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

J Clin Invest. 2000 Jan;105(2):151-9. doi: 10.1172/JCI8087.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biological Transport / drug effects
  • Cells, Cultured
  • Cholesterol / metabolism
  • Cholesterol Esters / metabolism
  • Down-Regulation
  • Female
  • Fluorescent Dyes
  • Humans
  • Intracellular Fluid / metabolism
  • Leptin / pharmacology
  • Lipid Metabolism
  • Lipids / pharmacokinetics
  • Lipoproteins, HDL / metabolism*
  • Lipoproteins, HDL / pharmacokinetics
  • Liver / cytology
  • Liver / drug effects
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Obesity / metabolism*
  • Receptors, Cell Surface / metabolism
  • Transferrin / metabolism


  • Cholesterol Esters
  • Fluorescent Dyes
  • Leptin
  • Lipids
  • Lipoproteins, HDL
  • Receptors, Cell Surface
  • Transferrin
  • Cholesterol