Biogenesis of lipoprotein(a) in human and animal hepatocytes.
The atherogenic plasma lipoprotein complex Lp(a) consists of low density lipoprotein (LDL) and the highly polymorphic glycoprotein apolipoprotein(a) covalently linked by a disulfide bridge. A size polymorphism of apolipoprotein(a) results from a variable number of tandemly arranged kringle IV repeats. The largely varying plasma concentration of Lp(a) is nonnormally distributed in the population and correlates inversely with the molecular mass of apolipoprotein(a). In vivo turnover studies have revealed that differences in Lp(a) plasma concentrations reflect different synthesis rather than degradation. Plasma Lp(a) originates exclusively in the liver. Detailed studies of the intracellular metabolism of apolipoprotein(a) in transfected human hepatoma cells as well as in primary baboon hepatocytes have revealed an unusual secretory pathway of this protein. Due to complex folding and processing, an immature precursor form of apolipoprotein(a) is retained in the endoplasmic reticulum for a prolonged time. This retention leads to a massive accumulation in the endoplasmic reticulum which stands in contrast to most secretory proteins. Since the retention time correlates positively with the apolipoprotein(a) isoform size, this intracellular mechanism could explain the inverse correlation between the isoform size and plasma concentrations observed in the general population. These findings therefore demonstrate a novel cellular regulatory mechanism lor a secretory human plasma protein with genetically controlled concentrations. The majority of the above-mentioned studies revealed another unusual feature of the biogenesis of Lp(a). The mature Lp(a) complex is formed, at least in the investigated cell models, only following separate secretion of apolipoprotein(a) and LDL-like particles. Work that is related to both aspects of Lp(a) formation, both from our laboratory and from other authors, is reviewed.
Lobentanz
E M
EM
Institute of Medical Biology and Human Genetics, University of Innsbruck, Austria.
Dieplinger
H
H
D000818:Animals; D001054:Apolipoproteins A / Q000378:metabolism; D006801:Humans; D017270:Lipoprotein(a) / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*
D001054:Apolipoproteins A; D017270:Lipoprotein(a)