title: Bile acids reduce endocytosis of high-density lipoprotein (HDL) in HepG2 cells.
abstract: High-density lipoprotein (HDL) transports lipids to hepatic cells and the majority of HDL-associated cholesterol is destined for biliary excretion. Cholesterol is excreted into the bile directly or after conversion to bile acids, which are also present in the plasma as they are effectively reabsorbed through the enterohepatic cycle. Here, we provide evidence that bile acids affect HDL endocytosis. Using fluorescent and radiolabeled HDL, we show that HDL endocytosis was reduced in the presence of high concentrations of taurocholate, a natural non-cell-permeable bile acid, in human hepatic HepG2 and HuH7 cells. In contrast, selective cholesteryl-ester (CE) uptake was increased. Taurocholate exerted these effects extracellularly and independently of HDL modification, cell membrane perturbation or blocking of endocytic trafficking. Instead, this reduction of endocytosis and increase in selective uptake was dependent on SR-BI. In addition, cell-permeable bile acids reduced HDL endocytosis by farnesoid X receptor (FXR) activation: chenodeoxycholate and the non-steroidal FXR agonist GW4064 reduced HDL endocytosis, whereas selective CE uptake was unaltered. Reduced HDL endocytosis by FXR activation was independent of SR-BI and was likely mediated by impaired expression of the scavenger receptor cluster of differentiation 36 (CD36). Taken together we have shown that bile acids reduce HDL endocytosis by transcriptional and non-transcriptional mechanisms. Further, we suggest that HDL endocytosis and selective lipid uptake are not necessarily tightly linked to each other.
authors.affiliation: Department of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Clemens
authors.initials: C
authors.lastname: Röhrl
authors.affiliation: Department of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Eigner
authors.affiliation: Department of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Fruhwürth
authors.affiliation: Department of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Herbert
authors.initials: H
authors.lastname: Stangl
mesh_terms: D001647:Bile Acids and Salts / Q000494:pharmacology*; D018955:CD36 Antigens / Q000378:metabolism; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008075:Lipoproteins, HDL / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D013656:Taurocholic Acid / Q000494:pharmacology; D014168:Transferrin / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D018955:CD36 Antigens; D002635:Chenodeoxycholic Acid; D007555:Isoxazoles; D008075:Lipoproteins, HDL; D018160:Receptors, Cytoplasmic and Nuclear; D051122:Scavenger Receptors, Class B; D013656:Taurocholic Acid; D014168:Transferrin; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064