Liu Li, Clipstone Neil A
Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois 60611, USA.
J Cell Biochem. 2007 Jan 1;100(1):161-73. doi: 10.1002/jcb.21044.
Prostaglandin F2alpha (PGF2alpha) is a potent physiological inhibitor of adipocyte differentiation, however the specific signaling pathways and molecular mechanisms involved in mediating its anti-adipogenic effects are not well understood. In the current study, we now provide evidence that PGF2alpha inhibits adipocyte differentiation via a signaling pathway that requires heterotrimeric G-protein G alpha q subunits, the elevation of the intracellular calcium concentration ([Ca2+]i), and the activation of the Ca2+/calmodulin-regulated serine/threonine phosphatase calcineurin. We show that while this pathway acts to inhibit an early step in the adipogenic cascade, it does not interfere with the initial mitotic clonal expansion phase of adipogenesis, nor does it affect either the expression, DNA binding activity or differentiation-induced phosphorylation of the early transcription factor C/EBPbeta. Instead, we find that PGF2alpha inhibits adipocyte differentiation via a calcineurin-dependent mechanism that acts to prevent the expression of the critical pro-adipogenic transcription factors PPARgamma and C/EBPalpha. Furthermore, we demonstrate that the inhibitory effects of PGF2alpha on both the expression of PPARgamma and C/EBPalpha and subsequent adipogenesis can be attenuated by treatment of preadipocytes with the histone deacetylase (HDAC) inhibitor trichostatin A. Taken together, these results indicate that PGF2alpha inhibits adipocyte differentiation via a G alpha q-Ca2+-calcineurin-dependent signaling pathway that acts to block expression of PPARgamma and C/EBPalpha by a mechanism that appears to involves an HDAC-sensitive step.
前列腺素F2α（PGF2α）是一种有效的脂肪细胞分化生理抑制剂，然而，介导其抗脂肪生成作用的具体信号通路和分子机制尚未完全清楚。在本研究中，我们现在提供证据表明，PGF2α通过一条需要异源三聚体G蛋白Gαq亚基、细胞内钙浓度（[Ca2+]i）升高以及Ca2+/钙调蛋白调节的丝氨酸/苏氨酸磷酸酶钙调神经磷酸酶激活的信号通路来抑制脂肪细胞分化。我们表明，虽然该通路作用于抑制脂肪生成级联反应的早期步骤，但它不干扰脂肪生成的初始有丝分裂克隆扩增阶段，也不影响早期转录因子C/EBPβ的表达、DNA结合活性或分化诱导的磷酸化。相反，我们发现PGF2α通过一种钙调神经磷酸酶依赖性机制抑制脂肪细胞分化，该机制可防止关键的促脂肪生成转录因子PPARγ和C/EBPα的表达。此外，我们证明，用组蛋白去乙酰化酶（HDAC）抑制剂曲古抑菌素A处理前脂肪细胞，可以减弱PGF2α对PPARγ和C/EBPα表达以及随后脂肪生成的抑制作用。综上所述，这些结果表明，PGF2α通过一条Gαq-Ca2+-钙调神经磷酸酶依赖性信号通路抑制脂肪细胞分化，该通路通过一种似乎涉及HDAC敏感步骤的机制来阻断PPARγ和C/EBPα的表达。
