Increased gene expression of liver SREBP-2 in experimental chronic renal failure.
Sterol regulatory element-binding protein-2 (SREBP-2) is a transcription factor regarded as the main regulator of cholesterol homeostasis. Therefore, increased level of SREBP-2 could be responsible for hypercholesterolemia, which is observed in experimental chronic renal failure (CRF). This study was designed primary to evaluate the impact of experimental CRF (5/6 nephrectomy model) on rat liver SREBP-2 gene expression. In CRF rats, a twofold increase in SREBP-2 mRNA level, as well as in mature SREBP-2 protein abundance was found, when compared to control animals. It was associated with enhanced activity and mRNA abundance of liver HMG-CoA reductase, a rate-limiting enzyme for cholesterol biosynthesis. A twofold increase in liver cholesterologenesis rate was also noted. We conclude that experimental CRF is associated with increased liver SREBP-2 gene expression. This is probably the cause for enhanced HMG-CoA reductase gene expression and, consequently, for increase in liver cholesterol synthesis in CRF rats. Despite increased SREBP-2 gene expression we found LDL-receptor mRNA level to be lower than in controls, suggesting SREBP-2 independent mechanisms of LDL-receptor transcriptional regulation in CRF rats. Enhanced cholesterol synthesis and decreased LDL-receptor mRNA level are probably responsible for an almost fourfold increase in serum cholesterol concentration in CRF rats.
Chmielewski
Michal
M
Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, ul. Debinki 7, 80-211 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*; D004195:Disease Models, Animal; D004790:Enzyme Induction; D015870:Gene Expression; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis / Q000235:genetics; D006937:Hypercholesterolemia / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D009392:Nephrectomy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
D012333:RNA, Messenger; D011973:Receptors, LDL; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases