Effect of cyclosporine on HMG-CoA reductase, cholesterol 7 alpha-hydroxylase, LDL receptor, HDL receptor, VLDL receptor, and lipoprotein lipase expressions

Long-term administration of cyclosporine (CsA) has been shown to cause hype rcholesteremia, hypertriglyceridemia, and elevations of plasma low-density and very low-density lipoprotein (LDL and VLDL) levels in humans. This stud y was undertaken to explore the effects of CsA on expressions of the key li pid regulatory enzymes and receptors. Thus, hepatic expressions of choleste rol 7 alpha-hydroxylase (the rate-limiting step in cholesterol conversion t o bile acids), LDL receptor, and high-density lipoprotein (HDL) receptor pr oteins, as well as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductas e activity were determined in rats treated with CsA (18 mg/kg/day) or place bo for 3 weeks. In addition, skeletal muscle and adipose tissue expressions of lipoprotein lipase and VLDL receptor were measured. Western blot analys is was used for all protein measurements using appropriate antibodies again st 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 7 alpha-hydroxylas e in the liver and a severe reduction of lipoprotein lipase abundance in sk eletal muscle and adipose tissue. However, hepatic LDL receptor and HDL rec eptor expressions and HMG-CoA reductase activity were not altered by CsA th erapy. Likewise, skeletal muscle and adipose tissue VLDL receptor protein e xpressions were unaffected by CsA administration under the given condition. In conclusion, CsA administration for 3 weeks resulted in a significant re duction of hepatic cholesterol 7 alpha-hydroxylase and marked down-regulati on of skeletal muscle and adipose tissue lipoprotein lipase abundance in ra ts. The former abnormality can contribute to hypercholesterolemia by limiti ng cholesterol catabolism, whereas the latter may contribute to hypertrigly ceridemia and VLDL accumulation by limiting triglyceride-rich lipoprotein c learance in CsA-treated animals.