Nicholson A C, Hajjar D P, Zhou X, He W, Gotto A M, Han J
Department of Pathology, Center of Vascular Biology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Br J Pharmacol. 2007 Jul;151(6):807-15. doi: 10.1038/sj.bjp.0707250. Epub 2007 Jun 4.
Adipocyte differentiation in vitro is coordinately activated by two transcription factors, peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT enhancer binding protein alpha (C/EBPalpha), but it is inhibited by preadipocyte factor-1 (pref-1). Statins, inhibitors of HMG-CoA reductase and de novo cholesterol synthesis, can have pleiotropic effects which influence adipocyte phenotype by ill-defined mechanisms. We investigated the effects of pitavastatin (NK-104) on adipocyte differentiation and the transcriptional pathways involved.
The effects of pitavastatin on adipocyte differentiation were evaluated by the formation of oil droplets, content of cellular triglyceride and expression of adipocyte-specific genes. Regulatory mechanisms were assessed by analysis of PPARgamma, C/EBPalpha and pref-1 expression.
Pitavastatin significantly inhibited adipocyte differentiation of 3T3-L1 preadipocytes in response to adipogenic inducers. Evidence for inhibition included fewer Oil Red O positive droplets, less cellular triglyceride and decreased expression of adipocyte-specific genes, including fatty acid binding protein (aP2), CD36, adipsin and glucose transporter 4 (GLUT4). The inhibitory effects of pitavastatin on adipocyte differentiation of 3T3-L1 preadipocytes were time and concentration dependent. Pitavastatin significantly blocked induction of PPARgamma expression, but not C/EBPalpha expression or DNA binding activity of PPARgamma. Also, pitavastatin induced pref-1 expression in preadipocytes and maintained expression of pref-1 at high levels in differentiated cells.
Our data suggest that pitavastatin inhibits adipocyte differentiation by blocking PPARgamma expression and activating pref-1 expression. These studies may have implications in the regulation of adipogenesis in response to statins.
体外脂肪细胞分化由两种转录因子协同激活，即过氧化物酶体增殖物激活受体γ（PPARγ）和CCAAT增强子结合蛋白α（C/EBPα），但前脂肪细胞因子-1（pref-1）可抑制其分化。他汀类药物是HMG-CoA还原酶和从头胆固醇合成的抑制剂，可产生多效性作用，通过不明机制影响脂肪细胞表型。我们研究了匹伐他汀（NK-104）对脂肪细胞分化及相关转录途径的影响。
通过油滴形成、细胞甘油三酯含量及脂肪细胞特异性基因表达来评估匹伐他汀对脂肪细胞分化的影响。通过分析PPARγ、C/EBPα和pref-1表达来评估调节机制。
匹伐他汀显著抑制3T3-L1前脂肪细胞对成脂诱导剂的脂肪细胞分化。抑制证据包括油红O阳性脂滴减少、细胞甘油三酯减少以及脂肪细胞特异性基因表达降低，这些基因包括脂肪酸结合蛋白（aP2）、CD36、脂联素和葡萄糖转运蛋白4（GLUT4）。匹伐他汀对3T3-L1前脂肪细胞脂肪细胞分化的抑制作用具有时间和浓度依赖性。匹伐他汀显著阻断PPARγ表达的诱导，但不影响C/EBPα表达或PPARγ的DNA结合活性。此外，匹伐他汀诱导前脂肪细胞中pref-1表达，并在分化细胞中维持pref-1的高水平表达。
我们的数据表明，匹伐他汀通过阻断PPARγ表达和激活pref-1表达来抑制脂肪细胞分化。这些研究可能对他汀类药物响应下的脂肪生成调节具有启示意义。
