Research Article| Volume 191, ISSUE 2, P326-332, April 2007

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.


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        • Oda H.
        • Keane W.F.
        Lipid abnormalities in end stage renal disease.
        Nephrol Dial Transplant. 1998; 13: 45-49
        • Chmielewski M.
        • Sucajtys E.
        • Swierczynski J.
        • Rutkowski B.
        • Boguslawski W.
        Contribution of increased HMG-CoA reductase gene expression to hypercholesterolemia in experimental chronic renal failure.
        Mol Cell Biochem. 2003; 246: 187-191
        • Szolkiewicz M.
        • Sucajtys E.
        • Chmielewski M.
        • et al.
        Increased rate of cholesterologenesis—a possible cause of hypercholesterolemia in experimental chronic renal failure in rats.
        Horm Metab Res. 2002; 34: 234-237
        • Chmielewski M.
        • Nieweglowski T.
        • Swierczynski J.
        • Rutkowski B.
        • Boguslawski W.
        Diurnal rhythm of cholesterol biosynthesis in experimental chronic renal failure.
        Mol Cell Biochem. 2001; 228: 33-37
        • Horton J.D.
        • Goldstein J.L.
        • Brown M.S.
        SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.
        J Clin Invest. 2002; 109: 1125-1131
        • Horton J.D.
        • Shimomura I.
        • Brown M.S.
        • Hammer R.E.
        • Goldstein J.L.
        • Shimano H.
        Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2.
        J Clin Invest. 1998; 101: 2331-2339
        • Miserez A.R.
        • Muller P.Y.
        • Barella L.
        • et al.
        Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia.
        Atherosclerosis. 2002; 164: 15-26
        • Robinet P.
        • Vedie B.
        • Chironi G.
        • et al.
        Characterization of polymorphic structure of SREBP-2 gene: role in atherosclerosis.
        Atherosclerosis. 2003; 168: 381-387
        • Rodriguez C.
        • Martinez-Gonzalez J.
        • Sanchez-Gomez S.
        • Badimon L.
        LDL downregulates CYP51 in porcine vascular endothelial cells and in the arterial wall through a sterol regulatory element binding protein-2-dependent mechanism.
        Circ Res. 2001; 88: 268-274
        • Korczynska J.
        • Stelmanska E.
        • Nogalska A.
        • et al.
        Upregulation of lipogenic enzymes genes expression in white adipose tissue of rats with chronic renal failure is associated with higher level of sterol regulatory element binding protein-1.
        Metabolism. 2004; 53: 1060-1065
        • Jiang T.
        • Liebman S.E.
        • Lucia M.S.
        • Phillips C.L.
        • Levi M.
        Calorie restriction modulates renal expression of sterol regulatory element binding proteins, lipid accumulation, and age-related renal disease.
        J Am Soc Nephrol. 2005; 16: 2385-2394
        • Sun L.
        • Halaihel N.
        • Zhang W.
        • Rogers T.
        • Levi M.
        Role of sterol regulatory element-binding protein 1 in regulation of renal lipid metabolism and glomerulosclerosis in diabetes mellitus.
        J Biol Chem. 2002; 277: 18919-18927
        • Swierczynski J.
        • Korczynska J.
        • Szolkiewicz M.
        • et al.
        Low leptin mRNA level in adipose tissue and normoleptinemia in experimental chronic renal failure.
        Exp Nephrol. 2001; 9: 54-59
        • Kochan Z.
        • Karbowska J.
        • Swierczynski J.
        Unususal increase of lipogenesis in rat white adipose tissue after multiple cycles of starvation-refeeding.
        Metabolism. 1997; 46: 10-17
        • Sperry W.
        • Webb M.
        A revision of the Schoenheimer-Sperry method for cholesterol determination.
        J Biol Chem. 1950; 187: 97-106
        • Shapiro D.J.
        • Nordstrom J.L.
        • Mitschelen J.J.
        • Rodwell V.W.
        • Schimke R.T.
        Micro assay for 3-hydroxy-3-methylglutaryl-CoA reductase in rat liver and in L-cell fibroblasts.
        Biochim Biophys Acta. 1974; 370: 369-377
        • Chomczynski P.
        • Sacchi N.
        Single-step method of RNA isolation by acid guanidinium thiocyanate- phenol-chloroform extraction.
        Anal Biochem. 1987; 162: 156-159
        • Freeman W.M.
        • Walker S.J.
        • Vrana K.E.
        Quantitative RT-PCR: pitfalls and potential.
        Biotechniques. 1999; 26: 24-25
        • Marone M.
        • Mozzetti S.
        • De Ritis D.
        • Pierelli L.
        • Scambia G.
        Semiquantitative RT-PCR analysis to assess the expression levels of multiple transcripts from the same sample.
        Biol Proc Online. 2001; 3: 19-25
        • Ide T.
        • Ashakumary L.
        • Takahashi Y.
        • Kushiro M.
        • Fukuda N.
        • Sugano M.
        Sesamin a sesame lignan, decreases fatty acid synthesis in rat liver accompanying the down-regulation of sterol regulatory element binding protein-1.
        Biochim Biophys Acta. 2001; 1534: 1-13
        • Vaziri N.D.
        • Liang K.H.
        Acyl-coenzyme A: cholesterol acyltransferase inhibition ameliorates proteinuria, hyperlipidemia, lecithin-cholesterol acyltransferase, SRB-1, and low-denisty lipoprotein receptor deficiencies in nephrotic syndrome.
        Circulation. 2004; 110: 419-425
        • Liang K.
        • Kim C.H.
        • Vaziri N.D.
        HMG-CoA reductase inhibition reverses LCAT and LDL receptor deficiencies and improves HDL in rats with chronic renal failure.
        Am J Physiol Renal Physiol. 2005; 288: F539-F544
        • Hall E.A.
        • Ren S.
        • Hylemon P.B.
        • et al.
        Mitochondrial cholesterol transport: a possible target in the management of hyperlipidemia.
        Lipids. 2005; 40: 1237-1244
        • Eberle D.
        • Hegarty B.
        • Bossard P.
        • Ferre P.
        • Foufelle F.
        SREBP transcription factors: master regulators of lipid homeostasis.
        Biochimie. 2004; 86: 839-848
        • Zoccali C.
        • Mallamaci F.
        • Tripepi G.
        Inflammation and atherosclerosis in end-stage renal disease.
        Blood Purif. 2003; 21: 29-36
        • Klahr S.
        • Morrissey J.
        Progression of chronic renal disease.
        Am J Kidney Dis. 2003; 41: S3-S7
        • Luger A.
        • Kovarik J.
        • Stummvoll H.K.
        • Urbanska A.
        • Luger T.A.
        Blood-membrane interaction in hemodialysis leads to increased cytokine production.
        Kidney Int. 1987; 32: 84-88
        • Ruan X.Z.
        • Varghese Z.
        • Powis S.H.
        • Moorhead J.F.
        Dysregulation of LDL receptor under the influence of inflammatory cytokines: a new pathway for foam cell formation.
        Kidney Int. 2001; 60: 1716-1725
        • Demoulin J.B.
        • Ericsson J.
        • Kallin A.
        • Rorsman C.
        • Ronnstrand L.
        • Heldin C.H.
        Platelet-derived growth factor stimulates membrane lipid synthesis through activation of phosphatidylinositol 3-kinase and sterol regulatory element-binding proteins.
        J Biol Chem. 2004; 279: 35392-35402