In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.

Jong, M.C.; Dahlmans, V.E.H.; Gorp, Patrick J. van; Dijk, Ko Willems van; Breuer, M.; Hofker, Marten H.; Havekes, Louis M.

doi:10.1172/jci119036

Cited by 109 publications

(114 citation statements)

References 38 publications

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“…The Ad-APOE3 was kindly provided by Dr. S. Santamarina Fojo (Betheseda, MD) and Ad-␤-Gal by Dr. J. Hertz (Dallas, TX). The recombinant adenovirus was propagated and titrated in a way similar to that already described (17). For storage, the virus was supplemented with mouse serum albumin (0.2%) and glycerol (10%).…”

Section: Methodsmentioning

confidence: 99%

Apolipoprotein E Participates in the Regulation of Very Low Density Lipoprotein-Triglyceride Secretion by the Liver

Mensenkamp¹,

Jong²,

Goor³

et al. 1999

Journal of Biological Chemistry

121

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ApoE-deficient mice on low fat diet show hepatic triglyceride accumulation and a reduced very low density lipoprotein (VLDL) triglyceride production rate. To establish the role of apoE in the regulation of hepatic VLDL production, the human APOE3 gene was introduced into apoE-deficient mice by cross-breeding with APOE3 transgenics (APOE3/apoe؊/؊ mice) or by adenoviral transduction. APOE3 was expressed in the liver and, to a lesser extent, in brain, spleen, and lung of transgenic APOE3/apoe؊/؊ mice similar to endogenous apoe. Plasma cholesterol levels in APOE/apoe؊/؊ mice (3.4 ؎ 0.5 mM) were reduced when compared with apoe؊/؊ mice (12.6 ؎ 1.4 mM) but still elevated when compared with wild type control values (1.9 ؎ 0.1 mM). Hepatic triglyceride accumulation in apoE-deficient mice was completely reversed by introduction of the APOE3 transgene. The in vivo hepatic VLDL-triglyceride production rate was reduced to 36% of control values in apoE-deficient mice but normalized in APOE3/ apoe؊/؊ mice. Hepatic secretion of apoB was not affected in either of the strains. Secretion of 3 H-labeled triglycerides synthesized from [ 3 H]glycerol by cultured hepatocytes from apoE-deficient mice was four times lower than by APOE3/apoe؊/؊ or control hepatocytes. The average size of secreted VLDL particles produced by cultured apoE-deficient hepatocytes was significantly reduced when compared with those of APOE3/ apoe؊/؊ and wild type mice. Hepatic expression of human APOE3 cDNA via adenovirus-mediated gene transfer in apoE-deficient mice resulted in a reduction of plasma cholesterol depending on plasma apoE3 levels. The in vivo VLDL-triglyceride production rate in these mice was increased up to 500% compared with LacZ-injected controls and correlated with the amount of apoE3 per particle. These findings indicate a regulatory role of apoE in hepatic VLDL-triglyceride secretion, independent from its role in lipoprotein clearance.Apolipoprotein E is an important constituent of triglyceriderich lipoproteins such as VLDL 1 and chylomicrons and is essential for effective receptor-mediated uptake of their remnants (1). High levels of apoE delay lipoprotein lipase-mediated lipolysis of these lipoproteins (2, 3). ApoE deficiency in mice leads to elevated plasma cholesterol concentrations because of the accumulation of VLDL-and chylomicron-remnants (␤-VLDL), which results from impaired hepatic uptake of these particles (4 -6). As a consequence, atherosclerotic lesions rapidly develop in apoE-deficient mice (Refs. 5 and 7; for review see Ref. 8). A secretion-recapture role for apoE has been proposed in which the apoprotein is secreted by hepatocytes into the space of Disse to interact with heparan sulfate proteoglycans, followed by binding and internalization of circulating lipoproteins (9, 10). Data from in vitro studies indicate that apoE may also serve a function in intracellular metabolism and distribution of lipids after their uptake by macrophages (11) and hepatoma cells (12). Recent studies from our laboratory have shown that apoE defi...

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Section: Methodsmentioning

confidence: 99%

Apolipoprotein E Participates in the Regulation of Very Low Density Lipoprotein-Triglyceride Secretion by the Liver

Mensenkamp¹,

Jong²,

Goor³

et al. 1999

Journal of Biological Chemistry

121

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“…147,148) Transgenic mice overexpressing human apoC-I exhibit elevated levels of cholesterol and TG owing to the accumulation of cholesterol-enriched VLDL, VLDL remnants, and LDL. 149,150) In human apoC-I-transgenic mice, the elevated lipid levels are primarily associated with decreased uptake of apoB-containing lipoproteins by the liver rather than with disturbed lipolysis of lipoproteins. 149,150) Surprisingly, ApoC1-knockout mice show normal serum lipid levels on a chow diet.…”

Section: )mentioning

confidence: 99%

“…149,150) In human apoC-I-transgenic mice, the elevated lipid levels are primarily associated with decreased uptake of apoB-containing lipoproteins by the liver rather than with disturbed lipolysis of lipoproteins. 149,150) Surprisingly, ApoC1-knockout mice show normal serum lipid levels on a chow diet. 151) 4.4.…”

Section: )mentioning

confidence: 99%

Metabolism and Modification of Apolipoprotein B-Containing Lipoproteins Involved in Dyslipidemia and Atherosclerosis

Morita

2016

Biological & Pharmaceutical Bulletin

132

108

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Increased levels of apolipoprotein B (apoB)-containing lipoproteins, such as low density lipoproteins (LDL) and chylomicron remnants, are associated with the development of atherosclerosis. Chylomicrons containing apoB-48 are secreted from the intestine during the postprandial state, whereas very low density lipoproteins (VLDL) containing apoB-100 are constitutively formed in the liver. Chylomicron remnants and VLDL remnants are produced by the lipoprotein lipase-mediated lipolysis of triglycerides, which is activated by apolipoprotein C-II bound on the particle surfaces. The hepatic uptake of these remnants is facilitated by apolipoprotein E (apoE), but is inhibited by apolipoproteins C-I, C-II and C-III. In the plasma, VLDL remnants are further converted into LDL by the hydrolysis of triglycerides. ApoB-100 is responsible for the hepatic uptake of LDL. LDL receptor, LDL receptor-related protein and heparan sulfate proteoglycans are involved in the hepatic clearance of lipoproteins containing apoB-100 and/or apoE. The subendothelial retention and modification of apoB-containing lipoproteins are crucial events in the initiation of atherosclerosis. In the subendothelium, the uptake of modified lipoproteins by macrophages leads to the formation of foam cells storing excess amounts of cholesteryl esters and subsequently to apoptosis. This review describes the current knowledge about the metabolism and modification of apoB-containing lipoproteins involved in dyslipidemia and atherogenesis. In particular, I focus on the effects of apolipoproteins, lipid composition and particle size on lipoprotein metabolism and on the roles of cholesterol, sphingomyelinase and apoB denaturation in macrophage foam cell formation and apoptosis. A detailed understanding of these mechanisms will help to develop new therapeutic strategies.

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“…]triglyceride-labeled VLDL turnover studies were based on a previously described method (21). [ 3 H]Palmitic acid (Amersham Biosciences) in toluene was evaporated under nitrogen and redissolved in 0.9% NaCl containing 2 mg/ml bovine serum albumin to a final concentration of 1 mCi/ml.…”

Section: In Vivo Turnover Studies Using [ 3 H]triglyceride-labeled Vlmentioning

confidence: 99%

ANGPTL3 Decreases Very Low Density Lipoprotein Triglyceride Clearance by Inhibition of Lipoprotein Lipase

Shimizugawa¹,

Ono

Shimamura

et al. 2002

Journal of Biological Chemistry

324

258

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KK/San is a mutant mouse strain established in our laboratory from KK obese mice. KK/San mice show low plasma lipid levels compared with wild-type KK mice despite showing signs of hyperglycemia and hyperinsulinemia. Recently, we identified a mutation in the gene encoding angiopoietin-like protein 3 (Angptl3) in KK/ San mice, and injection of adenoviruses encoding Angptl3 or recombinant ANGPTL3 protein to mutant KK/San mice raised plasma lipid levels. To elucidate the regulatory mechanism of ANGPTL3 on lipid metabolism, we focused on the metabolic pathways of triglyceride in the present study. Overexpression of Angptl3 in KK/San mice resulted in a marked increase of triglyceride-enriched very low density lipoprotein (VLDL). In vivo studies using Triton WR1339 revealed that there is no significant difference between mutant and wild-type KK mice in the hepatic VLDL triglyceride secretion rate. However, turnover studies using radiolabeled VLDL revealed that the clearance of 3 H-triglyceride-labeled VLDL was significantly enhanced in KK/San mice, whereas the clearance of 125 I-labeled VLDL was only slightly enhanced. In vitro analysis of recombinant protein revealed that ANGPTL3 directly inhibits LPL activity. These data strongly support the hypothesis that ANGPTL3 is a new class of lipid metabolism modulator, which regulates VLDL triglyceride levels through the inhibition of LPL activity.Hyperlipidemia is a major risk factor of coronary heart disease. Variations in human plasma lipid levels result from both genetic and environmental factors. Genetic factors account for more than 50% of the variation in plasma lipid levels in the human population (1-4). Naturally occurring mutations that affect lipid metabolism in mice have also been reported (5-7). In most cases, the mutated genes have not yet been identified, but elucidating the mutations could lead to the identification of the relevant genes.KK obese mice have a multigenic syndrome of moderate obesity and a diabetic phenotype that resembles human hereditary type 2 diabetes; they show signs of hyperinsulinemia, hyperglycemia, and hyperlipidemia (8 -10). We have found that KK mice in our laboratory (KK/San) have significantly low plasma lipid levels despite showing signs of hyperinsulinemia and hyperglycemia (11). Genetic analysis shows that the mutant phenotype of KK/San mice is inherited recessively as a Mendelian trait. We therefore named this locus hypl (for hypolipidemia). We observed the autosomal recessive hypl phenotype in the progeny of the KK/San strain and mapped the locus to the middle of chromosome 4. We identified a mutation in the gene encoding angiopoietin-like protein 3 (Angptl3) as the cause of the hypl trait (12). The mRNA of Angptl3 is predominantly localized in the liver. The expression of Angptl3 in KK/San mice was found to be 1/30 to 1/40 that of wild-type mice. Overexpression of Angptl3 using adenoviruses or by an intravenous injection of the recombinant protein in KK/San mice elicited a marked increase in circulating plasma total cholesterol...

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In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway.

Cited by 109 publications

References 38 publications

Apolipoprotein E Participates in the Regulation of Very Low Density Lipoprotein-Triglyceride Secretion by the Liver

Apolipoprotein E Participates in the Regulation of Very Low Density Lipoprotein-Triglyceride Secretion by the Liver

Metabolism and Modification of Apolipoprotein B-Containing Lipoproteins Involved in Dyslipidemia and Atherosclerosis

ANGPTL3 Decreases Very Low Density Lipoprotein Triglyceride Clearance by Inhibition of Lipoprotein Lipase

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