Cyclosporin-induced dyslipoproteinemia is associated with selective activation of SREBP-2.
The use of cyclosporin A has contributed greatly to the success of organ transplantation. However, cyclosporin-associated side effects of hypertension, nephrotoxicity, and dyslipoproteinemia have tempered these benefits. Cyclosporin-induced dyslipoproteinemia may be an important risk factor for the accelerated atherosclerosis observed posttransplantation. Using a mouse model, we treated Swiss-Webster mice for 6 days with a daily dose of 20 microg/g body wt of cyclosporin and observed significant elevations of plasma cholesterol, triglyceride, and apolipoprotein B (apoB) levels relative to vehicle-alone treated control animals. Measurement of the rate of secretion of very low-density lipoprotein (VLDL) by the liver in vivo showed that cyclosporin treatment led to a significant increase in the rate of hepatic VLDL triglyceride secretion. Total apoB secretion was unaffected. Northern analysis showed that cyclosporin A treatment increased the abundance of hepatic mRNA levels for a number of key genes involved in cholesterol biosynthesis relative to vehicle-alone treated animals. Two key transcriptional factors, sterol regulatory element-binding protein (SREBP)-1 and SREBP-2, also showed differential expression; SREBP-2 expression was increased at the mRNA level, and there was an increase in the active nuclear form, whereas the mRNA and the nuclear form of SREBP-1 were reduced. These results show that the molecular mechanisms by which cyclosporin causes dyslipoproteinemia may, in part, be mediated by selective activation of SREBP-2, leading to enhanced expression of lipid metabolism genes and hepatic secretion of VLDL triglyceride.
Wu
J
J
Division of Endocrinology, Diabetes, and Medical Genetics, Medical University of South Carolina, Charleston, South Carolina 29425-2222, USA.
Zhu
Y H
YH
Patel
S B
SB
D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D000818:Animals; D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D001055:Apolipoproteins B / Q000378:metabolism; D015243:Cholesterol, VLDL / Q000378:metabolism; D003327:Coronary Disease / Q000139:chemically induced / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects*; D003577:Cytochrome P-450 Enzyme System; D004268:DNA-Binding Proteins / Q000235:genetics*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000235:genetics; D064429:Fatty Acid Synthases / Q000235:genetics; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D006951:Hyperlipoproteinemias / Q000139:chemically induced* / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007167:Immunotherapy / Q000009:adverse effects; D016350:Leucine Zippers / Q000235:genetics; D008049:Lipase / Q000235:genetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D011973:Receptors, LDL / Q000235:genetics; D013230:Stearoyl-CoA Desaturase / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols / Q000096:biosynthesis / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism
D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D001055:Apolipoproteins B; D015243:Cholesterol, VLDL; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D011973:Receptors, LDL; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols; D014157:Transcription Factors; D014280:Triglycerides; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D006903:Hydroxymethylglutaryl CoA Reductases; D013250:Steroid Hydroxylases; C115867:oxysterol 7-alpha-hydroxylase; D013230:Stearoyl-CoA Desaturase; D064429:Fatty Acid Synthases; D013186:Farnesyl-Diphosphate Farnesyltransferase; D008049:Lipase; D000103:Acetyl-CoA Carboxylase