title: Perfluoroalkyl sulfonates cause alkyl chain length-dependent hepatic steatosis and hypolipidemia mainly by impairing lipoprotein production in APOE*3-Leiden CETP mice.
abstract: Perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) are stable perfluoroalkyl sulfonate (PFAS) surfactants, and PFHxS and PFOS are frequently detected in human biomonitoring studies. Some epidemiological studies have shown modest positive correlations of serum PFOS with non-high-density lipoprotein (HDL)-cholesterol (C). This study investigated the mechanism underlying the effect of PFAS surfactants on lipoprotein metabolism. APOE*3-Leiden.CETP mice were fed a Western-type diet with PFBS, PFHxS, or PFOS (30, 6, and 3 mg/kg/day, respectively) for 4-6 weeks. Whereas PFBS modestly reduced only plasma triglycerides (TG), PFHxS and PFOS markedly reduced TG, non-HDL-C, and HDL-C. The decrease in very low-density lipoprotein (VLDL) was caused by enhanced lipoprotein lipase-mediated VLDL-TG clearance and by decreased production of VLDL-TG and VLDL-apolipoprotein B. Reduced HDL production, related to decreased apolipoprotein AI synthesis, resulted in decreased HDL. PFHxS and PFOS increased liver weight and hepatic TG content. Hepatic gene expression profiling data indicated that these effects were the combined result of peroxisome proliferator-activated receptor alpha and pregnane X receptor activation. In conclusion, the potency of PFAS to affect lipoprotein metabolism increased with increasing alkyl chain length. PFHxS and PFOS reduce plasma TG and total cholesterol mainly by impairing lipoprotein production, implying that the reported positive correlations of serum PFOS and non-HDL-C are associative rather than causal.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bijland
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.forename: Elsbet J
authors.initials: EJ
authors.lastname: Pieterman
authors.forename: Annemarie C E
authors.initials: AC
authors.lastname: Maas
authors.forename: José W
authors.initials: JW
authors.lastname: van der Hoorn
authors.forename: Marjan J
authors.initials: MJ
authors.lastname: van Erk
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Ko
authors.initials: K
authors.lastname: Willems van Dijk
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Chang
authors.forename: David J
authors.initials: DJ
authors.lastname: Ehresman
authors.forename: John L
authors.initials: JL
authors.lastname: Butenhoff
authors.forename: Hans M G
authors.initials: HM
authors.lastname: Princen
mesh_terms: D017738:Alkanesulfonic Acids / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics*; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism; D005466:Fluorocarbons / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D021281:Quantitative Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry / Q000633:toxicity; D013501:Surface-Active Agents / Q000737:chemistry / Q000633:toxicity*
chemical_list: D017738:Alkanesulfonic Acids; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D005466:Fluorocarbons; D013451:Sulfonic Acids; D013501:Surface-Active Agents; C471071:perfluorohexanesulfonic acid; C076994:perfluorooctane sulfonic acid; C108042:perfluorobutane