Apolipoprotein AV Accelerates Plasma Hydrolysis OfTriglyceride-Rich Lipoproteins By Interaction With Proteoglycan BoundLipoprotein Lipase

Journal Article · Tue Feb 22 04:00:00 EST 2005 · The Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M411412200· OSTI ID:859742

Merkel, Martin; Loeffler, Britta; Kluger, Malte; Fabig, Nathalie; Geppert, Gesa; Pennacchio, Len A; Laatsch, Alexander; Heeren, Joerg

Apolipoprotein A5 (APOA5) is associated with differences intriglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasmatriglycerides. To elucidate the mechanism by which apoAV influences plasma triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In hAPOA5 transgenic mice(hAPOA5tr), catabolism of chylomicrons and 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 crossbreeding a human LPL transgene with the apoa5 knockout, and the hAPOA5tr to an LPL deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5 deficient mice,however, over expression 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 HDL, 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 proteoglycans bound LPL for lipolysis.

• Research Organization: Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
• Sponsoring Organization: USDOE. Office of Management Budget and Evaluation; NationalInstitutes of Health Grant RHL071954A
• DOE Contract Number: AC02-05CH11231
• OSTI ID: 859742
• Report Number(s): LBNL--57936; BnR: 400412000
• Journal Information: The Journal of Biological Chemistry, Journal Name: The Journal of Biological Chemistry Journal Issue: 22 Vol. 280
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
APOLIPOPROTEINS
Apolipoprotein A5 hyperlipidemia
CATABOLISM
CELL CULTURES
CHEMISTRY
CHYLOMICRONS
FUNCTIONALS
HYDROLYSIS
IN VITRO
LIPASES
LIPOPROTEINS
MICE
PLASMA
PRODUCTION
TRIGLYCERIDES