Delayed postprandial retinyl palmitate and squalene removal in a patient heterozygous for apolipoprotein A-IFIN mutation (Leu 159 → Arg) and low HDL cholesterol level without coronary artery disease

Gylling, Helena; Relas, Heikki; Miettinen, Helena E.; Radhakrishnan, Rajaratnam; Miettinen, Tatu A.

doi:10.1016/s0021-9150(96)05961-8

Cited by 6 publications

(4 citation statements)

References 15 publications

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“…The affected members have a decreased HDL concentration presumably due to rapid catabolism. However, they do not have any signs of amyloidosis [40–42]. This observation clearly shows that the location of the mutation determines whether the apoA‐I is amyloidogenic.…”

Section: Discussionmentioning

confidence: 80%

Apolipoprotein A‐I induced amyloidosis

et al. 1998

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Amyloidosis is characterized by extracellular deposits of protein fibrils with a high content of L L-sheets in secondary structure. The protein forms together with proteoglycans amyloid fibrils causing organ damage and serious morbidity. Intact apolipoprotein A-I (apoA-I) is an important protein in lipid metabolism regulating the synthesis and catabolism of high density lipoproteins (HDL). Usually, apoA-I is not associated with amyloidosis. However, four naturally occuring mutant forms of apoA-I are known so far resulting in amyloidosis. The most important feature of all variants is the very similar formation of N-terminal fragments which were found in the amyloid deposits (residues 1^83 to 1^94). The new insights in the understanding of the association of apoA-I with HDL, its metabolism, and its hypothesized structural findings may explain a common mechanism for the genesis of apoA-I induced amyloidosis. Here we summarized the specific features of all known amyloidogenic variants of apoA-I and speculate about its metabolic pathway, which may have general implications for the metabolism of apoA-I.z 1998 Federation of European Biochemical Societies.

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Section: Discussionmentioning

confidence: 80%

Apolipoprotein A‐I induced amyloidosis

et al. 1998

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“…Protein Expression and the Ability of Mutant ApoA-I Forms to Activate LCAT and Promote ABCA1-Mediated Cholesterol Efflux in Vitro. We have generated recombinant adenoviruses expressing the WT apoA-I and the apoA-I(Leu141Arg) Pisa and apoA-I(Leu159Arg) FIN mutants that were found in human patients ( 13 , 22 , − . To assess the expression and secretion of the two mutants compared to WT apoA-I, we infected HTB13 cells grown in 5 mL of medium in 100 mm diameter dishes with recombinant adenoviruses harboring the WT or the mutant apoA-I genes using an moi of 20.…”

Section: Resultsmentioning

confidence: 99%

“…In the current study, we investigated the effect of two naturally occurring apoA-I mutations, apoA-I(Leu141Arg) Pisa and apoA-I(Leu159Arg) FIN , on the biogenesis of HDL. These mutations have been associated with very low HDL cholesterol and apoA-I levels as well as hypo-α lipoproteinemia in human subjects ( 13 , − . Using adenovirus-mediated gene transfer of these mutants in apoA-I -/- mice, we found that both mutations fail to form discoidal or spherical HDL particles and are associated with very low plasma HDL levels.…”

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confidence: 99%

LCAT can Rescue the Abnormal Phenotype Produced by the Natural ApoA-I Mutations (Leu141Arg)_Pisa and (Leu159Arg)_FIN

et al. 2007

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To explain the etiology and find a mode of therapy of genetically determined low levels of high-density lipoprotein (HDL), we have generated recombinant adenoviruses expressing apolipoprotein A-I (apoA-I)(Leu141Arg)Pisa and apoA-I(Leu159Arg)FIN and studied their properties in vitro and in vivo. Both mutants were secreted efficiently from cells but had diminished capacity to activate lecithin/cholesterol acyltransferase (LCAT) in vitro. Adenovirus-mediated gene transfer of either of the two mutants in apoA-I-deficient (apoA-I-/-) mice resulted in greatly decreased total plasma cholesterol, apoA-I, and HDL cholesterol levels. The treatment also decreased the cholesteryl ester to total cholesterol ratio (CE/TC), caused accumulation of prebeta1-HDL and small size alpha4-HDL particles, and generated only few spherical HDL particles, as compared to mice expressing wild-type (WT) apoA-I. Simultaneous treatment of the mice with adenoviruses expressing either of the two mutants and human LCAT normalized the plasma apoA-I, HDL cholesterol levels, and the CE/TC ratio, restored normal prebeta- and alpha-HDL subpopulations, and generated spherical HDL. The study establishes that apoA-I(Leu141Arg)Pisa and apoA-I(Leu159Arg)FIN inhibit an early step in the biogenesis of HDL due to inefficient esterification of the cholesterol of the prebeta1-HDL particles by the endogenous LCAT. Both defects can be corrected by treatment with LCAT.

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“…A single amino acid substitution within the sixth helical repeat, L159R apoA-I, or apoA-I Fin , was identified in a kindred in Finland in 1996 (8)(9)(10). Affected family members were found to be heterozygous for the mutation and to have only 20% as much HDL cholesterol and 25% as much apoA-I in plasma as unaffected family members.…”

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confidence: 99%

Ratio determination of plasma wild-type and L159R apoA-I using mass spectrometry: tools for studying apoA-IFin

Owen

Bharadwaj

Thomas

et al. 2007

Journal of Lipid Research

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In this report, methods are described to isolate milligram quantities of a mutant apolipoprotein A-I (apoA-I) protein for use in structure-function studies. Expression of the L159R apoA-I mutation in humans reduces the concentration of plasma wild-type apoA-I, thus displaying a dominant negative phenotype in vivo. Earlier attempts to express and isolate this mutant protein resulted in extensive degradation and protein misfolding. Using an Escherichia coli expression system used predominantly for the isolation of soluble apoA-I mutant proteins, we describe the expression and purification of L159R apoA-I (apoA-I Fin ) from inclusion bodies. In addition, we describe a mass spectrometric method for measuring the L159R-to-wild-type apoA-I ratio in a 1 ml plasma sample. These new methods will facilitate further studies into the mechanism behind the dominant negative phenotype associated with the expression of the L159R apoA-I protein in humans.-Owen, J. S., M. S. Bharadwaj, M. J. Thomas, S. Bhat, M. P. Samuel, and M. G. Sorci-Thomas. Ratio determination of plasma wild-type and L159R apoA-I using mass spectrometry: tools for studying apoA-I Fin . J. Lipid Res. 2007. 48: 226-234.

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Delayed postprandial retinyl palmitate and squalene removal in a patient heterozygous for apolipoprotein A-IFIN mutation (Leu 159 → Arg) and low HDL cholesterol level without coronary artery disease

Cited by 6 publications

References 15 publications

Apolipoprotein A‐I induced amyloidosis

Apolipoprotein A‐I induced amyloidosis

LCAT can Rescue the Abnormal Phenotype Produced by the Natural ApoA-I Mutations (Leu141Arg)_Pisa and (Leu159Arg)_FIN

Ratio determination of plasma wild-type and L159R apoA-I using mass spectrometry: tools for studying apoA-IFin

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Delayed postprandial retinyl palmitate and squalene removal in a patient heterozygous for apolipoprotein A-IFIN mutation (Leu 159 → Arg) and low HDL cholesterol level without coronary artery disease

Cited by 6 publications

References 15 publications

Apolipoprotein A‐I induced amyloidosis

Apolipoprotein A‐I induced amyloidosis

LCAT can Rescue the Abnormal Phenotype Produced by the Natural ApoA-I Mutations (Leu141Arg)Pisa and (Leu159Arg)FIN

Ratio determination of plasma wild-type and L159R apoA-I using mass spectrometry: tools for studying apoA-IFin

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LCAT can Rescue the Abnormal Phenotype Produced by the Natural ApoA-I Mutations (Leu141Arg)_Pisa and (Leu159Arg)_FIN