Hepatic triglyceride lipase promotes low density lipoprotein receptor-mediated catabolism of very low density lipoproteins in vitro.
We demonstrate here that hepatic triglyceride lipase (HTGL) enhances VLDL degradation in cultured cells by a LDL receptor-mediated mechanism. VLDL binding at 4 degrees C and degradation at 37 degrees C by normal fibroblasts was stimulated by HTGL in a dose-dependent manner. A maximum increase of up to 7-fold was seen at 10 microg/ml HTGL. Both VLDL binding and degradation were significantly increased (4-fold) when LDL receptors were up-regulated by treatment with lovastatin. HTGL also stimulated VLDL degradation by LDL receptor-deficient FH fibroblasts but the level of maximal degradation was 40-fold lower than in lovastatin-treated normal fibroblasts. A prominent role for LDL receptors was confirmed by demonstration of similar HTGL-promoted VLDL degradation by normal and LRP-deficient murine embryonic fibroblasts. HTGL enhanced binding and internalization of apoprotein-free triglyceride emulsions, however, this was LDL receptor-independent. HTGL-stimulated binding and internalization of apoprotein-free emulsions was totally abolished by heparinase indicating that it was mediated by HSPG. In a cell-free assay HTGL competitively inhibited the binding of VLDL to immobilized LDL receptors at 4 degrees C suggesting that it may directly bind to LDL receptors but may not bind VLDL particles at the same time. We conclude that the ability of HTGL to enhance VLDL degradation is due to its ability to concentrate lipoprotein particles on HSPG sites on the cell surface leading to LDL receptor-mediated endocytosis and degradation.
Medh
J D
JD
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Bowen
S L
SL
Fry
G L
GL
Ruben
S
S
Hill
J
J
Wong
H
H
Chappell
D A
DA
D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D019763:Heparin Lyase / Q000378:metabolism; D006801:Humans; D008049:Lipase / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D011971:Receptors, Immunologic / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*; D000511:alpha-Macroglobulins / Q000378:metabolism
D008079:Lipoproteins, VLDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D000511:alpha-Macroglobulins; D008049:Lipase; D019763:Heparin Lyase