Increased expression of apolipoprotein E in transgenic rabbits results in reduced levels of very low density lipoproteins and an accumulation of low density lipoproteins in plasma.

Fan, Jianglin; Ji, Zhong-Sheng; Huang, Yadong; Silva, H. De; Sanan, David A.; Mahley, Robert W.; Innerarity, Thomas L.; Taylor, John M.

doi:10.1172/jci1599

Cited by 79 publications

(54 citation statements)

References 70 publications

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“…The HDL C is thought to be HDL 1 which acquire rich cholesterol esters and apolipoprotein E [5]. Since apolipoprotein E is an important ligand for lipoprotein receptors, such as LDL receptor [6], LDL receptor related protein (LRP) [1], and cell surface proteoglycans [3], a certain pathway for clearance of apoE-rich lipoproteins may be disturbed in Shetland sheepdogs. In addition, marked hypercholesterolemia (over 500 mg/ dl) in Shetland sheepdogs was characterized by increase in preβ~β-lipoproteins (Fig.…”

Section: Discussionmentioning

confidence: 99%

Hypercholesterolemia in Shetland Sheepdogs.

Sato

Agoh

Kaneshige

et al. 2000

The Journal of Veterinary Medical Science

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ABSTRACT. Plasma lipoprotein cholesterol in 64 clinically healthy Shetland sheepdogs was evaluated to assess whether the breed is more susceptible to hypercholesterolemia. The incidence of hypercholesterolemia was clearly higher in Shetland sheepdogs and mean plasma cholesterol level was significantly higher in Shetland sheepdogs than in control dogs. Blood biochemical examinations did not evidence the abnormalities, which imply the causative disorders, and thyroid hormone levels were not significantly different from the controls. These results suggest that the cholesterolemia is a primary disorder. Cholesterol fractionation by agarose gel electrophoresis and ultracentrifugation revealed that accumulation of α 2 -migrating lipoproteins was the common characteristic of dogs showing cholesterol level over 250 mg/dl in the breed. Increase in preβ~β-lipoproteins was also found in Shetland sheepdogs with marked hypercholesterolemia over 500 mg/dl. Therefore, Shetland sheepdogs may include more dogs with primary disorders in lipoprotein metabolism, which cause hypercholesterolemia, at least in Japan. KEY WORDS: cholesterol, high density lipoprotein, low density lipoprotein, Shetland sheepdog.

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Section: Discussionmentioning

confidence: 99%

Hypercholesterolemia in Shetland Sheepdogs.

Sato

Agoh

Kaneshige

et al. 2000

The Journal of Veterinary Medical Science

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“…Plasma TG, total cholesterol (TC), HDL cholesterol (HDL-C), and free fatty acids (FFA) were determined using Wako assay kits (22). For the determination of the apolipoprotein distribution in transgenic rabbit lipoproteins, plasma lipoproteins were isolated by sequential ultracentrifugation as described (23). These lipoprotein fractions were subjected to agarose gel electrophoresis and stained with Fat red 7B or transferred to a nitrocellulose membrane for immunoblotting with goat anti-apoB, -apoAI, and -apoE polyclonal Abs (Rockland Inc., Gilbertsville, PA), and immunocomplexed proteins were identified by reaction with a horseradish peroxidase-conjugated horse Ab to goat IgG, followed by enhanced chemiluminescent detection (ECL kit; Amersham Pharmacia Biotech) (22).…”

Section: Methodsmentioning

confidence: 99%

“…For example, expression of either human hepatic lipase or lecithin:cholesterol acyltransferase in transgenic rabbits caused protection against atherosclerosis (42,43) but enhanced the lesion formation in transgenic mice (44,45). Overexpression of apoE in mice caused inhibition of atherosclerosis (46) but led to accumulation of plasma LDL in transgenic rabbits accompanied by spontaneous atherosclerosis (23). Therefore, transgenic rabbits are useful as an alternative complementary tool to reveal the precise functions of these genes in lipoprotein metabolism and atherosclerosis.…”

Section: Fig 8 Electron Microscopic Analysis Of Lipoproteinsmentioning

confidence: 99%

Overexpression of Lipoprotein Lipase in Transgenic Rabbits Inhibits Diet-induced Hypercholesterolemia and Atherosclerosis

Fan¹,

Unoki²,

Kojima³

et al. 2001

Journal of Biological Chemistry

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Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of TG-rich lipoproteins. To elucidate the physiological roles of LPL in lipid and lipoprotein metabolism, we generated transgenic rabbits expressing human LPL. In postheparinized plasma of transgenic rabbits, the human LPL protein levels were about 650 ng/ml, and LPL enzymatic activity was found at levels up to 4-fold greater than that in nontransgenic littermates. Increased LPL activity in transgenic rabbits was associated with as much as an 80% decrease in plasma triglycerides and a 59% decrease in high density lipoprotein-cholesterol. Analysis of the lipoprotein density fractions revealed that increased expression of the LPL transgene resulted in a remarkable reduction in the level of very low density lipoproteins as well as in the level of intermediate density lipoproteins. In addition, LDL cholesterol levels in transgenic rabbits were significantly increased. When transgenic rabbits were fed a cholesterol-rich diet, the development of hypercholesterolemia and aortic atherosclerosis was dramatically suppressed in transgenic rabbits. These results demonstrate that systemically increased LPL activity functions in the metabolism of all classes of lipoproteins, thereby playing a crucial role in plasma triglyceride hydrolysis and lipoprotein conversion, and that overexpression of LPL protects against diet-induced hypercholesterolemia and atherosclerosis. Lipoprotein lipase (LPL)1 plays a crucial role in lipid metabolism and transport by catalyzing the hydrolysis of triglyceriderich (TG-rich) lipoproteins such as chylomicrons and very low density lipoproteins (VLDL). Through the hydrolysis of TG in these particles, LPL converts these lipoproteins to denser lipoproteins such as chylomicron remnants, intermediate density lipoprotein (IDL), and low density lipoproteins (LDL) (1-3). This process generates free fatty acids (FFA), which are taken up and used for metabolic energy or stored as TG after reesterification and also results in the generation of surface remnants, which give rise to high density lipoproteins (HDL). It has been suggested that LPL influences not only plasma TG levels but also plasma HDL levels (4).LPL is mainly produced by mesenchymal cells such as adipose and muscle cells and then transported to the luminal surface of the vascular endothelium, where it is bound to heparan sulfate proteoglycans (HSPG). Small amounts of LPL are also present in other types of tissues, including the adrenals, brain, lung, and spleen (5). Furthermore, LPL is also expressed by macrophages and smooth muscle cells in atherosclerotic lesions (6, 7), suggesting that LPL modulates vascular functions and may be involved in atherogenesis. Elucidation of the precise roles of LPL in atherosclerosis has been compounded by the fact that LPL has multiple functions in lipoprotein metabolism through its catalytic properties and acts as a ligand for the LDL receptor-related protein (8) or a bridge between lipoproteins and HSPG (9). In humans, it has been found that familial L...

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“…infusion of apoE in cholesterol-fed rabbits and the demonstration of accelerated clearance of β-VLDL remnants from the blood and their uptake by the liver (10). In transgenic mice and rabbits, overexpression of apoE accelerated remnant clearance (11)(12)(13). Furthermore, apoE was localized to the sinusoids in the space of Disse, and after infusion of remnant lipoproteins, apoE disappeared from the sinusoids and appeared in hepatocytes (14).…”

Section: Role Of Apoe In Remnant Binding and Uptakementioning

confidence: 99%