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J Biol Chem, Vol. 274, Issue 7, 4140-4146, February 12, 1999
From the Division of Molecular Medicine, Department of Medicine,
Columbia University, New York, New York 10032
Abnormalities of plasma high density lipoprotein
(HDL) levels commonly reflect altered metabolism of the major HDL
apolipoproteins, apoA-I and apoA-II, but the regulation of
apolipoprotein metabolism is poorly understood. Two mouse models of
obesity, ob/ob and db/db, have markedly
increased plasma HDL cholesterol levels. The purpose of this study was
to evaluate mechanisms responsible for increased HDL in
ob/ob mice and to assess potential reversibility by leptin administration. ob/ob mice were found to have increased HDL
cholesterol (2-fold), apoA-I (1.3-fold), and apoA-II (4-fold). ApoA-I
mRNA was markedly decreased (to 25% of wild-type) and apoA-II
mRNA was unchanged, suggesting a defect in HDL catabolism. HDL
apoprotein turnover studies using nondegradable radiolabels confirmed a
decrease in catabolism of apoA-I and apoA-II and a 4-fold decrease in
hepatic uptake in ob/ob mice compared with wild-type, but
similar renal uptake. Low dose leptin treatment markedly lowered HDL
cholesterol and apoA-II levels in both ob/ob mice and in
lean wild-type mice, and it restored apoA-I mRNA to normal levels
in ob/ob mice. These changes occurred without significant
alteration in body weight. Moreover, ob/ob neuropeptide
Y
/ mice, despite marked attenuation of diabetes and
obesity phenotypes, showed no change in HDL cholesterol levels relative
to ob/ob mice. Thus, increased HDL levels in
ob/ob mice reflect a marked hepatic catabolic defect for
apoA-I and apoA-II. In the case of apoA-I, this is offset by decreased
apoA-I mRNA, resulting in apoA-II-rich HDL particles. The studies
reveal a specific HDL particle catabolic pathway that is down-regulated
in ob/ob mice and suggest that HDL apolipoprotein turnover
may be regulated by obesity and/or leptin signaling.
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