Serum CETP status is independently associated with reduction rates in LDL-C in pitavastatin-treated diabetic patients and possible involvement of LXR in its association.
Serum CETP status is independently associated with reduction rates in LDL-C in pitavastatin-treated diabetic patients and possible involvement of LXR in its association.
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DOI：
10.1186/s12944-016-0223-6
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发表时间：
2016-03-17
影响因子：
4.5
通讯作者：
Yoshida H
中科院分区：
文献类型：
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作者：
Shimada A;Kimura H;Oida K;Kanehara H;Bando Y;Sakamoto S;Wakasugi T;Saga T;Ito Y;Kamiyama K;Mikami D;Iwano M;Hirano T;Yoshida H
他汀类药物降低胆固醇酯转移蛋白（CETP）水平，CETP水平与肝脏脂质含量以及血清低密度脂蛋白-胆固醇（LDL-C）水平呈正相关。然而，CETP状态与他汀类药物诱导的LDL-C水平降低之间的关系尚未详细阐明。我们在此研究了CETP状态对2型糖尿病高胆固醇血症患者匹伐他汀降脂作用的影响，以及匹伐他汀诱导CETP水平改变的分子机制。53例患者接受2 mg匹伐他汀治疗3个月。在匹伐他汀治疗前后测量血清LDL-C、小密度（sd）LDL-C和CETP水平。匹伐他汀，T0901317，肝X受体（LXR）的特异性激动剂，反映肝胆固醇含量，和LXR沉默CETP mRNA表达在HepG 2细胞的影响也进行了检查，通过实时PCR测定。匹伐他汀治疗使LDL-C、sdLDL-C和CETP水平分别降低39%、42%和23%。尽管基线时CETP和LDL-C水平之间不存在显著相关性，但基线CETP水平及其百分比变化是LDL-C和sdLDL-C水平变化的独立阳性决定因素。T0901317（0.5 μM）的LXR激活（一种类似于肝脏胆固醇蓄积的体外条件）使HepG 2细胞中的CETP mRNA水平增加约220%，而LXR沉默显著降低了CETP表达的增加。匹伐他汀（5 μM）使基础CETP mRNA水平降低21%，T0901317完全逆转了这一点。基线CETP水平可以预测匹伐他汀的降脂作用。匹伐他汀诱导的CETP降低可能部分归因于LXR活性降低，可通过随后的肝胆固醇合成下降预测。UMIN临床试验登记研究ID UMIN 000019020
Statins decrease cholesteryl ester transfer protein (CETP) levels, which have been positively associated with hepatic lipid content as well as serum low density lipoproteins-cholesterol (LDL-C) levels. However, the relationship between the CETP status and statin-induced reductions in LDL-C levels has not yet been elucidated in detail. We herein examined the influence of the CETP status on the lipid-reducing effects of pitavastatin in hypercholesterolemic patients with type 2 diabetes mellitus as well as the molecular mechanism underlying pitavastatin-induced modifications in CETP levels. Fifty-three patients were treated with 2 mg of pitavastatin for 3 months. Serum levels of LDL-C, small dense (sd) LDL-C, and CETP were measured before and after the pitavastatin treatment. The effects of pitavastatin, T0901317, a specific agonist for liver X receptor (LXR) that reflects hepatic cholesterol contents, and LXR silencing on CETP mRNA expression in HepG2 cells were also examined by a real-time PCR assay. The pitavastatin treatment decreased LDL-C, sdLDL-C, and CETP levels by 39, 42, and 23 %, respectively. Despite the absence of a significant association between CETP and LDL-C levels at baseline, baseline CETP levels and its percentage change were an independent positive determinant for the changes observed in LDL-C and sdLDL-C levels. The LXR activation with T0901317 (0.5 μM), an in vitro condition analogous to hepatic cholesterol accumulation, increased CETP mRNA levels in HepG2 cells by approximately 220 %, while LXR silencing markedly diminished the increased expression of CETP. Pitavastatin (5 μM) decreased basal CETP mRNA levels by 21 %, and this was completely reversed by T0901317. Baseline CETP levels may predict the lipid-reducing effects of pitavastatin. Pitavastatin-induced CETP reductions may be partially attributed to decreased LXR activity, predictable by the ensuing decline in hepatic cholesterol synthesis. UMIN Clinical Trials Registry ID UMIN000019020