INHIBITORY EFFECTS OF SPECIFIC APOLIPOPROTEIN C-III ISOFORMS ON THE BINDING OF TRIGLYCERIDE-RICH LIPOPROTEINS TO THE LIPOLYSIS-STIMULATED RECEPTOR

ApoC-III overexpression in mice results in severe hypertriglyceridemia due primarily to a delay in the clearance of triglyceride-rich lipopr oteins. We have, in primary cultures of rat hepatocytes, characterized a lipolysis-stimulated receptor (LSR), The apparent number of LSR tha t are available on rat liver plasma membranes is negatively correlated with plasma triglyceride concentrations measured in the fed state, We therefore proposed that the primary physiological role of the LSR is to contribute to the cellular uptake of triglyceride-rich lipoproteins . We have now tested the effect of apoC-III on the binding of triglyce ride rich lipoproteins to LSR, Supplementation of I-125-very low densi ty lipoprotein (VLDL) with apoC-III inhibited the LSR-mediated binding , internalization, and degradation of I-125-VLDL in primary cultures o f rat hepatocytes. Studies using isolated rat liver plasma membranes s howed that enrichment of human VLDL and chylomicrons with synthetic or purified human apoC-III decreased their binding to the LSR by about 4 0%, Supplementation of triglyceride-rich lipoproteins under the same c onditions with human apoC-II had no such inhibitory effect, despite th e fact that this apoprotein bound as efficiently as apoC-III to these particles. Preincubation of LDL with apoC-III did not modify its bindi ng to LSR, Partitioning studies using I-125-apoC-III showed that this lack of effect was due to apoC-III's inability to efficiently associat e with LDL. Purified human apoC-III1 was as efficient as the synthetic nonsialylated form of apoC-III in inhibiting binding of VLDL to LSR, However, despite a 2-fold greater binding of apoC-III2 to VLDL, this i soform was a less efficient inhibitor of the binding of VLDL to LSR th an apoC-III1 or nonsialylated apoC-III, Desialylation of apoC-III2 by treatment with neuraminidase increased the inhibition of VLDL binding to LSR to a level similar to that observed with apoC-III1 and nonsialy lated apoC-III. We propose that apoC-III regulates in part the rate of removal of triglyceride-rich particles by inhibiting their binding to the ESR, and that the level of inhibition is determined by the degree of apoC-III sialylation.