title: LDL receptor gene transcription is selectively induced by t10c12-CLA but not by c9t11-CLA in the human hepatoma cell line HepG2.
abstract: Conjugated linoleic acids (CLA) have attracted scientific interest due to their potential beneficial effects on atherosclerosis. Recently, a mixture of CLA isomers was demonstrated to upregulate LDL receptor expression in the human hepatoma cell line HepG2. However, the underlying mechanisms remain to be resolved. Thus, the aim of this study was to elucidate how CLA mediates upregulation of LDL receptor in HepG2 cells and whether this upregulation is isomer-specific. The results revealed that LDL receptor promoter activity and mRNA expression were strongly induced upon treatment with t10c12-CLA (P<0.05), whereas c9t11-CLA and linoleic acid (LA) had no effect. In addition, only treatment with t10c12-CLA markedly induced mRNA expression of SREBP-2 and HMG-CoA reductase and slightly induced that of SREBP-1 (P<0.05). Using SREBP-2 knockdown cells, we could demonstrate that the effect of t10c12-CLA on LDL receptor gene transcription was significantly reduced when compared to control cells (P<0.05). When using SREBP-1 knockdown cells the effect of t10c12-CLA on LDL receptor mRNA only slightly decreased compared to control cells. In addition, using different deletion constructs of the LDL receptor gene promoter we showed that the induction of the LDL receptor by t10c12-CLA is independent of the AP-1 motif in the LDL receptor promoter. In conclusion, the present study revealed that transcriptional activation of the LDL receptor gene by t10c12-CLA is dependent on the upregulation of SREBP-2 and is probably due to the activation of the SRE-1 in the LDL receptor gene promoter in HepG2 cells. Thus, the decreased plasma cholesterol levels in response to CLA as observed in a limited number of animal and human studies might be explained by an enhanced uptake of VLDL and LDL cholesterol via hepatic LDL receptors. However, it provides no explanation for the outcome of most human studies reporting unaltered or even increased plasma and LDL cholesterol concentrations in response to supplementation with CLA.
authors.affiliation: Institut für Ernährungswissenschaften, Martin-Luther-Universität Halle-Wittenberg, Emil-Abderhalden-Str. 26, D-06108 Halle (Saale), Germany. robert.ringseis@landw.uni-halle.de
authors.forename: Robert
authors.initials: R
authors.lastname: Ringseis
authors.forename: Bettina
authors.initials: B
authors.lastname: König
authors.forename: Beatrice
authors.initials: B
authors.lastname: Leuner
authors.forename: Sandra
authors.initials: S
authors.lastname: Schubert
authors.forename: Norbert
authors.initials: N
authors.lastname: Nass
authors.forename: Gabriele
authors.initials: G
authors.lastname: Stangl
authors.forename: Klaus
authors.initials: K
authors.lastname: Eder
mesh_terms: D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D019787:Linoleic Acid / Q000494:pharmacology; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D044243:Linoleic Acids, Conjugated; D012333:RNA, Messenger; D011973:Receptors, LDL; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D018808:Transcription Factor AP-1; C503589:cis-9, trans-11-conjugated linoleic acid; C496197:trans-10,cis-12-conjugated linoleic acid; D002784:Cholesterol; D019787:Linoleic Acid; D006903:Hydroxymethylglutaryl CoA Reductases