Correlation among oxysterol potencies in the regulation of the degradation of 3-hydroxy-3-methylglutaryl CoA reductase, the repression of 3-hydroxy-3-methylglutaryl CoA synthase and affinities for the oxysterol receptor.
25-Hydroxycholesterol regulates cholesterol biosynthesis by two mechanisms: repression of the transcription of the genes for several cholesterogenic enzymes and acceleration of the degradation of the enzyme 3-hydroxy-3-methylglutaryl CoA reductase. In the present work the structural features which govern oxysterol potency were determined separately for each regulatory mechanism. Regulation of degradation was tested using a 3-hydroxy-3-methylglutaryl CoA reductase-beta-galactosidase fusion protein. Repression of enzyme synthesis was tested by measuring 3-hydroxy-3-methylglutaryl CoA synthase activity since this protein is not regulated by a degradative mechanism. Oxysterol activities were highly correlated between the two assays (R = .959) demonstrating that the degradative and repressor mechanisms share an element which determines oxysterol regulatory potency. Correlation of these results with previous data for the affinity of these oxysterols for the oxysterol receptor suggests that the receptor is the element involved in both these regulatory pathways.
Taylor
F R
FR
Jackson Laboratory, Bar Harbor, ME 04609.
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003600:Cytosol / Q000201:enzymology; D004794:Enzyme Repression; D006888:Hydroxycholesterols / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000096:biosynthesis / Q000378:metabolism*; D007700:Kinetics; D007739:L Cells / Q000201:enzymology; D051379:Mice; D011987:Receptors, Steroid / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D013261:Sterols / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014162:Transfection; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism; D000098825:Oxysterol Binding Proteins
D006888:Hydroxycholesterols; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D013261:Sterols; D000098825:Oxysterol Binding Proteins; C007997:25-hydroxycholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D006904:Hydroxymethylglutaryl-CoA Synthase; D001616:beta-Galactosidase