Graduate Institute of Medical Sciences, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.
Biochem Pharmacol. 2012 Aug 15;84(4):522-31. doi: 10.1016/j.bcp.2012.05.022. Epub 2012 Jun 9.
Fenofibrate, a fibric acid derivative, is known to possess lipid-lowering effects. Although fenofibrate may activate peroxisome proliferator-activated receptor (PPAR)α and regulate the transcription of several genes, the underlying mechanisms are poorly understood. In this study, we demonstrated that incubation of C2C12 myotubes with fenofibrate increased adipose triglyceride lipase (ATGL) expression and suppressed fatty acid synthase (FAS) level, thereby decreasing intracellular triglyceride accumulation when cells were incubated at high-glucose condition. Fenofibrate increased the phosphorylation of AMP-activated protein kinase (AMPK), which subsequently increased fatty acid β-oxidation. AMPK phosphorylation was reduced by pretreatment with GW9662 (a PPARα inhibitor), suggesting that AMPK may be a downstream effector of PPARα. Pretreatment with compound C (an AMPK inhibitor) or GW9662 blocked fenofibrate-induced ATGL expression and the lipid-lowering effect. Our results suggest that AMPK is as an upstream regulator of ATGL. With further exploration, we demonstrated that fenofibrate stimulated FoxO1 translocation from the cytosol to nuclei by immunefluorescence assay, chromatin immuneprecipitation assay, and reporter assay. Furthermore, oral administration of fenofibrate ameliorated the body weight, visceral fat and serum biochemical indexes in db/db mice. Taken together, our results suggest that the lipid-lowering effect of fenofibrate was achieved by activating PPARα and AMPK signaling pathway that resulted in increasing ATGL expression, lipolysis, and fatty acid β-oxidation.
非诺贝特是一种纤维酸衍生物，已知具有降低血脂的作用。虽然非诺贝特可能会激活过氧化物酶体增殖物激活受体（PPAR）α并调节几种基因的转录，但其中的机制尚不清楚。在这项研究中，我们证明了在高葡萄糖条件下孵育 C2C12 肌管时，非诺贝特孵育会增加脂肪甘油三酯脂肪酶（ATGL）的表达并抑制脂肪酸合成酶（FAS）水平，从而减少细胞内甘油三酯的积累。非诺贝特增加了 AMP 激活的蛋白激酶（AMPK）的磷酸化，从而增加了脂肪酸的β氧化。用 GW9662（PPARα抑制剂）预处理会降低 AMPK 的磷酸化，表明 AMPK 可能是 PPARα 的下游效应物。用化合物 C（AMPK 抑制剂）或 GW9662 预处理会阻止非诺贝特诱导的 ATGL 表达和降血脂作用。我们的结果表明 AMPK 是 ATGL 的上游调节剂。通过免疫荧光测定、染色质免疫沉淀测定和报告基因测定，我们进一步证明了非诺贝特通过刺激 FoxO1 从细胞质向核内易位来发挥作用。此外，口服非诺贝特可改善 db/db 小鼠的体重、内脏脂肪和血清生化指标。综上所述，我们的结果表明，非诺贝特的降脂作用是通过激活 PPARα 和 AMPK 信号通路来实现的，该通路导致 ATGL 表达增加、脂肪分解和脂肪酸β氧化。
