Nd. Vaziri et al., Effect of cyclosporine on HMG-CoA reductase, cholesterol 7 alpha-hydroxylase, LDL receptor, HDL receptor, VLDL receptor, and lipoprotein lipase expressions, J PHARM EXP, 294(2), 2000, pp. 778-783
Citations number
35
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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.