plasma of apolipoprotein E knock-out mice, which develop extensive atherosclerosis, are highly susceptible to hydrolysis and aggregation by S-SMase at pH 7.4; a high SM:PC ratio in these lipoproteins appears to be an important factor in their susceptibility to S-SMase. Most importantly, LDL extracted from human atherosclerotic lesions, which is enriched in sphingomyelin compared with plasma LDL, is hydrolyzed by S-SMase at pH 7.4 10-fold more than same donor plasma LDL, suggesting that LDL is modified in the arterial wall to increase its susceptibility to S-SMase. In summary, atherogenic lipoproteins are excellent substrates for S-SMase, even at neutral pH, making this enzyme a leading candidate for the arterial wall SMase that hydrolyzes LDL-SM and causes subendothelial LDL aggregation.

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“…8 In contrast, h apoC-III expression, in normal or in LDL receptor-deficient mice, resulted in increased atherosclerosis. 9,10 ApoA-IV, involved in RCT-like apoA-I, 1 also has antiatherogenic properties, inasmuch as overexpression of apoA-IV reduced aortic lesions. 11,12 The foregoing observations indicate that the apoA-I/C-III/A-IV gene cluster is of major interest in relation to atherogenesis.…”

mentioning

confidence: 99%

Expression of Human Apolipoprotein A-I/C-III/A-IV Gene Cluster in Mice Induces Hyperlipidemia but Reduces Atherogenesis

Vergnes

Baroukh

Ostos

et al. 2000

ATVB

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Abstract-The apolipoprotein (apo)A-I/C-III/A-IV gene cluster is involved in lipid metabolism and atherosclerosis.Overexpression of apoC-III in mice causes hypertriglyceridemia and induces atherogenesis, whereas overexpression of apoA-I or apoA-IV increases cholesterol in plasma high density lipoprotein (HDL) and protects against atherosclerosis. Each gene has been studied alone in transgenic mice but not in combination as the entire cluster. To determine which phenotype is produced by the expression of the entire gene cluster, transgenic mice were generated with a 33-kb human DNA fragment. The results showed that the transgene contained the necessary elements to direct hepatic and intestinal expression of the 3 genes. In the pooled data, plasma concentrations were 257Ϯ9, 7.1Ϯ0.5, and 1.0Ϯ0.2 mg/dL for human apoA-I, apoC-III, and apoA-IV, respectively (meanϮSEM). Concentrations of these apolipoproteins were higher in males than in females. Human apoA-I and apoC-III concentrations were positively correlated, suggesting that they are coregulated. Transgenic mice exhibited gross hypertriglyceridemia and accumulation of apoB 48 -containing triglyceride-rich lipoproteins. Plasma triglyceride and cholesterol concentrations were correlated positively with human apoC-III concentration, and HDL cholesterol was correlated with apoA-I concentration. In an apoE-deficient background, despite being markedly hypertriglyceridemic, cluster transgenic animals compared with nontransgenic animals showed a 61% reduction in atherosclerosis. This suggests that apoA-I and/or apoA-IV can protect against atherosclerosis even in the presence of severe hyperlipidemia. These mice provide a new model for studies of the regulation of the 3 human genes in combination. Key Words: transgenic mice Ⅲ hypertriglyceridemia Ⅲ cholesterol Ⅲ lipoproteins Ⅲ atherosclerosis P lasma lipoproteins influence the development of atherosclerosis, and their concentrations are associated with the risk of coronary heart disease. 1 The genes for 3 apolipoproteins, apoA-I, apoC-III, and apoA-IV, are grouped together in a cluster on 17 kb of human chromosome 11. 2 ApoA-I is the major protein component of HDL. Through its ability to promote cholesterol efflux from cultured cells and to activate lecithin:cholesterol acyltransferase (LCAT), it is involved in reverse cholesterol transport (RCT). 1 Expression of the human apoA-I ( h apoA-I) gene decreases the development of fatty lesions in cholesterol-fed transgenic (Tg) mice 3 and in apoE-deficient (apoE Ϫ/Ϫ ) mice. 4 ApoA-I deficiency in mice did not increase atherogenesis in a normal background 5 but did so in hypercholesterolemic mice expressing human apoB. 6 ApoC-III is a component of HDL and triglyceride-rich lipoproteins (TGRLs). Plasma apoC-III concentration is positively correlated with triglyceride concentration. By inhibiting TGRL catabolism, apoC-III induces hypertriglyceridemia in Tg mice. 7 Expression of the gene was not atherogenic in apoE Ϫ/Ϫ mice. 8 In contrast, h apoC-III expression, in normal or in LDL ...

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A Mouse Model with Features of Familial Combined Hyperlipidemia

Cited by 126 publications

References 28 publications

The emergence of mouse models of atherosclerosis and their relevance to clinical research

The emergence of mouse models of atherosclerosis and their relevance to clinical research

Secretory Sphingomyelinase, a Product of the Acid Sphingomyelinase Gene, Can Hydrolyze Atherogenic Lipoproteins at Neutral pH

Expression of Human Apolipoprotein A-I/C-III/A-IV Gene Cluster in Mice Induces Hyperlipidemia but Reduces Atherogenesis

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