Expression of the human apolipoprotein A-I: polymorphisms and drug effects

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In course of apolipoprotein genes analysis, we found a polymorphism of APOA5 gene, c.553G>T in Japanese patients with hypertriglyceridemia. This polymorphism causes the change of amino acid substitution of a cysteine for a glycine. The frequencies of -1131T>C and c.553G>T polymoiphisms in 95 Japanese patients with hypertriglyceridemia and 119 unrelated normolipidemic subjects were determined by restriction-fragment-length-polymorphisms. The frequencies of the T allele at -1131bp (0.511) and the t allele at c.553G>T (0.205) in patients with hypertriglyceridemia were significantly higher than those in normolipidemic subjects (0.315 and 0.105), respectively (p<0.01and p<0.02). The two polymorphic sites were in strong linkage disequilibrium. These results suggest that the polymorphisms, -1131T>C and c.553G>T were associated with hypertriglyceridemia in Japanese population. Statin treatment reduces the levels of LDL cholesterol and triglyceride, and increases the levels of the antiatherogenic HDL. We investigated their ability to modulate APOA5 gene expression and consequently influence plasma triglyceride levels. Promoter activity of the APOA5 gene was estimated by measuring luciferase activity of plasmids with a APOA5 promoter region transfected into human hepatoma HepG2 cells. Treatment with pitavastatin significantly increased APOA5 expression and mRNA levels in human HepG2 cells, and cotransfection of a PPARa treatment resulted in a significant increase of APOA5 expression. These effects were reversed by the addition of mevalonate or geranylgeranyl pyrophosphate, implicating HMG-CoA reductase as the relevant target of these drugs.