Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan-bound lipoprotein lipase.
Apolipoprotein A5 (APOA5) is associated with differences in triglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasma triglycerides. To elucidate the mechanism by which apoAV influences plasma triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In human APOA5 transgenic mice (hAPOA5tr), catabolism of chylomicrons and very low density lipoprotein (VLDL) was accelerated due to a faster plasma hydrolysis of triglycerides by lipoprotein lipase (LPL). Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by cross-breeding a human LPL transgene with the apoa5 knock-out and the hAPOA5tr to an lpl-deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5-deficient mice; however, overexpression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr high density lipoprotein, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL-mediated hydrolysis of VLDL triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line. A direct interaction between LPL and apoAV was found by ligand blotting. It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycan-bound LPL for lipolysis.
Merkel
Martin
M
Department of Internal Medicine IUniversity Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany. merkel@uke.uni-hamburg.de
Loeffler
Britta
B
Kluger
Malte
M
Fabig
Nathalie
N
Geppert
Gesa
G
Pennacchio
Len A
LA
Laatsch
Alexander
A
Heeren
Joerg
J
D000495:Allosteric Site; D000818:Animals; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000378:metabolism / Q000502:physiology*; D001054:Apolipoproteins A; D015153:Blotting, Western; D016466:CHO Cells; D002914:Chylomicrons / Q000378:metabolism; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006493:Heparin / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008071:Lipoprotein Lipase / Q000737:chemistry*; D008074:Lipoproteins / Q000737:chemistry; D008079:Lipoproteins, VLDL / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D011509:Proteoglycans / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D013997:Time Factors; D014280:Triglycerides / Q000737:chemistry* / Q000378:metabolism
C437704:APOA5 protein, human; C499058:Apoa5 protein, mouse; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A; D002914:Chylomicrons; D008024:Ligands; D008055:Lipids; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D011509:Proteoglycans; D011994:Recombinant Proteins; D014280:Triglycerides; D006493:Heparin; D008071:Lipoprotein Lipase