THE EFFECT OF THE HMG-COA REDUCTASE INHIBITOR SIMVASTATIN AND OF CHOLESTYRAMINE ON HEPATIC APOLIPOPROTEIN MESSENGER-RNA LEVELS IN THE RAT

We have administered the hypolipaemic drugs simvastatin and cholestyramine to rats, both separately and together, to determine whether drug-induced changes in plasma apo lipoprotein levels occur through regulation of hepatic genes coding for apolipoproteins (apos) AI, AIV, E and B. Cholestyramine alone had little effect on either the plasma levels of the apolipoproteins studied or their hepatic mRNA levels. However, simvastatin, either alone or in combination with cholestyramine, produced marked changes in both of these parameters. While simvastatin plus cholestyramine lowered mRNAs for apo AIV, apo E and apo B by 50%, 37% and 55%, respectively, the treatment resulted in an increase of 150% in apo AI mRNA. This combined drug treatment caused a lowering in plasma concentration of all four apolipoproteins which failed to reach significance with apo E. Relative to controls, the values decreased to 83 +/- 14% for apo AI, 67 +/-8% for apo AIV and 73 +/- 15 for apo B. An important novel finding of the present study, was that hypolipaemic drugs caused the apo B mRNA levels in rat liver to decrease. Previous reports have shown that although dietary fat or hormones caused marked changes in the concentration of circulating lipoproteins, they failed to alter apo B mRNA content. We suggest that the synthesis of apo B is subject to both pre- and post-translational regulation.