Feedback inhibition of cholesterol biosynthesis by dietary cholesterol in experimental chronic renal failure.
OBJECTIVE
Enhanced liver cholesterol synthesis is present in experimental chronic renal failure (CRF), even though cholesterol concentrations in blood and liver are increased, suggesting that CRF results in disturbed cholesterolegenesis feedback regulation.


METHODS
This study sought to elucidate whether dietary cholesterol exerts inhibitory effects on liver cholesterologenesis in CRF rats.


METHODS
Male Wistar rats were used. Experimental CRF was achieved by a 5/6 nephrectomy model. Cholesterologenesis was measured (1) in vivo by tritiated water incorporation into cholesterol, and (2) in vitro (using liver slices) by [(14)C]-acetate and [(3)H]-mevalonate incorporation into cholesterol. In addition, the mRNA abundance of 3-hydroxy-3-methylglutaryl-CoA reductase, a rate-limiting enzyme in cholesterologenesis pathway, as well as its activity, was determined. Finally, the mRNA level of liver sterol regulatory element-binding protein-2, a nuclear transcription factor engaged in intracellular cholesterol homeostasis, was measured.


RESULTS
Experimental CRF was associated with significantly increased concentrations of serum and liver cholesterol. In vitro and in vivo cholesterologenesis was enhanced in CRF rats. A cholesterol-enriched diet resulted in a significant decrease in (1) in vivo and in vitro cholesterol synthesis, (2) 3-hydroxy-3-methylglutaryl-CoA reductase gene expression, and (3) the level of liver sterol regulatory element-binding protein-2 mRNA in CRF rats.


CONCLUSIONS
Despite elevated plasma and liver cholesterol concentrations, cholesterologenesis is increased in CRF rats. It is, however, inhibited by dietary cholesterol. These results suggest that a feedback inhibition of cholesterologenesis by dietary cholesterol is preserved in experimental CRF.
Chmielewski
Michal
M
Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdansk, Gdansk, Poland. chmiel@amg.gda.pl
Sucajtys-Szulc
Elzbieta
E
Kossowska
Ewa
E
Swierczynski
Julian
J
Rutkowski
Boleslaw
B
Boguslawski
Wojciech
W
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D004195:Disease Models, Animal; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism
D002791:Cholesterol, Dietary; D012333:RNA, Messenger; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases