title: Defective HDL particle uptake in ob/ob hepatocytes causes decreased recycling, degradation, and selective lipid uptake.
abstract: 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.
authors.affiliation: The Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA. dls51@columbia.edu
authors.forename: D L
authors.initials: DL
authors.lastname: Silver
authors.forename: N
authors.initials: N
authors.lastname: Wang
authors.forename: A R
authors.initials: AR
authors.lastname: Tall
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005456:Fluorescent Dyes; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology; D050356:Lipid Metabolism; D008055:Lipids / Q000493:pharmacokinetics; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000493:pharmacokinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism
chemical_list: D002788:Cholesterol Esters; D005456:Fluorescent Dyes; D020738:Leptin; D008055:Lipids; D008075:Lipoproteins, HDL; D011956:Receptors, Cell Surface; D014168:Transferrin; D002784:Cholesterol