Defective HDL particle uptake in ob/ob hepatocytes causes decreased recycling, degradation, and selective lipid uptake

被引:96
作者
Silver, DL [1 ]
Wang, N [1 ]
Tall, AR [1 ]
机构
[1] Columbia Univ, Dept Med, Div Mol Med, New York, NY 10032 USA
关键词
D O I
10.1172/JCI8087
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Levels of plasma HDL are determined in part by catabolism in the liver. However, it is unclear how the hepatic catabolism of holo-HDL is regulated or mediated. Recently, we found that ob/ob mice have defective liver catabolism of HDL apoproteins in vivo that can be reversed by low-dose leptin treatment. Here we examined HDL catabolism and trafficking at the cellular level using isolated hepatocytes. We demonstrate that ob/ob hepatocytes have reduced binding, association, degradation, and resecretion of HDL apoproteins and 50% less selective lipid uptake relative to wild-type hepatocytes. In addition, HDL apoproteins were found to colocalize with transferrin in the general endosomal recycling compartment (ERC) in wild-type hepatocytes. However, the localization to the ERC was markedly reduced in ob/ob hepatocytes. Filipin staining of cellular cholesterol revealed decreased cholesterol in the ERC in ob/ob hepatocytes. Defects in HDL cell association and cholesterol distribution were reversed by leptin administration. The findings show a major defect in HDL uptake and recycling in ob/ob hepatocytes and suggest that HDL recycling through the ERC plays a role in the determination of plasma HDL protein and cholesterol levels.
引用
收藏
页码:151 / 159
页数:9
相关论文
共 28 条
[1]   HUMAN HDL CHOLESTEROL LEVELS ARE DETERMINED BY APOA-I FRACTIONAL CATABOLIC RATE, WHICH CORRELATES INVERSELY WITH ESTIMATES OF HDL PARTICLE-SIZE [J].
BRINTON, EA ;
EISENBERG, S ;
BRESLOW, JL .
ARTERIOSCLEROSIS AND THROMBOSIS, 1994, 14 (05) :707-720
[2]   Hepatic lipase: new insights from genetic and metabolic studies [J].
Cohen, JC ;
Vega, GL ;
Grundy, SM .
CURRENT OPINION IN LIPIDOLOGY, 1999, 10 (03) :259-267
[3]  
DELAMATRE JG, 1990, J LIPID RES, V31, P191
[4]   Degradation of macrophage ApoE in a nonlysosomal compartment - Regulation by sterols [J].
Duan, HW ;
Lin, CY ;
Mazzone, T .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (49) :31156-31162
[5]  
FEINGOLD KR, 1984, DIABETOLOGIA, V26, P234
[6]   TURNOVER OF APOPROTEINS A-I AND A-II OF HIGH-DENSITY LIPOPROTEIN AND THE RELATIONSHIP TO OTHER LIPOPROTEINS IN NORMAL AND HYPERLIPIDEMIC INDIVIDUALS [J].
FIDGE, N ;
NESTEL, P ;
ISHIKAWA, T ;
REARDON, M ;
BILLINGTON, T .
METABOLISM-CLINICAL AND EXPERIMENTAL, 1980, 29 (07) :643-653
[7]  
Fidge NH, 1999, J LIPID RES, V40, P187
[8]  
GLASS CK, 1983, J BIOL CHEM, V258, P7161
[9]   LIPOPROTEIN RECEPTORS AND THE CONTROL OF PLASMA LDL CHOLESTEROL LEVELS [J].
GOLDSTEIN, JL ;
BROWN, MS .
EUROPEAN HEART JOURNAL, 1992, 13 :34-36
[10]   Cubilin, the endocytic receptor for intrinsic factor-vitamin B12 complex, mediates high-density lipoprotein holoparticle endocytosis [J].
Hammad, SM ;
Stefansson, S ;
Twal, WO ;
Drake, CJ ;
Fleming, P ;
Remaley, A ;
Brewer, HB ;
Argraves, WS .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (18) :10158-10163