PPAR gamma ligand troglitazone lowers cholesterol synthesis in HepG2 and Caco-2 cells via a reduced concentration of nuclear SREBP-2.
Cholesterol synthesis in animal cells is regulated by sterol regulatory element-binding protein (SREBP)-2. The objective of this study was to investigate whether activation of peroxisome proliferator-activatedreceptor (PPAR)-gamma influences the SREBP-2 dependent cholesterol synthesis in liver and intestinal cells. Therefore, HepG2 and Caco-2 cells were incubated with and without 10 or 30 microM of troglitazone, a synthetic PPAR gamma agonist, for 4 hrs. Incubation with 10 or 30 microM of troglitazone caused a significant, dose-dependent reduction of cholesterol synthesis in both HepG2 and Caco-2 cells (P < 0.05). HepG2 and Caco-2 cells incubated with 10 or 30 microM of troglitazone had also lower mRNA concentrations and lower nuclear protein concentrations of SREBP-2 than untreated control cells (P < 0.05). mRNA concentrations of the SREBP-2 target genes HMG-CoA reductase and LDL receptor were also reduced in HepG2 and Caco-2 cells treated with 30 microM of troglitazone compared to control cells (P < 0.05). In conclusion, this study shows that PPAR gamma activation by troglitazone lowers the cholesterol synthesis in HepG2 and Caco-2 cells by reducing the concentration of nuclear SREBP-2 and successive downregulation of its target genes involved in cholesterol synthesis.
Klopotek
Anett
A
Institute of Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, D-06108 Halle/Saale, Germany.
Hirche
Frank
F
Eder
Klaus
K
D015153:Blotting, Western; D018938:Caco-2 Cells; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis*; D002839:Chromans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects / Q000235:genetics; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D011973:Receptors, LDL / Q000187:drug effects / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000187:drug effects* / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
D002839:Chromans; D047495:PPAR gamma; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; D011973:Receptors, LDL; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D045162:Thiazolidinediones; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D000077288:Troglitazone