PPAR-β/δ activation promotes phospholipid transfer protein expression
PPAR-β/δ activation promotes phospholipid transfer protein expression
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DOI：
10.1016/j.bcp.2015.01.016
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发表时间：
2015-03-15
影响因子：
5.8
通讯作者：
Carles Escola-Gil, Joan
中科院分区：
文献类型：
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作者：
Chehaibi, Khouloud;Cedo, Lidia;Carles Escola-Gil, Joan
过氧化物酶体增殖物激活受体（PPAR）-β/δ已成为治疗血脂异常的有前景的治疗靶点，包括对HDL胆固醇（HDL-C）的有益作用。在目前的研究中，我们确定了PPAR-beta/delta激动剂GW 0742对小鼠和培养的人类细胞中HDL组成和肝脏HDL相关基因表达的影响。在用GW 0742（10 mg/kg/天）或媒介物溶液处理14天的C57 BL/6野生型、LDL受体（LDLR）缺陷型小鼠和PPAR-beta/delta缺陷型小鼠中进行实验。GW 0742可上调小鼠肝脏磷脂转运蛋白（PLTP）基因表达，提高血清PLTP活性。当给予野生型小鼠时，GW 0742显著增加血清HDL-C和HDL磷脂; GW 0742还提高了血清产生prep-HDL形成的潜力。GW 0742介导的对肝脏Pltp表达和血清酶活性的影响在PPAR-beta/delta缺陷小鼠中完全消除。GW 0742还刺激小鼠J774巨噬细胞、分化的人THP-1巨噬细胞和人肝癌Huh 7中PLTP mRNA的表达。总的来说，我们的研究结果表明，在培养的细胞和小鼠肝脏中，GW 0742激活的PPAR-beta/delta对Pltp表达有共同的转录上调，导致血清PLTP活性增强。我们的研究结果还表明，PPAR-beta/delta激活可以调节PLT介导的prep-HDL形成和巨噬细胞胆固醇流出。(C)2015 Elsevier Inc. All rights reserved.
The peroxisome proliferator-activated receptor (PPAR)-beta/delta has emerged as a promising therapeutic target for treating dyslipidemia, including beneficial effects on HDL cholesterol (HDL-C). In the current study, we determined the effects of the PPAR-beta/delta agonist GW0742 on HDL composition and the expression of liver HDL-related genes in mice and cultured human cells. The experiments were carried out in C57BL/6 wild-type, LDL receptor (LDLR)-deficient mice and PPAR-beta/delta-deficient mice treated with GW0742 (10 mg/kg/day) or a vehicle solution for 14 days. GW0742 upregulated liver phospholipid transfer protein (Pltp) gene expression and increased serum PLTP activity in mice. When given to wildtype mice, GW0742 significantly increased serum HDL-C and HDL phospholipids; GW0742 also raised serum potential to generate prep-HDL formation. The GW0742-mediated effects on liver Pltp expression and serum enzyme activity were completely abolished in PPAR-beta/delta-deficient mice. GW0742 also stimulated PLTP mRNA expression in mouse J774 macrophages, differentiated human THP-1 macrophages and human hepatoma Huh7. Collectively, our findings demonstrate a common transcriptional upregulation by GW0742-activated PPAR-beta/delta of Pltp expression in cultured cells and in mouse liver resulting in enhanced serum PLTP activity. Our results also indicate that PPAR-beta/delta activation may modulate PLTP-mediated prep-HDL formation and macrophage cholesterol efflux. (C) 2015 Elsevier Inc. All rights reserved.