Effect of cyclosporine on HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, HDL receptor, VLDL receptor, and lipoprotein lipase expressions.
Long-term administration of cyclosporine (CsA) has been shown to cause hypercholesteremia, hypertriglyceridemia, and elevations of plasma low-density and very low-density lipoprotein (LDL and VLDL) levels in humans. This study was undertaken to explore the effects of CsA on expressions of the key lipid regulatory enzymes and receptors. Thus, hepatic expressions of cholesterol 7alpha-hydroxylase (the rate-limiting step in cholesterol conversion to bile acids), LDL receptor, and high-density lipoprotein (HDL) receptor proteins, as well as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity were determined in rats treated with CsA (18 mg/kg/day) or placebo for 3 weeks. In addition, skeletal muscle and adipose tissue expressions of lipoprotein lipase and VLDL receptor were measured. Western blot analysis was used for all protein measurements using appropriate antibodies against the respective proteins. CsA-treated animals showed mild but significant elevations of plasma cholesterol and triglyceride concentrations. This was associated with a marked down-regulation of cholesterol 7alpha-hydroxylase in the liver and a severe reduction of lipoprotein lipase abundance in skeletal muscle and adipose tissue. However, hepatic LDL receptor and HDL receptor expressions and HMG-CoA reductase activity were not altered by CsA therapy. Likewise, skeletal muscle and adipose tissue VLDL receptor protein expressions were unaffected by CsA administration under the given condition. In conclusion, CsA administration for 3 weeks resulted in a significant reduction of hepatic cholesterol 7alpha-hydroxylase and marked down-regulation of skeletal muscle and adipose tissue lipoprotein lipase abundance in rats. The former abnormality can contribute to hypercholesterolemia by limiting cholesterol catabolism, whereas the latter may contribute to hypertriglyceridemia and VLDL accumulation by limiting triglyceride-rich lipoprotein clearance in CsA-treated animals.
Vaziri
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ND
Division of Nephrology, Department of Medicine, University of California, Irvine 92668, USA.
Liang
K
K
Azad
H
H
D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis*; D016572:Cyclosporine / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008071:Lipoprotein Lipase / Q000096:biosynthesis*; D008075:Lipoproteins, HDL; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D016601:RNA-Binding Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000096:biosynthesis; D018110:Receptors, Lipoprotein / Q000096:biosynthesis*; D014280:Triglycerides / Q000097:blood
D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D008075:Lipoproteins, HDL; D016601:RNA-Binding Proteins; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D014280:Triglycerides; C036053:VLDL receptor; C031616:high density lipoprotein receptors; C075197:high density lipoprotein binding protein; D016572:Cyclosporine; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase; D008071:Lipoprotein Lipase