Genetic differences in cholesterol absorption in 129/Sv and C57BL/6 mice: effect on cholesterol responsiveness

Jolley, Christopher D.; Dietschy, John M.; Turley, Stephen D.

doi:10.1152/ajpgi.1999.276.5.g1117

Cited by 37 publications

(39 citation statements)

References 43 publications

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“…This finding, however, is in agreement with previous studies in which the increase of total cholesterol in C57BL/6 mice fed the HC-P diet (2.1-to 2.9-fold) (24)(25)(26) was comparable with that in animals fed the HC-W diet (2.2-fold) (27). In contrast with a widely accepted concept, addition of fat to the hypercholesterolemic diet, not cholate, increases cholesterol absorption (28). Although total fat accounts for 21% of the composition of the HC-W diet used in this study, it represents only 15% in the HC-P diet.…”

Section: Discussionsupporting

confidence: 91%

Interaction between mild hypercholesterolemia, HDL-cholesterol levels, and angiotensin II in intimal hyperplasia in mice

Cunha

Martin-McNulty

Vincelette

et al. 2006

Journal of Lipid Research

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Two month old C57BL/6 mice were placed on three different diets: 1) normal diet (NC; 0.025% cholesterol), 2) hypercholesterolemic Western-type diet (HC-W; 0.2% cholesterol), and 3) hypercholesterolemic Paigen-type diet (HC-P; 1.25% cholesterol plus 0.5% cholic acid). At 6 months of age, the animals underwent ligation of the left carotid artery and were randomly assigned to vehicle (PBS, subcutaneous) or angiotensin II (Ang II; 1.4 mg/kg/ day, subcutaneous) treatment for 4 weeks. Low density lipoprotein-cholesterol levels were similarly increased in both HC diets (NC, 4 6 3 mg/dl; HC-W, 123 6 17 mg/dl; HC-P, 160 6 14 mg/dl). However, the levels of high density lipoprotein-cholesterol (HDL-C) were reduced only in animals fed the HC-P diet (NC, 82 6 6 mg/dl; HC-W, 79 6 7 mg/dl; HC-P, 58 6 7 mg/dl). In Ang II-treated mice, carotid artery ligation induced intimal smooth muscle cell proliferation to a similar extent in NC-and HP-W-fed animals. However, a significantly larger intimal area developed in ligated vessels from Ang II-treated mice fed the HC-P diet (3.6-fold higher than in Ang II-treated NC mice). Together, these results show the accelerating effect of mild hypercholesterolemia, reduced HDL-C levels, and Ang II on intimal hyperplasia after carotid artery ligation in mice. Proliferation of smooth muscle cell (SMCs) and migration into the intima is the hallmark of restenosis after vascular interventions (angioplasty, stent or vein graft placement) (1-3) and an important feature of preatherosclerotic lesions (4). It is well established that hypercholesterolemia accelerates atherosclerosis development; however, studies addressing the effect of circulating cholesterol on intimal SMC proliferation have yielded conflicting results. For instance, Theilmeier et al. (5) showed that hypercholesterolemia decreased the population of SMCs in atheromatous lesions in postangioplasty porcine coronary arteries. In contrast, in a recent study, Kahn et al. (6) observed accelerated angioplasty-induced intimal hyperplasia in aortas from hypercholesterolemic rabbits. In both studies, circulating levels of cholesterol were 9-and 18-fold higher than control levels, exceeding the pathophysiologic range of human hypercholesterolemia. Additionally, the concomitant development of spontaneous atheromatous plaque found in these studies adds another important level of interaction between macrophage/foam cell-derived mediators and SMC proliferation (7).In addition to changes in hemodynamic forces (e.g., low shear stress) (8) as predisposing factors for intimal hyperplasia development, locally produced neurohumoral mediators, particularly angiotensin II (Ang II) (9), may be equally important in determining such predisposition. Increased vascular levels of Ang II and the expression of its AT1 receptors were found in intimal SMCs of aortas from aging nonhuman primates (10) and in in-stent restenotic lesions of human coronary arteries (11). More importantly, in vitro studies showing synergism between lipoproteins and Ang II in inducing...

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Section: Discussionsupporting

confidence: 91%

Interaction between mild hypercholesterolemia, HDL-cholesterol levels, and angiotensin II in intimal hyperplasia in mice

Cunha

Martin-McNulty

Vincelette

et al. 2006

Journal of Lipid Research

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“…1D). These findings are consistent with previous studies showing that increased dietary cholesterol leads to significant accumulation of cholesterol in the plasma and liver of mice despite compensatory mechanisms such as down-regulation of hepatic cholesterol synthesis and enhanced biliary sterol secretion (42)(43)(44). Hepatic Overexpression of hABCG5/G8 Enhances Biliary Sterol Secretion in Liver G5/G8 Transgenic Mice on the 4% C Diet-As discussed above, on the 4% C diet, not only is ABCG5/G8 gene expression enhanced but in addition, hepatic cholesterol concentrations and hence, the amount of cholesterol substrate available for transport by liver ABCG5/G8 is increased.…”

Section: Hepatobiliary Sterol Concentrations Sterol Secretion Ratessupporting

confidence: 93%

Hepatic ABCG5 and ABCG8 Overexpression Increases Hepatobiliary Sterol Transport but Does Not Alter Aortic Atherosclerosis in Transgenic Mice

Basso

Shamburek

et al. 2004

Journal of Biological Chemistry

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The individual roles of hepatic versus intestinal ABCG5 and ABCG8 in sterol transport have not yet been investigated. To determine the specific contribution of liver ABCG5/G8 to sterol transport and atherosclerosis, we generated transgenic mice that overexpress human ABCG5 and ABCG8 in the liver but not intestine (liver G5/G8-Tg) in three different genetic backgrounds: C57Bl/6, apoE-KO, and low density lipoprotein receptor (LDLr)-KO. Hepatic overexpression of ABCG5/G8 enhanced hepatobiliary secretion of cholesterol and plant sterols by 1.5-2-fold, increased the amount of intestinal cholesterol available for absorption and fecal excretion by up to 27%, and decreased the accumulation of plant sterols in plasma by ϳ25%. However, it did not alter fractional intestinal cholesterol absorption, fecal neutral sterol excretion, hepatic cholesterol concentrations, or hepatic cholesterol synthesis. Consequently, overexpression of ABCG5/G8 in only the liver had no effect on the plasma lipid profile, including cholesterol, HDL-C, and non-HDL-C, or on the development of proximal aortic atherosclerosis in C57Bl/6, apoE-KO, or LDLr-KO mice. Thus, liver ABCG5/G8 facilitate the secretion of liver sterols into bile and serve as an alternative mechanism, independent of intestinal ABCG5/G8, to protect against the accumulation of dietary plant sterols in plasma. However, in the absence of changes in fractional intestinal cholesterol absorption, increased secretion of sterols into bile induced by hepatic overexpression of ABCG5/G8 was not sufficient to alter hepatic cholesterol balance, enhance cholesterol removal from the body or to alter atherogenic risk in liver G5/G8-Tg mice. These findings demonstrate that overexpression of ABCG5/G8 in the liver profoundly alters hepatic but not intestinal sterol transport, identifying distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism.Sitosterolemia, also known as phytosterolemia (1-9) is a rare genetic disorder characterized by elevated plasma and tissue levels of plant, shellfish, and animal sterols and the development of tendon and tuberous xanthomas, hemolytic episodes, arthritis, and premature coronary artery disease. The ATPbinding cassette (ABC) 1 half-transporters ABCG5 and ABCG8 (ABCG5/G8) have been recently identified as the genes defective in sitosterolemia (10 -12). The increased plasma and tissue levels of animal and plant sterols found in sitosterolemic patients have been attributed to enhanced absorption and decreased biliary excretion (1-4, 6, 8, 13-16). Unlike cholesterol, sitosterol accumulation does not inhibit HMGCoA reductase activity in human monocyte-derived macrophages (17). The inadequate down-regulation of HMGCoA reductase activity by plant sterols may promote foam cell formation and explain, in part, the increased risk of atherosclerosis in sitosterolemia (17).Several lines of evidence implicate ABCG5/G8 in intestinal and biliary sterol transport. First, ABCG5/G8 are expressed in the liver and small intestine and, to a lesser degree, in th...

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“…15,16 Furthermore, 129Sv mice absorb dietary cholesterol more effectively than C57BL/6 mice. 17 Possibly an even more telling difference between these mouse strains is the platelet content of transforming growth factor ␤-1 (TGF-␤1), which is 4-fold higher in C57BL/6 mice than in 129Sv mice. 18 It is possible that TGF-␤1 protects against rupture by increasing matrix synthesis and decreasing the degree of inflammation within the plaque, and indeed, inhibition of TGF-␤1 at the level of its receptor produces an unstable phenotype in the lesions of apoE knockout mice on a C57BL/6 background.…”

Section: Strain Differencesmentioning

confidence: 99%

Characteristics of Intact and Ruptured Atherosclerotic Plaques in Brachiocephalic Arteries of Apolipoprotein E Knockout Mice

Williams

Johnson

Carson

et al. 2002

ATVB

209

178

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Abstract-The brachiocephalic arteries of fat-fed apolipoprotein E knockout mice develop plaques that frequently rupture and form luminal thromboses. The morphological characteristics of plaques without evidence of instability or with healed previous ruptures (intact) and vessels with acutely ruptured plaques (ruptured) have now been defined, to understand the process of plaque destabilization in more detail. Ninety-eight apolipoprotein E knockout mice were fed a diet supplemented with 21% lard and 0.15% cholesterol, for 5 to 59 weeks. Of these 98 mice, 51 had an acutely ruptured plaque in the brachiocephalic artery. See cover and page 713The apolipoprotein E (apoE) knockout mouse has become established as a model of hypercholesterolemia and atherosclerotic lesion development. 2-5 After 6 months on a high-fat diet, advanced fibrous plaques are observed with thin luminal elastin and collagen fibers capping small lipid-rich globular lesions. 5 Four studies have now reported that the lesions of apoE knockout mice can spontaneously become unstable. 6 -9 The brachiocephalic (also known as the innominate) artery, which is the first branch from the aortic arch, bifurcating to form the right common carotid artery and the right subclavian artery, is a site of predilection for the development of such vulnerable lesions. It provides a small and well-defined area in which to study the progressive loss of plaque stability and, eventually, rupture.In a previous study, 7 a small number of apoE knockout mice were examined. All of these had died suddenly, which meant that it was not possible to perfusion fix their arteries. In the current study, the development and morphology of brachiocephalic artery plaques have been characterized in a cohort of 98 apoE knockout mice. Ruptured and intact lesions have been compared both in animals dying suddenly and in those that were perfusion fixed after scheduled termination. Methods AnimalsHomozygous apoE knockout mice 10 were obtained from Charles River Laboratories (Manston, Kent, UK). The strain background of these animals was 50% C57BL/6, 50% 129SvJ, as determined by fingerprinting of tail-tip DNA. The housing and care of the animals and all the procedures used in these studies were performed in accordance with the guidelines and regulations of the University of Bristol and the United Kingdom Home Office. HusbandryStarting at 6 to 8 weeks of age, 98 apoE knockout mice (51 male) were fed a high-fat rodent diet containing 21% fat from lard and supplemented with 0.15% (wt/wt) cholesterol (Special Diets Services) for a period of 5 to 59 weeks. Cages were checked daily, and any animals that had suffered sudden death were immediately removed and processed for histological examination. TerminationAnimals were anesthetized by intraperitoneal injection of sodium pentobarbitone before exsanguination by arterial perfusion via the

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Genetic differences in cholesterol absorption in 129/Sv and C57BL/6 mice: effect on cholesterol responsiveness

Cited by 37 publications

References 43 publications

Interaction between mild hypercholesterolemia, HDL-cholesterol levels, and angiotensin II in intimal hyperplasia in mice

Interaction between mild hypercholesterolemia, HDL-cholesterol levels, and angiotensin II in intimal hyperplasia in mice

Hepatic ABCG5 and ABCG8 Overexpression Increases Hepatobiliary Sterol Transport but Does Not Alter Aortic Atherosclerosis in Transgenic Mice

Characteristics of Intact and Ruptured Atherosclerotic Plaques in Brachiocephalic Arteries of Apolipoprotein E Knockout Mice

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