A possible mechanism that may explain the reduction of APOE mRNA is related to the inhibitory effect of statins on the synthesis of oxysterols, which are LXR ligands Autophagy inhibitor and would lead to a decreased expression of LXR target genes. LXR regulates APOE expression in macrophages and adipocytes though direct interaction with two duplicated enhancer elements placed downstream of the gene

and responsive to LXRs [12]. Besides the up regulation of gene expression, it was demonstrated that LXR activation by incubating with a LXR agonist increases apoE secretion in HepG2 cells [33]. In our sample, although no reduction of LXRA expression by atorvastatin was detected, positive correlation between APOE and LXRA expression was observed before and after treatments. However, we only measured mRNA levels of LXRA and the transcriptional activity of LXRα by interacting with the APOE promoter was not evaluated. Additionally, APOE mRNA reduction by atorvastatin was APOE genotype dependant in our sample that could give some additional explanation of influence of genotypes on variation in response to statins. However further studies using a larger sample size and if possible more adequate cellular models are necessary. HT effects on APOE expression have been investigated

mainly in brain tissues where HT seems to confer neuronal protection and regeneration [34]. Estradiol treatment in cultured neurons causes a rapid (4 h) elevation of apoE [35]. Additionally, when ovariectomized mice were continuously treated with CT99021 estradiol [36], APOE up-regulation at acute treatment (five days) was observed in brain tissues, but this effect was lacked with longer estradiol exposure (14–49 days). On the other hand, estradiol administration increased

hepatic apoE levels in mice without affecting APOE mRNA [37]. No differences on PBMC APOE mRNA were detected after HT treatment in next our study, however according with above mentioned early findings long term treatment and posttranscriptional regulation could explain this fact. Moreover, an additional limitation of our work is the measurement of mRNA levels but not apoE protein, which would have enable us to elucidate posttranscriptional regulation of APOE in postmenopausal women. APOE mRNA expression in PBMC was down-regulated by atorvastatin in a process probably mediated by LXRα though reduction of oxysterols and this was influenced by APOE genotypes, nevertheless HT and HT associated to atorvastatin did not influence APOE expression. The present study was supported by a grant from CNPq (Protocol # 474905/01-2). We thank the volunteers for their participation and physicians and nurses from Dislipidemia Section from Dante Pazzanese Institute of Cardiology for technical support during patient selection. M.H. Issa, F.D.V. Genvigir and S.A. Cavalli were recipients of fellowships from FAPESP and CAPES, Brazil. A.