ADIPOSE-TISSUE CHOLESTERYL ESTER TRANSFER PROTEIN MESSENGER-RNA IN RESPONSE TO PROBUCOL TREATMENT - CHOLESTEROL AND SPECIES DEPENDENCE

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. When animals were fed a cholesterol-free diet, probucol had no effect on plasma concentrations of HDL-C or CETP or on adipose tissue CETP mRNA abundance. Addition of cholesterol to the diet (0.5% w/w) resulted in significant increases both in plasma CETP and in the level of CETP mRNA in adipose tissue. When probucol was incorporated into the cholesterol-rich diet, there was a further and significant increase in plasma CETP and adipose tissue mRNA abundance and a decrease in HDL cholesterol. The effect of probucol on CETP gene expression may be mediated by alterations in a putative regulatory pool of cellular cholesterol and may, in turn, depend on net transport of cholesterol to and from specific tissues via chylomicrons, low density lipoproteins, or other lipoproteins.