The peroxisome-proliferator-activated receptor α agonist ciprofibrate severely aggravates hypercholesterolaemia and accelerates the development of atherosclerosis in mice lacking apolipoprotein E

被引:33
作者
Fu, T [1 ]
Kashireddy, P [1 ]
Borensztajn, J [1 ]
机构
[1] Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA
关键词
cholesterol; fibrate; lipoprotein remnant; scavenger receptor BI; triacylglycerol;
D O I
10.1042/BJ20030105
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
Mice lacking apolipoprotein E (apoE) are characterized by severe hypercholesterolaemia, caused by an abnormal accumulation of apolipoprotein B-48 (apoB-48)-carrying remnants of chylomicrons and very-low-density lipoproteins (VLDL) in the plasma, and by the spontaneous development of atherosclerotic lesions. Ciprofibrate is a hypolipidaemic compound that acts primarily by enhancing the oxidation of fatty acids in the liver and, consequently, decreasing the production of hepatic VLDL. In the present study, homozygous apoE-deficient mice were fed with a normal chow diet, supplemented with ciprofibrate. We report that, as anticipated, ciprofibrate treatment (a) stimulated hepatic fatty acid oxidation, as indicated by an increase in the mRNA levels of peroxisomal fatty acyl-CoA oxidase (AOX) and peroxisomal bifunctional enzyme, and (b) decreased the hepatic secretion of VLDL into the plasma, as determined by treating the animals with Triton WR-1339. Paradoxically, the apoE-deficient mice developed a 3-4-fold increase in their plasma cholesterol levels. A similar effect was observed in apoE-deficient mice treated with other peroxisome-proliferator-activated receptor alpha agonists (fenofibrate, bezatibrate and WY14,643). By FPLC of the plasma and Western-blot analysis, we determined that the enhanced hypercholesterolaemia was due to an increased accumulation of apoB-48-carrying lipoprotein remnants in the plasma. Consistent with this finding, atherosclerotic lesions in animals treated with ciprofibrate for 90 days were considerably more advanced than in untreated animals. These results indicate that the ciprofibrate-induced accumulation of apoB-48-carrying remnants in apoE-deficient mice is caused by the inhibition of an as yet uncharacterized apoE-independent mechanism of removal of remnant from the circulation by the liver.
引用
收藏
页码:941 / 947
页数:7
相关论文
共 25 条
  • [1] Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis
    Barbier, O
    Torra, IP
    Duguay, Y
    Blanquart, C
    Fruchart, JC
    Glineur, C
    Staels, B
    [J]. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2002, 22 (05) : 717 - 726
  • [2] Lamellar lipoproteins uniquely contribute to hyperlipidemia in mice doubly deficient in apolipoprotein E and hepatic lipase
    Bergeron, N
    Kotite, L
    Verges, M
    Blanche, P
    Hamilton, RL
    Krauss, RM
    Bensadoun, A
    Havel, RJ
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (26) : 15647 - 15652
  • [3] INHIBITION INVIVO OF LIPOPROTEIN-LIPASE (CLEARING-FACTOR LIPASE) ACTIVITY BY TRITON WR-1339
    BORENSZTAJN, J
    RONE, MS
    KOTLAR, TJ
    [J]. BIOCHEMICAL JOURNAL, 1976, 156 (03) : 539 - 543
  • [4] Induction of the phospholipid transfer protein gene accounts for the high density lipoprotein enlargement in mice treated with fenofibrate
    Bouly, M
    Masson, D
    Gross, B
    Jiang, XC
    Fievet, C
    Castro, G
    Tall, AR
    Fruchart, JC
    Staels, B
    Lagrost, L
    Luc, G
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (28) : 25841 - 25847
  • [5] The role of lipoprotein lipase and apoprotein E in the recognition of chylomicrons and chylomicron remnants by cultured isolated mouse hepatocytes
    Chang, SY
    Maeda, N
    Borensztajn, J
    [J]. BIOCHEMICAL JOURNAL, 1996, 318 : 29 - 34
  • [6] Identification of novel peroxisome proliferator-activated receptor α (PRARα) target genes in mouse liver using cDNA microarray analysis
    Cherkaoui-Malki, M
    Meyer, CM
    Cao, WQ
    Latruffe, N
    Yeldandi, AV
    Rao, MS
    Bradfield, CA
    Reddy, JK
    [J]. GENE EXPRESSION-THE JOURNAL OF LIVER RESEARCH, 2001, 9 (06): : 291 - 304
  • [7] Cooper AD, 1997, J LIPID RES, V38, P2173
  • [8] Crawford SE, 1999, J LIPID RES, V40, P797
  • [9] Reduction of atherosclerosis by the peroxisome proliferator-activated receptor α agonist fenofibrate in mice
    Duez, H
    Chao, YS
    Hernandez, M
    Torpier, G
    Poulain, P
    Mundt, S
    Mallat, Z
    Teissier, E
    Burton, CA
    Tedgui, A
    Fruchart, JC
    Fiévet, C
    Wright, SD
    Staels, B
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (50) : 48051 - 48057
  • [10] COMPARISON OF THE PEROXISOME PROLIFERATOR-INDUCED PLEIOTROPIC RESPONSE IN THE LIVER OF 9 STRAINS OF MICE
    DWIVEDI, RS
    ALVARES, K
    NEMALI, MR
    SUBBARAO, V
    REDDY, MK
    USMAN, MI
    RADEMAKER, AW
    REDDY, JK
    RAO, MS
    [J]. TOXICOLOGIC PATHOLOGY, 1989, 17 (01) : 16 - 26