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J Biol Chem. 1999 Feb 12;274(7):4140-6.

Increased high density lipoprotein (HDL), defective hepatic catabolism of ApoA-I and ApoA-II, and decreased ApoA-I mRNA in ob/ob mice. Possible role of leptin in stimulation of HDL turnover.

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Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.


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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