Transgenic mice expressing high plasma concentrations of human apolipoprotein B100 and lipoprotein(a).

Linton, MacRae F.; Farese, Robert V.; Chiesa, Giulia; Grass, David; Chin, Peter; Hammer, Robert E.; Hobbs, Helen H.; Young, Stephen G.

doi:10.1172/jci116927

Cited by 221 publications

(203 citation statements)

References 52 publications

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“…To determine if the bioactivity of conditioned medium was associated with the cell-modified LDL, the LDL were reisolated from the medium by fast performance liquid chromatography (FPLC) or ultracentrifugation as described (30). The FPLC fractions were tested for their ability to up-regulate SMC SR-A activity, and the bioactivity was compared with the LDL cholesterol elution pattern.…”

Section: Methodsmentioning

confidence: 99%

Class A Scavenger Receptor Up-regulation in Smooth Muscle Cells by Oxidized Low Density Lipoprotein

Mietus‐Snyder¹,

Gowri²,

Pitas³

2000

Journal of Biological Chemistry

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Section: Methodsmentioning

confidence: 99%

Class A Scavenger Receptor Up-regulation in Smooth Muscle Cells by Oxidized Low Density Lipoprotein

Mietus‐Snyder¹,

Gowri²,

Pitas³

2000

Journal of Biological Chemistry

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“…Cholesterol levels were measured with the Abbott Spectrum kit (Abbott Laboratories Diagnostics Division, Abbott Park, IL), and triglyceride levels were determined with the triglyceride/GB kit (Roche Molecular Biochemicals) (19). The plasma levels of mouse and human apoB100 were measured with monoclonal antibody-based radioimmunoassays (RIAs) (20,21).…”

Section: Methodsmentioning

confidence: 99%

“…Assessing the Distribution of Cholesterol within the Plasma Lipoproteins-The distribution of cholesterol within the plasma lipoproteins was assessed by size-fractionating 250 l of plasma (pooled from 7 female mice after a 4-h fast) by fast protein liquid chromatography (FPLC) on a Superose 6B 10/50 column (Amersham Pharmacia Biotech) (19).…”

Section: Methodsmentioning

confidence: 99%

A Deficiency of Microsomal Triglyceride Transfer Protein Reduces Apolipoprotein B Secretion

Leung¹,

Véniant²,

Kim³

et al. 2000

Journal of Biological Chemistry

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Microsomal triglyceride transfer protein (MTP) transfers lipids to apolipoprotein B (apoB) within the endoplasmic reticulum, a process that involves direct interactions between apoB and the large subunit of MTP. Recent studies with heterozygous MTP knockout mice have suggested that half-normal levels of MTP in the liver reduce apoB secretion. We hypothesized that reduced apoB secretion in the setting of half-normal MTP levels might be caused by a reduced MTP:apoB ratio in the endoplasmic reticulum, which would reduce the number of apoB-MTP interactions. If this hypothesis were true, half-normal levels of MTP might have little impact on lipoprotein secretion in the setting of halfnormal levels of apoB synthesis (since the ratio of MTP to apoB would not be abnormally low) and might cause an exaggerated reduction in lipoprotein secretion in the setting of apoB overexpression (since the MTP:apoB ratio would be even lower). To test this hypothesis, we examined the effects of heterozygous MTP deficiency on apoB metabolism in the setting of normal levels of apoB synthesis, half-normal levels of apoB synthesis (heterozygous Apob deficiency), and increased levels of apoB synthesis (transgenic overexpression of human apoB). Contrary to our expectations, half-normal levels of MTP reduced the plasma apoB100 levels to the same extent (ϳ25-35%) at each level of apoB synthesis. In addition, apoB secretion from primary hepatocytes was reduced to a comparable extent at each level of apoB synthesis. Thus, these results indicate that the concentration of MTP within the endoplasmic reticulum rather than the MTP:apoB ratio is the critical determinant of lipoprotein secretion. Finally, we found that heterozygosity for an apoB knockout mutation lowered plasma apoB100 levels more than heterozygosity for an MTP knockout allele. Consistent with that result, hepatic triglyceride accumulation was greater in heterozygous apoB knockout mice than in heterozygous MTP knockout mice. Microsomal triglyceride transfer protein (MTP)1 is expressed at high levels in the absorptive enterocytes of the intestine and hepatocytes, at moderate levels in the visceral endoderm of the yolk sac during embryonic development, and at relatively low levels in kidney and cardiac muscle (1-4). In each of these tissues, MTP plays a key role in the assembly and secretion of apoB-containing lipoproteins (1, 3, 5). MTP is located within the lumen of the endoplasmic reticulum (ER) and is thought to transfer lipids to apoB as that molecule is translated, allowing apoB to assume a proper conformation for forming a spherical lipoprotein with a neutral lipid core (6). In the absence of MTP, triglyceride-rich, apoB-containing lipoproteins cannot be assembled or secreted (3, 6, 7). The mechanism of MTP action has attracted considerable scrutiny. Of note, several lines of evidence have suggested that the assembly of lipoproteins involves a direct interaction between MTP and apoB. First, Wu et al. (8) demonstrated that apoB can be immunoprecipitated from the microsomes of cult...

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“…Following intravenous infusion of human LDL, but not of VLDL, into transgenic mice, Lp(a) that is indistinguishable from native Lp(a) found in humans is formed. Double transgenic mice expressing both human apo(a) and human apoB-100 synthesize bona fide Lp(a) directly [36,37]. It is interesting to note that the plasma apo(a) levels were higher in double transgenic mice than in those producing only apo(a), suggesting a faster removal rate of apo(a) that is not complexed to LDL.…”

Section: Assembly Of Lp(a): the Role Of Apo(a) Structurementioning

confidence: 99%

The assembly of lipoprotein Lp(a)

Frank¹,

Durovic²,

Kostner³

1996

Eur J Clin Investigation

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Transgenic mice expressing high plasma concentrations of human apolipoprotein B100 and lipoprotein(a).

Cited by 221 publications

References 52 publications

Class A Scavenger Receptor Up-regulation in Smooth Muscle Cells by Oxidized Low Density Lipoprotein

Class A Scavenger Receptor Up-regulation in Smooth Muscle Cells by Oxidized Low Density Lipoprotein

A Deficiency of Microsomal Triglyceride Transfer Protein Reduces Apolipoprotein B Secretion

The assembly of lipoprotein Lp(a)

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