Molecular basis for "null" lipoprotein(a) phenotypes and the influence of apolipoprotein(a) size on plasma lipoprotein(a) level in the baboon

Ann L. White, James E. Hixson, David L. Rainwater, Robert E. Lanford

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

High plasma levels of lipoprotein(a) (Lp(a)) and its unique apolipoprotein, apo(a), are an independent risk factor for cardiovascular disease. Plasma Lp(a) levels vary over a 1000-fold range and are determined by the apo(a) locus, which has at least 34 alleles expressing apo(a) isoforms with molecular weights from <300,000 to >800,000. In addition, "null" apo(a) alleles produce no detectable plasma apo(a). We used primary cultures of baboon hepatocytes to investigate the molecular basis for null apo(a) phenotypes. Immunoprecipitation of apo(a) after radiolabeling of hepatocytes revealed that some null alleles gave rise to intracellular protein products that were not secreted. Pulse-chase analysis and endoglycosidase digests demonstrated that these proteins were retained in the endoplasmic reticulum. We also examined the molecular basis for the documented inverse correlation between apo(a) size and plasma Lp(a) concentration. Steady-state labeling and pulsechase analysis of hepatocytes from animals expressing two isoforms of apo(a) revealed that the endoplasmic reticulum residence time of secreted apo(a) isoforms was determined by their size. This accounted for the inverse relationship between isoform size and level of secretion. We conclude that the efficiency of post-translational processing of apo(a) is a major determinant of plasma Lp(a) concentration.

Original languageEnglish (US)
Pages (from-to)9060-9066
Number of pages7
JournalJournal of Biological Chemistry
Volume269
Issue number12
StatePublished - Mar 25 1994
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

Fingerprint Dive into the research topics of 'Molecular basis for "null" lipoprotein(a) phenotypes and the influence of apolipoprotein(a) size on plasma lipoprotein(a) level in the baboon'. Together they form a unique fingerprint.

  • Cite this