The effect of three serum basic proteins on the mass of lipids in normal and hyperapoB fibroblasts.

Kwiterovich, Peter O.; Motevalli, Mahnaz; Miller, Michael

doi:10.1161/01.atv.14.1.1

Cited by 11 publications

(12 citation statements)

References 27 publications

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“…Apo CI thus joins the list of genes that may be involved in the etiology of familial combined hyperlipidemia (50)(51)(52)(53)(54)(55). In one population-based genetic association study, homozygosity for the minor allele of a HpaI restriction fragment length polymorphism in the apo CI promoter was found in 97% of ⑀2/⑀2 individuals with type III hyperlipidemia, 17% of normal controls and 22% of ⑀2/⑀2 individuals without hyperlipidemia (56).…”

Section: Discussionmentioning

confidence: 99%

Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl.

Shachter¹,

Ebara²,

Ramakrishnan³

et al. 1996

J. Clin. Invest.

107

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Section: Discussionmentioning

confidence: 99%

Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl.

Shachter¹,

Ebara²,

Ramakrishnan³

et al. 1996

J. Clin. Invest.

107

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“…As well, there may be decreased phosphorylation of phospholipase C-␥, which may lead to decreased production of diacylglycerol and IP 3 , and decreased protein kinase C activity. Inhibiting protein kinase C activity prevents the effects of BP I and BP II from being manifested in both normal and hyperapoB cells (10); however, the stimulation of protein kinase C by an analogue of diacylglycerol appears normal in the hyperapoB cells (10).…”

Section: Discussionmentioning

confidence: 99%

Abnormal Protein Tyrosine Phosphorylation in Fibroblasts from Hyperapobetalipoproteinemia Subjects

Motevalli¹,

Goldschmidt‐Clermont²,

Virgil³

et al. 1997

Journal of Biological Chemistry

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The stimulatory effects of three normal human serum basic proteins (BP), BP I (M r 14,000, pI 9.10), BP II (M r 27, 500, pI 8.48), and BP III (M r 55,000, pI 8.73) on cellular triglyceride and cholesterol formation require intact protein-tyrosine kinase phosphorylation (TKP). Here we examined whether there is an abnormality in TKP in cultured fibroblasts from 11 patients with hyperapobetalipoproteinemia (hyperapoB) that manifest two acylation-stimulatory defects, decreased stimulation of triglyceride synthesis by BP I but enhanced formation of cholesterol by BP II. Soluble and insoluble proteins in Triton X-100 extracts were isolated by immunoprecipitation with a monoclonal anti-phosphotyrosine antibody (MAPA) bound to agarose beads and by ultracentrifugation, respectively, from confluent fibroblasts after incubation for 24 h in supplemented serum-free and lipid-free medium (DMEM/F12). Western blots of insoluble proteins showed that group (Gp) II (M r 36,000 -55,000) and Gp III (M r 14,000 -35,000) from hyperapoB cells, grown in DMEM/F12 medium without BP, had significantly decreased reactivity to MAPA. No significant differences in reactivity to MAPA were detected between normal and hyperapoB cells for Gp I (M r 97-120,000). BP II, but not BP I or BP III, reversed the decreased reactivity of Gp II and Gp III to MAPA in hyperapoB cells. Sodium vanadate, an inhibitor of phosphotyrosine phosphatases, did not reverse the deficiency in TKP or the 50% deficiency in the stimulation of mass triglyceride by BP I in hyperapoB cells. Tyrosinephosphorylated Erk-2, a mitogen-activated protein kinase, identified as one of the proteins in Gp II, was significantly decreased in hyperapoB cells. These results provide further evidence for abnormal protein TKP in hyperapoB cells and suggest a possible link between atherosclerotic changes in hyperapoB patients and growth factors upstream from mitogen-activated protein kinase.Hyperapobetalipoproteinemia (hyperapoB) 1 is a lipoprotein disorder that is prevalent in patients with premature coronary artery disease (1, 2). HyperapoB is characterized by an increased number of small, dense low density lipoprotein (LDL) particles, a phenotype shared with familial combined hyperlipidemia, LDL subclass pattern B, familial dyslipidemic hypertension, and syndrome X (2, 3). Two metabolic defects have been described in hyperapoB. First, there is overproduction of apolipoprotein B and very low density lipoprotein (VLDL) particles (3, 4). Second, the clearance of postprandial triglyceriderich particles is delayed, accompanied by an abnormal removal of free fatty acids (5, 6). Incorporation of free fatty acids into triglycerides is deficient in hyperapoB adipocytes, which may lead to an increase in postprandial free fatty acids, which then flux back to the liver, leading to overproduction of apolipoprotein B and VLDL (3-7).We (8 -12) and others (13-18) have studied the role of certain human serum basic proteins that have been linked to the pathogenesis of hyperapoB. We isolated three basic proteins ...

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“…Fractions in peak I that did not react against an antibody to light chain (a contaminating BP) were used to isolate BP II further by preparative SDS gel electrophoresis and electroelution. 8,10 The final purified BP II did not react on Western blots to antibodies against C 3a des-Arg, light chain, prealbumin, apolipoprotein A-I, sterol carrier protein-2, protein 422, or ASP.…”

Section: Isolation and Characterization Of Bp IImentioning

confidence: 99%

“…The eight relatives have been previously characterized and include five hyperapoB probands, the hyperapoB sibling of one proband, and two children of another proband (one normal, one hyperapoB). 8,10 Four of the five kindreds were ascertained through index cases with hyperapoB and CAD from the Johns Hopkins CAD Study.…”

Section: Human Materialsmentioning

confidence: 99%

“…BP II was isolated from normal volunteers and characterized as previously described, 8,10 with the following modifications. For the initial purification step to obtain a mixture of BPs, human serum (25 mL) was applied to a DEAE-Affi Gel Blue column (2.5ϫ32 cm), and several unbound peaks containing a mixture of BPs eluted with 125 mL of 0.02 mol/L phosphate, pH 8.0.…”

Section: Isolation and Characterization Of Bp IImentioning

confidence: 99%

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Differential Effect of Genistein on the Stimulation of Cholesterol Production by Basic Protein II in Normal and HyperapoB Fibroblasts

Kwiterovich

Motevalli

1998

ATVB

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Abstract-We studied further the basis for the abnormal effect of human serum basic protein II (BP II) on cholesterol production in hyperapobetalipoproteinemia (hyperapoB) fibroblasts and whether this effect involves protein tyrosine kinase phosphorylation (TKP). Genistein, a specific inhibitor of TKP was used as a probe. Compared with normal cells, BP II stimulated significantly the cellular mass of total cholesterol (6.4-fold), unesterified cholesterol (3.6-fold), and esterified cholesterol (6.7-fold) in hyperapoB fibroblasts. The addition of genistein to BP II in hyperapoB cells markedly inhibited these abnormal stimulatory effects of BP II on cell sterol mass. In normal cells, the addition of genistein to BP II produced an opposite effect: a marked stimulation in the mass of total (5.5-fold) and esterified (18.3-fold) cholesterol and a decrease in unesterified cholesterol (3.4-fold). These effects of genistein on the formation of cellular cholesterol by BP II were both time and concentration dependent. The inhibition of the stimulatory effect of BP II on cholesterol production by genistein in hyperapoB cells may be mediated through 3-hydroxy 3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of cholesterol biosynthesis, since the rate of incorporation of [ 14 C]acetate, but not [ 3 H]mevalonate, into unesterified cholesterol was decreased by genistein in the hyperapoB cells. When the mass of cell total cholesterol in the cells treated with BP II was subtracted from those treated with BP II plus genistein, a negative number was produced in each of the six hyperapoB cell lines, while each of the normal cell lines retained a positive number. The mean difference for the mass of total cholesterol between the hyperapoB and normal fibroblasts under these conditions was 128.2 nmol/mg cell protein, a difference that was separated by Ͼ3 SD. This study supports further the tenet that there is a defect in the response of hyperapoB cells to BP II and that this defect results in an abnormality in cholesterol metabolism that appears mediated through a protein TKP-mediated process. (Arterioscler Thromb Vasc Biol. 1998;18:57-64.) Key Words: tyrosine kinase phosphorylation Ⅲ familial combined hyperlipidemia Ⅲ atherosclerosis H yperapobetalipoproteinemia is a lipoprotein disorder that is prevalent in patients with premature CAD.1,2 HyperapoB is characterized by an increased number of small, dense LDL particles, a phenotype shared with familial combined hyperlipidemia, LDL subclass pattern B, familial dyslipidemic hypertension, and syndrome X.2,3 Two metabolic defects have been described in patients with hyperapoB. First, there is overproduction of apolipoprotein B and VLDL particles. 3,4 Second, the clearance of postprandial triglyceride-rich particles is delayed, accompanied by an abnormal removal of FFA. 5,6 The stimulation of the incorporation of FFA into triglycerides of adipocytes by a low-molecular-weight serum BP (called ASP) is deficient in hyperapoB cells.7 It has been postulated that this defect leads to ...

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The effect of three serum basic proteins on the mass of lipids in normal and hyperapoB fibroblasts.

Cited by 11 publications

References 27 publications

Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl.

Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl.

Abnormal Protein Tyrosine Phosphorylation in Fibroblasts from Hyperapobetalipoproteinemia Subjects

Differential Effect of Genistein on the Stimulation of Cholesterol Production by Basic Protein II in Normal and HyperapoB Fibroblasts

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