Activation of PPARalpha lowers synthesis and concentration of cholesterol by reduction of nuclear SREBP-2.
To elucidate the mechanisms underlying the cholesterol lowering effects of PPARalpha agonists we investigated key regulators of cholesterol synthesis and uptake in rats and in the rat hepatoma cell line Fao after treatment with the PPARalpha agonists clofibrate and WY 14,643, respectively. In rat liver as well as in Fao cells, PPARalpha activation led to a decrease of transcriptionally active nuclear SREBP-2. mRNA concentrations of the key regulators of SREBP processing, Insig-1 in rat liver and Insig-1 and Insig-2a in Fao cells, were increased upon PPARalpha activation. Thus we suggest, that the observed reduction of the amount of nuclear SREBP-2 was due to an inhibition of the processing of the precursor protein. Both, in rat liver and in Fao cells, mRNA concentrations of the SREBP-2 target genes HMG-CoA reductase (EC1.1.1.34) and LDL receptor were reduced after treatment with the PPARalpha agonists. Furthermore, treatment of Fao cells with WY 14,643 reduced cholesterol synthesis. As a result, the amount of total cholesterol in liver, plasma and lipoproteins of clofibrate treated rats and in WY 14,643 treated Fao cells was decreased compared to control animals and cells, respectively. In conclusion, we could show a novel link between PPARalpha and cholesterol metabolism by demonstrating that PPARalpha activation lowers cholesterol concentration by reducing the abundance of nuclear SREBP-2.
König
Bettina
B
Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, D-06108 Halle (Saale), Germany. bettina.koenig@landw.uni-halle.de
Koch
Alexander
A
Spielmann
Julia
J
Hilgenfeld
Christian
C
Stangl
Gabriele I
GI
Eder
Klaus
K
D042962:Acyl-CoA Oxidase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism*; D015243:Cholesterol, VLDL / Q000378:metabolism; D002994:Clofibrate / Q000008:administration & dosage / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
D000924:Anticholesteremic Agents; D015243:Cholesterol, VLDL; C465387:Cyp4a1protein, rat; C491574:Insig1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D047493:PPAR alpha; D011743:Pyrimidines; D012333:RNA, Messenger; D011973:Receptors, LDL; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014280:Triglycerides; C006253:pirinixic acid; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D000072470:Cytochrome P450 Family 4; D042962:Acyl-CoA Oxidase; D002994:Clofibrate