Probucol raises plasma CETP 31% while paradoxically lowering adipose CETP mRNA, suggesting effects beyond local synthesis (J Lipid Res 1993)

Probucol treatment results in an increase in plasma concentrations of cholesteryl ester transfer protein (CETP) which may account, in part, for the effects of this agent on plasma concentrations of HDL cholesterol. We have examined the mechanism by which probucol increases plasma CETP and have determined the associated changes in the plasma distribution of high density lipoprotein (HDL) particles. Studies were carried out in nine hypercholesterolemic subjects and five normal volunteers. Probucol treatment resulted in a 31% increase in plasma concentrations of CETP and a 23% decrease in HDL cholesterol (P < 0.01). The plasma concentration of LpA-I decreased by 40% (P < 0.01) whereas no change occurred in the LpA-I/A-II subclass of HDL. Plasma CETP increased significantly by 1 week of therapy and remained stable over 10 to 14 weeks of therapy. In spite of the significant increase in plasma concentrations of CETP, the abundance of CETP mRNA in peripheral adipose tissue decreased markedly (P < 0.001). These results suggested that probucol may alter CETP synthesis in another tissue such as liver or, alternatively, may have other effects on CETP secretion into or catabolism out of the plasma pool. Further studies were carried out in hamsters because, in this species, adipose tissue is a major site and liver is a negligible site for CETP synthesis. Hamsters were fed probucol with or without dietary cholesterol because this species was previously shown to respond to dietary cholesterol with an increase in adipose tissue mRNA levels and in plasma CETP concentrations, thus providing the opportunity to determine whether probucol would alter these parameters independently of the dietary cholesterol effect.(ABSTRACT TRUNCATED AT 250 WORDS)