Studying apolipoprotein turnover with stable isotope tracers - correct analysis is by modeling enrichments

Rajasekhar Ramakrishnan

Pediatrics, Columbia University, New York, NY 10032

Corresponding Author: rr6{at}columbia.edu

Lipoprotein kinetic parameters are determined from mass spectrometry data after administering mass isotopes of amino acids, which label proteins endogenously. The standard procedure, from Foster et al. (J. Lipid Res. 34:2193-2205, 1993), is to model the isotopic content of the labeled precursor amino acid and of proteins of interest as tracer-to-tracee ratio (TTR. It is shown here that even though the administered tracer alters amino acid mass and turnover, apolipoprotein synthesis is unaltered and hence the apolipoprotein system is in a steady state with the total (labeled plus unlabeled) masses and fluxes remaining constant. The correct model formulation for apolipoprotein kinetics is shown to be in terms of tracer enrichment, not of TTR. The needed mathematical equations are derived. A theoretical error analysis is carried out to calculate the magnitude of error in published results using TTR modeling. It is shown that TTR modeling leads to a consistent underestimate of the fractional synthetic rate. In constant infusion studies, the bias error percent is shown to equal approximately the plateau enrichment, generally under 10%. It is shown that, in bolus studies, the underestimation error can be larger. Thus, for mass isotope studies with endogenous tracers, apolipoproteins are in a steady state and the data should be fitted by modeling enrichments.

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