title: Cholesterol efflux from THP-1 macrophages is impaired by the fatty acid component from lipoprotein hydrolysis by lipoprotein lipase.
abstract: Lipoprotein lipase (LPL) is an extracellular lipase that primarily hydrolyzes triglycerides within circulating lipoproteins. Macrophage LPL contributes to atherogenesis, but the mechanisms behind it are poorly understood. We hypothesized that the products of lipoprotein hydrolysis generated by LPL promote atherogenesis by inhibiting the cholesterol efflux ability by macrophages. To test this hypothesis, we treated human THP-1 macrophages with total lipoproteins that were hydrolyzed by LPL and we found significantly reduced transcript levels for the cholesterol transporters ATP binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor BI. These decreases were likely due to significant reductions for the nuclear receptors liver-X-receptor-α, peroxisome proliferator activated receptor (PPAR)-α, and PPAR-γ. We prepared a mixture of free fatty acids (FFA) that represented the ratios of FFA species within lipoprotein hydrolysis products, and we found that the FFA mixture also significantly reduced cholesterol transporters and nuclear receptors. Finally, we tested the efflux of cholesterol from THP-1 macrophages to apolipoprotein A-I, and we found that the treatment of THP-1 macrophages with the FFA mixture significantly attenuated cholesterol efflux. Overall, these data show that the FFA component of lipoprotein hydrolysis products generated by LPL may promote atherogenesis by inhibiting cholesterol efflux, which partially explains the pro-atherogenic role of macrophage LPL.
authors.affiliation: Department of Biochemistry, Memorial University of Newfoundland, St. John's, NL, A1B 3X9, Canada.
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, Memorial University of Newfoundland, St. John's, NL, A1B 3X9, Canada.
authors.forename: Narmadaa
authors.initials: N
authors.lastname: Thyagarajan
authors.affiliation: Department of Biochemistry, Memorial University of Newfoundland, St. John's, NL, A1B 3X9, Canada.
authors.forename: Breanne M
authors.initials: BM
authors.lastname: Coady
authors.affiliation: Department of Biochemistry, Memorial University of Newfoundland, St. John's, NL, A1B 3X9, Canada. Electronic address: rbrown@mun.ca.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Brown
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology; D002784:Cholesterol / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008074:Lipoproteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051122:Scavenger Receptors, Class B / Q000378:metabolism
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D005230:Fatty Acids, Nonesterified; D008074:Lipoproteins; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D002784:Cholesterol; D008071:Lipoprotein Lipase
keywords: Atherosclerosis; Cholesterol efflux; Fatty acid; Lipoprotein; Lipoprotein lipase; Macrophage