title: Mechanisms by which lipoprotein lipase alters cellular metabolism of lipoprotein(a), low density lipoprotein, and nascent lipoproteins. Roles for low density lipoprotein receptors and heparan sulfate proteoglycans.
abstract: We sought to investigate effects of lipoprotein lipase (LpL) on cellular catabolism of lipoproteins rich in apolipoprotein B-100. LpL increased cellular degradation of lipoprotein(a) (Lp(a)) and low density lipoprotein (LDL) by 277% +/- 3.8% and 32.5% +/- 4.1%, respectively, and cell association by 509% +/- 8.7% and 83.9% +/- 4.0%. The enhanced degradation was entirely lysosomal. Enhanced degradation of Lp(a) had at least two components, one LDL receptor-dependent and unaffected by heparitinase digestion of the cells, and the other LDL receptor-independent and heparitinase-sensitive. The effect of LpL on LDL degradation was entirely LDL receptor-independent, heparitinase-sensitive, and essentially absent from mutant Chinese hamster ovary cells that lack cell surface heparan sulfate proteoglycans. Enhanced cell association of Lp(a) and LDL was largely LDL receptor-independent and heparitinase-sensitive. The ability of LpL to reduce net secretion of apolipoprotein B-100 by HepG2 cells by enhancing cellular reuptake of nascent lipoproteins was also LDL receptor-independent and heparitinase-sensitive. None of these effects on Lp(a), LDL, or nascent lipoproteins required LpL enzymatic activity. We conclude that LpL promotes binding of apolipoprotein B-100-rich lipoproteins to cell surface heparan sulfate proteoglycans. LpL also enhanced the otherwise weak binding of Lp(a) to LDL receptors. The heparan sulfate proteoglycan pathway represents a novel catabolic mechanism that may allow substantial cellular and interstitial accumulation of cholesteryl ester-rich lipoproteins, independent of feedback inhibition by cellular sterol content.
authors.affiliation: Department of Physiology and Biochemistry, Medical College of Pennsylvania, Philadelphia 19129.
authors.forename: K J
authors.initials: KJ
authors.lastname: Williams
authors.forename: G M
authors.initials: GM
authors.lastname: Fless
authors.forename: K A
authors.initials: KA
authors.lastname: Petrie
authors.forename: M L
authors.initials: ML
authors.lastname: Snyder
authors.forename: R W
authors.initials: RW
authors.lastname: Brocia
authors.forename: T L
authors.initials: TL
authors.lastname: Swenson
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000378:metabolism*; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002417:Cattle; D006224:Cricetinae; D003412:Cricetulus; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate / Q000502:physiology*; D006801:Humans; D007457:Iodine Radioisotopes; D008071:Lipoprotein Lipase / Q000378:metabolism*; D017270:Lipoprotein(a); D008074:Lipoproteins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D011133:Polysaccharide-Lyases / Q000378:metabolism; D011509:Proteoglycans / Q000502:physiology*; D011973:Receptors, LDL / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D007457:Iodine Radioisotopes; D008071:Lipoprotein Lipase; D017270:Lipoprotein(a); D008074:Lipoproteins; D008077:Lipoproteins, LDL; D011133:Polysaccharide-Lyases; D011509:Proteoglycans; D011973:Receptors, LDL; C021349:heparitinsulfate lyase