Monogenic primary hypercholesterolaemia in South Africa

Familial hypercholesterolaemia (FH) and familial defective apolipoprotein B-1OO (FDB) are the two major causes of monogenic primary hypercholesterolaemia. In this review, FH and FDB are defined in relation to normal lipoprotein metabolism. In South Africa FH affects about 1% of Afrikaners, Jews and Indians, while FDB is probably a much rarer disorder. In Afrikaners, three 'founder' mutations are responsible for more than 80% of FH. The population genetics that created the exceptionally high frequency of FH and comparatively low frequency of FDB in various South African populations are described. The genetic organisation and itinerary of the normal low-density lipoprotein (LDL) receptor are reviewed, with particular emphasis on the structure- function relationships in the LDL receptor that have been clarified by the mutations found in South Africa. Finally, the clinical relevance of research into FH in South Africa is discussed

Scavenger receptor BI mediates the selective uptake of oxidized cholesterol esters by rat liver

Biofarmaci

Effects of 5-bromo-2'-deoxyuridine on beating heart cell cultures from neonatal hamsters

[No abstract available]Articl

Familial hypercholesterolemia in South African Afrikaners. Pvu II and Stu I DNA polymorphisms in the LDL-receptor gene consistent with a predominating founder gene effect

Familial hypercholesterolemia (FH), at a prevalence of more than 1 in 100, is at least five times more common in one South African population group than in populations in North America and Europe. Fourteen homozygotic familial hypercholesterolemic subjects from this South African group were genotypes for two intragenic DNA restriction fragment length polymorphisms (RFLPs) in the LDL-receptor gene. A Stu I polymorphism is located in exon 8, and a Pvu II polymorphism, in intron 15. Of ten unrelated FH homozygotes genotyped for both RFLPs, nine were homozygous for an S+P- haplotype, and one was heterozygous for an S+P-/S-P+ haplotype. The remaining four were genotyped for Puv II only and were homozygous for P-. Compared with a previously determined population frequency for the latter, this represents an association (P < 0.05) between the frequency for the P- allele and FH in this population, and this finding is consistent with the 'founder gene effect' previously postulated to be present on genealogical and biochemical evidence.Articl

Identification of three isoform patterns of human serum amyloid A protein

Three patterns of human apo-SAA (serum amyloid A protein) isoforms have been identified by electrofocusing. In pattern 1, six major apo-SAA isoforms of pI 6.0, 6.4, 7.0, 7.4, 7.5 and 8.0 were found. In pattern 2, the apo-SAA isoforms of pI 7.4 and 8.0 were not detected, whereas in pattern 3 the pI-7.0 and -7.5 isoforms were lacking. Six patients displayed apo-SAA isoform pattern 1, 11 displayed pattern 2 and one displayed pattern 3.Articl

Human serum amyloid A protein. Behaviour in aqueous and urea-containing solutions and antibody production

Human serum amyloid A protein (apo-SAA) can be prepared by gel filtration of delipidated acute-phase high-density lipoprotein in the presence of urea. The resultant apo-SAA is soluble (>90% solubility) in a wide range of buffer solutions, with all of the six major isoforms of apo-SAA being equally soluble. In urea-containing solutions the isoforms behave qualitatively differently in various urea concentrations, probably reflecting subtle primary-structure variations. The higher-pI isoforms are only completely unfolded at >7 M-urea. By immunizing with apo-SAA adsorbed to acid treated bacteria (Salmonella minnesota R595), high-titre antibodies can easily be elicited in rabbits.Articl

Mammalian Wnt3a is released on lipoprotein particles

Little is known about the release and intercellular transport of Wnt proteins from mammalian cells. Lipoproteins may act as carriers for the intercellular movement and gradient formation of the lipid-linked morphogens Wingless and Hedgehog in Drosophila. To investigate whether such a mechanism can occur in mammals, we have studied Wnt release in cultured mammalian cells. Wnt3a associated with lipoproteins in the culture medium and not with extracellular vesicles or exosomes. Although Wnt3a was associated with both high-density lipoproteins (HDL) and low-density lipoproteins, only HDL allowed Wnt3a release from mouse fibroblasts. Remarkably, Wnt3a lacking its palmitate moiety was released in a lipoprotein-independent manner, demonstrating the dual role of palmitoylation in membrane and lipoprotein binding. We additionally found that Wnt3a can be released from enterocyte cell lines on endogenously expressed lipoproteins. We further discuss the physiological implications of our findings

Neutrophil association and degradation of normal and acute-phase high-density lipoprotein 3

The interaction of normal and acute-phase high-density lipoproteins of the subclass 3 (N-HDL3 and AP-HDL3) with human neutrophils and the accompanying degradation of HDL3 apolipoproteins have been studied in vitro. The chemical composition of normal and acute-phase HDL3 was similar except that serum amyloid A protein (apo-SAA) was a major apolipoprotein in AP-HDL3 (approx. 30% of total apolipoproteins). 125I-labelled AP-HDL3 was degraded 5-10 times faster than 125I-labelled N-HDL3 during incubation with neutrophils or neutrophil-conditioned medium. Apo-SAA, like apolipoprotein A-II (apo-A-II), was more susceptible than apolipoprotein A-I (apo-A-I) to the action of proteases released from the cells. The amounts of cell-associated AP-HDL3 apolipoproteins at saturation were up to 2.8 times greater than N-HDL3 apolipoproteins; while apo-A-I was the major cell-associated apolipoprotein when N-HDL3 was bound, apo-SAA constituted 80% of the apolipoproteins bound in the case of AP-HDL3. The associated intact apo-SAA was mostly surface-bound as it was accessible to the action of exogenous trypsin. α1-Antitrypsin-resistant (α1-AT-resistant) cellular degradation of AP-HDL3 apolipoproteins also occurred; experiments in which pulse-chase labelling was performed or lysosomotropic agents were used indicated that significant intracellular degradation occurred which points to the involvement of cell-surface proteases in this degradation.Articl