Reduced very-low-density lipoprotein fractional catabolic rate in apolipoprotein C1-deficient mice

被引:25
作者
Jong, MC
vanRee, JH
Dahlmans, VEH
Frants, RR
Hofker, MH
Havekes, LM
机构
[1] GAUBIUS LAB,TNO PREVENT & HLTH,NL-2301 CE LEIDEN,NETHERLANDS
[2] LEIDEN UNIV,DEPT HUMAN GENET,MGC,NL-2300 RA LEIDEN,NETHERLANDS
[3] UNIV LEIDEN HOSP,DEPT CARDIOL,NL-2300 RC LEIDEN,NETHERLANDS
[4] UNIV LEIDEN HOSP,DEPT INTERNAL MED,NL-2300 RC LEIDEN,NETHERLANDS
关键词
D O I
10.1042/bj3210445
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The function of apolipoprotein (apo) C1 in vivo is not clearly defined. Because transgenic mice overexpressing human apoC1 show elevated triacylglycerol (TG) levels [Simonet, Bucay, Pitas, Lauer and Taylor (1991) J. Biol. Chem. 266, 8651-8654], an as yet unknown role for apoC1 in TG metabolism has been suggested. Here we investigated directly the effect of the complete absence of apoC1 on very-low-density lipoprotein (VLDL)-TG lipolysis, clearance and production, by performing studies with the previously generated apoC1-deficient mice. On a sucrose-rich, low fat/low cholesterol (LFC) diet, apoC1-deficient mice accumulate in their circulation VLDL particles, which contain relatively lower amounts of lipids when compared with VLDL isolated from control mice. Lipolysis assays in vitro on VLDL from apoCl-deficient and control mice showed no differences in apparent K-m and V-max values (0.27 +/- 0.06 versus 0.24 +/- 0.03 mmol of TG/litre and 0.40+/-0.03 versus 0.36+/-0.03 mmol of nonesterified fatty acid (NEFA)/min per litre respectively). To correct for potential differences in the size of the VLDL particles, the resulting K-m values were also expressed relative to apoB concentration. Under these conditions apoC1-deficient VLDL displayed a lower, but not significant, K-m value when compared with control VLDL (3.44 +/- 0.71 versus 4.44 +/- 0.52 mmol of TG(2)/g apoB per litre). VLDL turnover studies with autologous injections of [H-3]TG-VLDL in vivo showed that the VLDL fractional catabolic rate (FCR) was decreased by up to 50 % in the apoC1-deficient mice when compared with control mice (10.5 +/- 3.4 versus 21.0 +/- 1.2/h of pool TG). No significant differences between apoC1-deficient and control mice were observed in the hepatic VLDL production estimated by Triton WR139 injections (0.19 +/- 0.02 versus 0.21 +/- 0.05 mmol/h of TG per kg) and in the extra-hepatic lipolysis of VLDL-TG (4.99 +/- 1.62 versus 3.46 +/- 1.52/h of pool TG) in vivo. Furthermore, [I-125]VLDL-apoB turnover experiments in viva also showed a 50 %, decrease in the FCR of VLDL in apoC1-deficient mice when compared with control mice on the LFC diet (1.1 +/- 0.3 versus 2.1 +/- 0.1/h of pool apoB). When mice were fed a very high fat/high cholesterol (HFC) diet, the VLDL-apoB FCR was further decreased in apoC1-deficient mice (0.4 +/- 0.1 versus 1.4 +/- 0.4/h of pool apoB). We conclude that, in apoC1-deficient mice, the FCR of VLDL is reduced because of impaired uptake of VLDL remnants by hepatic receptors, whereas the production and lipolysis of VLDL-TG is not affected.
引用
收藏
页码:445 / 450
页数:6
相关论文
共 25 条
[1]   MECHANISM OF HYPERTRIGLYCERIDEMIA IN HUMAN APOLIPOPROTEIN-(APO)-CIII TRANSGENIC MICE - DIMINISHED VERY LOW-DENSITY-LIPOPROTEIN FRACTIONAL CATABOLIC RATE ASSOCIATED WITH INCREASED APO-CIII AND REDUCED APO-E ON THE PARTICLES [J].
AALTOSETALA, K ;
FISHER, EA ;
CHEN, XL ;
CHAJEKSHAUL, T ;
HAYEK, T ;
ZECHNER, R ;
WALSH, A ;
RAMAKRISHNAN, R ;
GINSBERG, HN ;
BRESLOW, JL .
JOURNAL OF CLINICAL INVESTIGATION, 1992, 90 (05) :1889-1900
[2]   METABOLISM OF VERY LOW-DENSITY LIPOPROTEIN PROTEINS .1. PRELIMINARY IN-VITRO AND IN-VIVO OBSERVATIONS [J].
BILHEIMER, DW ;
LEVY, RI ;
EISENBERG, S .
BIOCHIMICA ET BIOPHYSICA ACTA, 1972, 260 (02) :212-+
[3]  
BLIGH EG, 1959, CAN J BIOCHEM PHYS, V37, P911
[4]  
CONNELLY PW, 1994, J BIOL CHEM, V269, P20554
[5]  
DESILVA HV, 1994, J BIOL CHEM, V269, P2324
[6]   COFACTOR ACTIVITY OF PROTEIN COMPONENTS OF HUMAN VERY LOW-DENSITY LIPOPROTEINS IN HYDROLYSIS OF TRIGLYCERIDES BY LIPOPROTEIN-LIPASE FROM DIFFERENT SOURCES [J].
HAVEL, RJ ;
FIELDING, CJ ;
OLIVECRO.T ;
SHORE, VG ;
FIELDING, PE ;
EGELRUD, T .
BIOCHEMISTRY, 1973, 12 (09) :1828-1833
[7]   COMPARISON BETWEEN USE OF ISOPROPANOL AND TETRAMETHYLUREA FOR SOLUBILIZATION AND QUANTITATION OF HUMAN-SERUM VERY LOW-DENSITY APOLIPOPROTEINS [J].
HOLMQUIST, L ;
CARLSON, K ;
CARLSON, LA .
ANALYTICAL BIOCHEMISTRY, 1978, 88 (02) :457-460
[8]   Both lipolysis and hepatic uptake of VLDL are impaired in transgenic mice coexpressing human apolipoprotein E*3Leiden and human apolipoprotein C1 [J].
Jong, MC ;
Dahlmans, VEH ;
vanGorp, PJJ ;
Breuer, ML ;
Mol, MJTM ;
vanderZee, A ;
Frants, RR ;
Hofker, MH ;
Havekes, LM .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1996, 16 (08) :934-940
[9]   DELAYED CLEARANCE OF VERY LOW-DENSITY AND INTERMEDIATE DENSITY LIPOPROTEINS WITH ENHANCED CONVERSION TO LOW-DENSITY LIPOPROTEIN IN WHHL RABBITS [J].
KITA, T ;
BROWN, MS ;
BILHEIMER, DW ;
GOLDSTEIN, JL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1982, 79 (18) :5693-5697
[10]  
LAUER SJ, 1988, J BIOL CHEM, V263, P7277