Mice expressing only covalent dimeric heparin binding-deficient lipoprotein lipase: muscles inefficiently secrete dimeric enzyme.
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Mice expressing only covalent dimeric heparin binding-deficient lipoprotein lipase: muscles inefficiently secrete dimeric enzyme. / Lutz, E Peer; Kako, Yuko; Yagyu, Hiroaki; Heeren, Joerg; Marks, Steven; Wright, Thamrah; Melford, Kristan; Ben-Zeev, Osnat; Radner, Herbert; Merkel, Martin; Bensadoun, André; Wong, Howard; Goldberg, Ira J.
in: J BIOL CHEM, Jahrgang 279, Nr. 1, 1, 2004, S. 238-244.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Mice expressing only covalent dimeric heparin binding-deficient lipoprotein lipase: muscles inefficiently secrete dimeric enzyme.
AU - Lutz, E Peer
AU - Kako, Yuko
AU - Yagyu, Hiroaki
AU - Heeren, Joerg
AU - Marks, Steven
AU - Wright, Thamrah
AU - Melford, Kristan
AU - Ben-Zeev, Osnat
AU - Radner, Herbert
AU - Merkel, Martin
AU - Bensadoun, André
AU - Wong, Howard
AU - Goldberg, Ira J
PY - 2004
Y1 - 2004
N2 - Lipoprotein lipase (LpL) hydrolyzes triglycerides of circulating lipoproteins while bound as homodimers to endothelial cell surface heparan sulfate proteoglycans. This primarily occurs in the capillary beds of muscle and adipose tissue. By creating a mouse line that expresses covalent dimers of heparin-binding deficient LpL (hLpLHBM-Dimer) in muscle, we confirmed in vivo that linking two LpL monomers in a head to tail configuration creates a functional LpL. The hLpLHBM-Dimer transgene produced abundant activity and protein in muscle, and the LpL was the expected size of a dimer (approximately 110 kDa). Unlike the heparin-binding mutant monomer, hLpLHBM-Dimer had the same stability as nonmutated LpL. The hLpLHBM-Dimer transgene prevented the neonatal demise of LpL knockout mice; however, these mice were hypertriglyceridemic. Postheparin plasma LpL activity was lower than expected with the robust expression in muscle and was no longer covalently linked. Studies in transfected cells showed that Chinese hamster lung cells, but not COS cells, also degraded tandem repeated LpL into monomers. Thus, although muscle can synthesize tethered, dimeric LpL, efficient production of this enzyme leading to secretion, and physiological function appears to favor secretion of a noncovalent dimer composed of monomeric subunits.
AB - Lipoprotein lipase (LpL) hydrolyzes triglycerides of circulating lipoproteins while bound as homodimers to endothelial cell surface heparan sulfate proteoglycans. This primarily occurs in the capillary beds of muscle and adipose tissue. By creating a mouse line that expresses covalent dimers of heparin-binding deficient LpL (hLpLHBM-Dimer) in muscle, we confirmed in vivo that linking two LpL monomers in a head to tail configuration creates a functional LpL. The hLpLHBM-Dimer transgene produced abundant activity and protein in muscle, and the LpL was the expected size of a dimer (approximately 110 kDa). Unlike the heparin-binding mutant monomer, hLpLHBM-Dimer had the same stability as nonmutated LpL. The hLpLHBM-Dimer transgene prevented the neonatal demise of LpL knockout mice; however, these mice were hypertriglyceridemic. Postheparin plasma LpL activity was lower than expected with the robust expression in muscle and was no longer covalently linked. Studies in transfected cells showed that Chinese hamster lung cells, but not COS cells, also degraded tandem repeated LpL into monomers. Thus, although muscle can synthesize tethered, dimeric LpL, efficient production of this enzyme leading to secretion, and physiological function appears to favor secretion of a noncovalent dimer composed of monomeric subunits.
M3 - SCORING: Zeitschriftenaufsatz
VL - 279
SP - 238
EP - 244
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 1
M1 - 1
ER -
