The intra‐uterine changes in the pregnant albino rat (Mus Norvegicus) deprived of vitamin E

Urner, John A.

doi:10.1002/ar.1090500205

Cited by 28 publications

(13 citation statements)

References 2 publications

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“…First, vitamin E is normally transported in the circulation by apo-B-containing lipoproteins (23). Second, the phenotype of vitamin E deficiency in pregnant rats, which includes fetal resorption and embryonic exencephalus (24)(25)(26), is similar to that in our apo-B-deficient mice. This phenotypic similarity led Homanics et al (6) to postulate that vitamin E deficiency may be responsible for the developmental abnormalities in their apo-B70 mice.…”

Section: Discussionmentioning

confidence: 55%

Knockout of the mouse apolipoprotein B gene results in embryonic lethality in homozygotes and protection against diet-induced hypercholesterolemia in heterozygotes.

Farese

Ruland

Flynn

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

236

174

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Apolipoprotein B is synthesized by the intestine and the liver in mammals, where it serves as the main structural component in the formation of chylomicrons and very low density lipoproteins, respectively. Apolipoprotein B is also expressed in mammalian fetal membranes. To examine the consequences of apolipoprotein B deficiency in mice, we used gene targeting in mouse embryonic stem cells to generate mice containing an insertional disruption of the 5' region of the apolipoprotein B gene. Mice that were heterozygous for the disrupted apolipoprotein B allele had an "20%o reduction in plasma cholesterol levels, markedly reduced plasma concentrations of the pre-f3 and 8-migrating lipoproteins, and an "70%o reduction in plasma apolipoprotein B levels. When fed a diet rich in fat and cholesterol, heterozygous mice were protected from diet-induced hypercholesterolemia; these mice, which constitute an animal model for hypobetalipoproteinemia, should be useful for studying the effects of decreased apolipoprotein B expression on atherogenesis. The breeding of heterozygous mice yielded no viable homozygous apolipoprotein B knockout mice. Most homozygous embryos were resorbed by midgestation (before gestational day 11.5); several embryos that survived until later in gestation exhibited exencephalus. The embryonic lethal phenotype was rescued by complementation with a human apolipoprotein B transgenei.e., human apolipoprotein B transgenic mice that were homozygous for the murine apolipoprotein B knockout mutation were viable. Our findings indicate that apolipoprotein B plays an essential role in mouse embryonic development.

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Section: Discussionmentioning

confidence: 55%

Knockout of the mouse apolipoprotein B gene results in embryonic lethality in homozygotes and protection against diet-induced hypercholesterolemia in heterozygotes.

Farese

Ruland

Flynn

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

236

174

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“…This fertility defect presumably resulted from vitamin E deficiency. Vitamin E is required to prevent fetal resorption in rodents (32,33), and vitamin E supplementation (1,000 units͞kg of diet) completely reversed the fertility defect (not shown). Ttpa Ϫ/Ϫ males had no obvious impairment in fertility.…”

Section: Resultsmentioning

confidence: 96%

Increased atherosclerosis in hyperlipidemic mice deficient in α-tocopherol transfer protein and vitamin E

Terasawa

Ladha

Leonard

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

224

156

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Although lipid peroxidation in the subendothelial space has been hypothesized to play a central role in atherogenesis, the role of vitamin E in preventing lipid peroxidation and lesion development remains uncertain. Here we show that in atherosclerosis-susceptible apolipoprotein E knockout mice, vitamin E deficiency caused by disruption of the ␣-tocopherol transfer protein gene (Ttpa) increased the severity of atherosclerotic lesions in the proximal aorta. The increase was associated with increased levels of isoprostanes, a marker of lipid peroxidation, in aortic tissue. These results show that vitamin E deficiency promotes atherosclerosis in a susceptible setting and support the hypothesis that lipid peroxidation contributes to lesion development. Ttpa ؊/؊ mice are a genetic model of vitamin E deficiency and should be valuable for studying other diseases in which oxidative stress is thought to play a role.antioxidants O xidative modification of lipoproteins (e.g., low-density lipoproteins) has been hypothesized to play a key role in the pathogenesis of atherosclerosis (1, 2). Because vitamin E is the most potent lipid-soluble antioxidant normally found on lipoproteins in the plasma, there is strong interest in the relationship between vitamin E levels and the development of atherosclerosis. In animal models and human clinical trials, studies of the effects of vitamin E supplementation on atherosclerosis have yielded conf licting results (3-8), and little is known about the effects of vitamin E deficiency on atherosclerosis development (9).The major form of vitamin E in human plasma and tissues is ␣-tocopherol (10). ␣-Tocopherol enrichment of plasma and tissues is mediated by the ␣-tocopherol transfer protein (␣-TTP), a cytosolic lipid-transfer protein expressed in the liver (11)(12)(13)(14). Although the mechanism is unknown (15), ␣-TTP is believed to selectively transfer ␣-tocopherol from lipoproteins taken up by hepatocytes via the endocytic pathway to newly secreted lipoproteins, which facilitate its delivery to peripheral tissues (12). Humans with ␣-TTP gene defects have extremely low plasma ␣-tocopherol concentrations and develop severe neurodegenerative disease unless they are treated with high doses of vitamin E (16-18).To investigate the relationship between vitamin E deficiency and atherosclerosis, we used gene targeting to disrupt the mouse ␣-TTP gene (Ttpa) and generate a genetic model of vitamin E deficiency. We then crossed the ␣-TTP-deficient mice (Ttpa Ϫ/Ϫ ) mice with apolipoprotein (apo) E knockout (Apoe Ϫ/Ϫ ) mice (19), which spontaneously develop atherosclerosis on a chow diet (20,21). This enabled us to generate Apoe Ϫ/Ϫ mice with different Ttpa genotypes (ϩ͞ϩ, ϩ͞Ϫ, and Ϫ͞Ϫ) to test the hypothesis that ␣-TTP and vitamin E deficiency increase atherosclerosis in a susceptible setting. Materials and MethodsGeneration of ␣-TTP Knockout Mice. A 14-kb 129͞Sv genomic clone containing the Ttpa gene was isolated and subcloned into pBSSKII. A sequence replacement vector was constructed by PCR amplifica...

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“…Although we have not yet observed clinical signs of neurologic disease (e.g., ataxia) in the a-tocopherol-deficient mice, we have not yet performed neuropathological studies to look for subtle neurological changes. Vitamin E deficiency in rats is known to cause sterility (39). We have not yet systematically examined the fertility of our a-tocopherol-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

A genetic model for absent chylomicron formation: mice producing apolipoprotein B in the liver, but not in the intestine.

Young¹,

Cham²,

Pitas³

et al. 1995

J. Clin. Invest.

118

114

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The formation of chylomicrons by the intestine is important for the absorption of dietary fats and fat-soluble vitamins (e.g., retinol, a-tocopherol). Apo B plays an essential structural role in the formation of chylomicrons in the intestine as well as the VLDL in the liver. We have developed genetically modified mice that express apo B in the liver but not in the intestine. By electron microscopy, the enterocytes of these mice lacked nascent chylomicrons in the endoplasmic reticulum and Golgi apparatus. Because these mice could not form chylomicrons, the intestinal villus enterocytes were massively engorged with fat, which was contained in cytosolic lipid droplets. These mice absorbed D-xylose normally, but there was virtually no absorption of retinol palmitate or cholesterol. The levels of a-tocopherol in the plasma were extremely low. Of note, the absence of chylomicron synthesis in the intestine did not appear to have a significant effect on the plasma levels of the apo B-containing lipoproteins produced by the liver. The mice lacking intestinal apo B expression represent the first genetic model of defective absorption of fats and fat-soluble vitamins and provide a useful animal model for studying nutrition and lipoprotein metabolism. (J. Clin. Invest. 1995. 96:2932-2946

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The intra‐uterine changes in the pregnant albino rat (Mus Norvegicus) deprived of vitamin E

Cited by 28 publications

References 2 publications

Knockout of the mouse apolipoprotein B gene results in embryonic lethality in homozygotes and protection against diet-induced hypercholesterolemia in heterozygotes.

Knockout of the mouse apolipoprotein B gene results in embryonic lethality in homozygotes and protection against diet-induced hypercholesterolemia in heterozygotes.

Increased atherosclerosis in hyperlipidemic mice deficient in α-tocopherol transfer protein and vitamin E

A genetic model for absent chylomicron formation: mice producing apolipoprotein B in the liver, but not in the intestine.

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