THE CELLULAR INTERNALIZATION AND DEGRADATION OF HEPATIC LIPASE IS MEDIATED BY LOW-DENSITY-LIPOPROTEIN RECEPTOR-RELATED PROTEIN AND REQUIRESCELL-SURFACE PROTEOGLYCANS

Hepatic lipase (HL) and lipoprotein lipase (LpL) are structurally rela ted lipolytic enzymes that have distinct functions in lipoprotein cata bolism. In addition to its lipolytic activity, LpL binds to very low d ensity lipoproteins and promotes their interaction with the low densit y lipoprotein receptor-related protein (LRP) (Chappell, D. A., Fry, G. L., Waknitz, M. A., Muhonen, L. E., Pladet M. W., Iverius, P. H., and Strickland, D. K. (1993) J. Biol. Chem. 268, 14168-14175). In vitro b inding assays revealed that HL also binds to purified LRP with a K-D o f 52 nM. Its binding to LRP is inhibited by the 39-kDa receptor associ ated protein (RAP), a known LRP antagonist, and by heparin. I-125-Labe led HL is rapidly internalized and degraded by HepG2 cell lines, and a pproximately 70% of the cellular internalization and degradation is bl ocked by either exogenously added RAP or anti LRP IgG. Mouse fibroblas ts that lack LRP display a greatly diminished capacity to internalize and degrade HL when compared to control fibroblasts. These data indica te that LRP-mediated cellular uptake of HL accounts for a substantial portion of the internalization of this molecule. Proteoglycans have be en shown to participate in the clearance of LpL, and consequently a ro le for proteoglycans in HL clearance pathway was also investigated. Ch inese hamster ovary cell lines that are deficient in proteoglycan bios ynthesis were unable to internalize or degrade I-125-HL despite the fa ct that these cells express LRP. Thus, the initial binding of HL to ce ll surface proteoglycans is an obligatory step for the delivery of the enzyme to LRP for endocytosis. A small, but significant, amount of I- 125-HL was internalized in LRP deficient cells indicating that an LRP independent pathway for HL internalization does exist. This pathway co uld involve cell surface proteoglycans, the LDL receptor, or some othe r unidentified surface protein.