The carboxyl-terminal domain of lipoprotein lipase binds to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and mediates binding of normal very low density lipoproteins to LRP.

Williams, Suzanne E.; Inoue, Ituro; Tran, Hoanh; Fry, Glenna L.; Pladet, M W; Iverius, Per-Henrik; Lalouel, Jean-Marc; Chappell, David; Strickland, Dudley K.

doi:10.1016/s0021-9258(17)37017-5

Cited by 113 publications

(20 citation statements)

References 37 publications

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“…We and others have reported earlier that LPL enhances VLDL degradation by cultured cells and that both LDL receptors and LRP are involved in this process (23,29,30,44,45). Here we investigated whether HTGL also stimulates VLDL catabolism and if the LDL receptor pathway is involved.…”

Section: Htgl Stimulates Vldl Degradation By Normal Fibroblastsmentioning

confidence: 91%

“…The carboxyl-terminal fragment of human LPL (amino acid residues 313-448) was produced in E. coli as a fusion protein with glutathione S -transferase (GST) as described previously (28) and designated as GST-LPLC. Using site-directed mutagenesis, tryptophan residues at positions 393 and 394 were changed to alanine to generate GST-LPLC ww (28,29). Monoclonal antibody IgG-4A4 directed against the cytoplasmic terminal 14 amino acids of the LDL receptor was obtained as a hybridoma from the American Type Culture Collection (Rockville, MD).…”

Section: Methodsmentioning

confidence: 99%

“…5B). GST-LPLC ww is a fusion protein of glutathione-S-transferase with the carboxyl-terminal non-catalytic fragment of LPL (amino acid residues 313-448) in which tryptophan residues at positions 393 and 394 are changed to alanine by site-directed mutagenesis (28,29). As a result of these substitutions, GST-LPLC ww is unable to bind lipoproteins but retains its ability to bind to both LDL receptors and LRP.…”

Section: Rap Partially Inhibits But Gst-lplc Ww Completely Inhibits Htgl-stimulated Vldl Degradationmentioning

confidence: 99%

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Hepatic triglyceride lipase promotes low density lipoprotein receptor-mediated catabolism of very low density lipoproteins in vitro

Medh

Bowen

Fry

et al. 1999

Journal of Lipid Research

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We demonstrate here that hepatic triglyceride lipase (HTGL) enhances VLDL degradation in cultured cells by a LDL receptor-mediated mechanism. VLDL binding at 4 ؇ C and degradation at 37 ؇ 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 g/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 lovastatintreated normal fibroblasts. A prominent role for LDL receptors was confirmed by demonstration of similar HTGLpromoted 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. HTGLstimulated 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 ؇ 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.

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Section: Htgl Stimulates Vldl Degradation By Normal Fibroblastsmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Rap Partially Inhibits But Gst-lplc Ww Completely Inhibits Htgl-stimulated Vldl Degradationmentioning

confidence: 99%

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Hepatic triglyceride lipase promotes low density lipoprotein receptor-mediated catabolism of very low density lipoproteins in vitro

Medh

Bowen

Fry

et al. 1999

Journal of Lipid Research

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“…The binding to TRLs is exclusively mediated by LPL, not GPIHBP1 (Figure 2) [46,47]. Although the molecular mechanism(s) of LPL-mediated TRL processing is not completely understood, several regions of the lipase molecule are known to be essential for its activation, TRL binding and substrate specificity [18,[48][49][50][51][52][53].…”

Section: Enzymatic Function Of Lplmentioning

confidence: 99%

The Importance of Lipoprotein Lipase Regulation in Atherosclerosis

et al. 2021

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Lipoprotein lipase (LPL) plays a major role in the lipid homeostasis mainly by mediating the intravascular lipolysis of triglyceride rich lipoproteins. Impaired LPL activity leads to the accumulation of chylomicrons and very low-density lipoproteins (VLDL) in plasma, resulting in hypertriglyceridemia. While low-density lipoprotein cholesterol (LDL-C) is recognized as a primary risk factor for atherosclerosis, hypertriglyceridemia has been shown to be an independent risk factor for cardiovascular disease (CVD) and a residual risk factor in atherosclerosis development. In this review, we focus on the lipolysis machinery and discuss the potential role of triglycerides, remnant particles, and lipolysis mediators in the onset and progression of atherosclerotic cardiovascular disease (ASCVD). This review details a number of important factors involved in the maturation and transportation of LPL to the capillaries, where the triglycerides are hydrolyzed, generating remnant lipoproteins. Moreover, LPL and other factors involved in intravascular lipolysis are also reported to impact the clearance of remnant lipoproteins from plasma and promote lipoprotein retention in capillaries. Apolipoproteins (Apo) and angiopoietin-like proteins (ANGPTLs) play a crucial role in regulating LPL activity and recent insights into LPL regulation may elucidate new pharmacological means to address the challenge of hypertriglyceridemia in atherosclerosis development.

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“…Accordingly, the N-terminal domain (aa 1-312) contains the catalytic center with a covering loop important for interaction with lipid substrates, heparin binding sites, and a binding site for the cofactor apolipoprotein C-II (3). The C-terminal domain (aa 313-448) was shown to contain binding sites for lipoproteins, for the ␣ 2 -macroglobulin receptor/low density lipoprotein receptor-related protein, and possibly for heparin (36)(37)(38). As the sequence similarity between the C-terminal sequences of LPL and PL is much weaker than that between the N-terminal sequences, the folding predictions concerning the C-terminal LPL domain are less certain.…”

mentioning

confidence: 99%

Detailed characterization of the binding site of the lipoprotein lipase-specific monoclonal antibody 5D2

Chang

Reich

Brunzell

et al. 1998

Journal of Lipid Research

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Monoclonal antibody (MAb) 5D2 recognizes lipoprotein lipases (LPL) from different species but not related lipases. This MAb is a unique reagent, used world-wide, because it differentiates between monomeric inactive and dimeric active LPL, inhibits human LPL enzyme activity, and binds to C-terminal LPL sequences involved in interactions with lipoproteins, lipoprotein receptors, and heparin. In this study we have analyzed the fine specificity of the MAb epitope recognition in order to better understand its functional properties and species-specific LPL immune reactivity. In peptide scan assays, MAb 5D2 reacted with all, except two, 13 amino acid-long peptides located between positions 380 and 410. Peptides from the amino terminal end of this region reacted more strongly than those from the carboxyl terminal end. Furthermore, only a peptide from the amino terminal end competed effectively with the binding of MAb 5D2 to native LPL bound to microtiter plates or nitrocellulose. A systematic peptide mutagenesis study indicated that 8 amino acids of the reactive region, mainly located in the amino terminal end, are critical for binding and probably directly interact with MAb 5D2. The experimentally determined antigenicities of species-specific LPL peptides and of the corresponding denatured fulllength LPL proteins on immunoblots were consistent with these findings. According to a proposed 3D-model for LPL, only the amino terminal end of the antigenic region is easily surface-accessible. These data combined with 3D-modelling of monoclonal antibody (MAb)-lipoprotein lipase (LPL) protein interaction provide new insight into the known biological effects of MAb 5D2 on LPL and the antigenic determinants that are recognized.-Chang, S-F., B. Reich, J. D. Brunzell, and H. Will. Detailed characterization of the binding site of the lipoprotein lipase-specific monoclonal antibody 5D2.

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The carboxyl-terminal domain of lipoprotein lipase binds to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and mediates binding of normal very low density lipoproteins to LRP.

Cited by 113 publications

References 37 publications

Hepatic triglyceride lipase promotes low density lipoprotein receptor-mediated catabolism of very low density lipoproteins in vitro

Hepatic triglyceride lipase promotes low density lipoprotein receptor-mediated catabolism of very low density lipoproteins in vitro

The Importance of Lipoprotein Lipase Regulation in Atherosclerosis

Detailed characterization of the binding site of the lipoprotein lipase-specific monoclonal antibody 5D2

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