Lipolysis exposes unreactive endogenous apolipoprotein E-3 in human and rat plasma very low density lipoprotein.

Sehayek, Ephraim; Lewin-Velvert, Uria; Chajek-Shaul, Tova; Eisenberg, Shlomo

doi:10.1172/jci115339

Cited by 72 publications

(51 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The difference between the uptake of control and transgenic VLDL was enhanced by pretreating the cells with lovastatin, suggesting an LDL receptor-mediated process. Previously it has been shown that rat (37,38) and human hypertriglyceridemic (39,40) VLDL uptake can occur through recognition of apo E on the VLDL by LDL receptors. This process was greatly increased by pretreating the VLDL with LPL (37) and it was suggested that the lipase allowed a conformational change in apo E to take place which in turn allowed receptor recognition.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.

Aalto‐Setälä¹,

Fisher²,

Chen³

et al. 1992

J. Clin. Invest.

Self Cite

422

312

View full text Add to dashboard Cite

Hypertriglyceridemia is common in the general population, but its mechanism is largely unknown. In previous work human apo CIII transgenic (HuCIIITg) mice were found to have elevated triglyceride levels. In this report, the mechanism for the hypertriglyceridemia was studied. Two different HuCIIITg mouse lines were used: a low expresser line with serum triglycerides of -280 mg/dl, and a high expressor line with serum triglycerides of -1,000 mg/dl. Elevated triglycerides were mainly in VLDL. VLDL particles were 1.5 times more triglyceride-rich in high expressor mice than in controls. The total amount of apo CIII (human and mouse) per VLDL particle was 2 and 2.5 times the normal amount in low and high expressors, respectively. Mouse apo E was decreased by 35 and 77% in low and high expresser mice, respectively. Under electron microscopy, VLDL particles from low and high expresser mice were found to have a larger mean diameter, 55.2±16.6 and 58.2±17.8 nm, respectively, compared with 51.0±13.4 nm from control mice. In in vivo studies, radiolabeled VLDL fractional catabolic rate (FCR) was reduced in low and high expresser mice to 2.58 and 0.77 pools/h, respectively, compared with 7.67 pools/h in controls, with no significant differences in the VLDL production rates. In an attempt to explain the reduced VLDL FCR in transgenic mice, tissue lipoprotein lipase (LPL) activity was determined in control and high expresser mice and no differences were observed. Also, VLDLs obtained from control and high expresser mice were found to be equally good substrates for purified LPL

show abstract

Section: Discussionmentioning

confidence: 99%

Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.

Aalto‐Setälä¹,

Fisher²,

Chen³

et al. 1992

J. Clin. Invest.

Self Cite

422

312

View full text Add to dashboard Cite

show abstract

“…Lipoproteins were separated by centrifugation in 6OTi or 5OTi rotors at 40C in an ultracentrifuge (model L5-50; Beckman Instruments Inc., Fullerton, CA) using standard techniques (5). The lipoproteins were washed once at a heavy density solution.…”

Section: Methodsmentioning

confidence: 99%

Lipoprotein lipase enhances binding of lipoproteins to heparan sulfate on cell surfaces and extracellular matrix.

Eisenberg

Sehayek

Olivecrona³

et al. 1992

J. Clin. Invest.

Self Cite

235

133

View full text Add to dashboard Cite

“…Reduced VLDL and IDL levels indicate that these particles were rapidly cleared from the plasma, possibly through the receptor-mediated uptake by the liver (29). It has been suggested that after hydrolysis of VLDL triglycerides by LPL, exposure of unreactive apoE, and conformational changes in apoB-100 may enhance binding of VLDL to the LDL receptor (30,31). Merkel et al (32) showed that hepatic expression of LPL increases VLDL mass clearance in LPL-KO mice.…”

Section: Figmentioning

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

View full text Add to dashboard Cite

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...

show abstract

Lipolysis exposes unreactive endogenous apolipoprotein E-3 in human and rat plasma very low density lipoprotein.

Cited by 72 publications

References 32 publications

Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.

Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.

Lipoprotein lipase enhances binding of lipoproteins to heparan sulfate on cell surfaces and extracellular matrix.

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

Contact Info

Product

Resources

About