出版社：American Society for Biochemistry and Molecular Biology
摘要：To better characterize the in vivo effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition on human lipid metabolism, an adolescent male with cholesteryl ester storage disease (CESD) was treated chronically with lovastatin. Therapy was associated with decreased liver-spleen size, improved but not normal serum lipids, a 26% decrease in hepatic cholesteryl ester, a 12% decrease in unesterified hepatic cholesterol, and a fourfold increase in hepatic low density lipoprotein (LDL) receptor protein. Hepatic mRNA levels for the LDL receptor and apolipoprotein (apo) B standardized to levels of hepatic gamma actin mRNA were unchanged with therapy. Kinetic studies revealed no change in the LDL fractional catabolic rate and a decrease in the LDL production rate. Size exclusion chromatography showed striking reductions in plasma very low density lipoprotein (VLDL) cholesterol and intermediate density lipoprotein (LDL) cholesterol but not LDL cholesterol with therapy. Mean LDL particle size and the LDL particle size range were increased by treatment. However, there was no difference in the ability of pretreatment or treatment LDL to bind to the LDL receptor on cultured cells consistent with previous studies in animals, indicating that lovastatin may alter LDL particles to impair interaction with the LDL receptor in vivo but not in vitro. Lovastatin therapy in CESD appears to be clinically beneficial and has complex effects on lipid metabolism that may include a dominant inhibitory effect on hepatic lipoprotein production, posttranscriptionally mediated induction of the LDL receptor, and alterations of LDL particles that interfere with their clearance by the LDL receptor in vivo.
