Berberine attenuates cAMP-induced lipolysis via reducing the inhibition of phosphodiesterase in 3T3-L1 adipocytes
Berberine attenuates cAMP-induced lipolysis via reducing the inhibition of phosphodiesterase in 3T3-L1 adipocytes
复制标题
小檗碱通过减少 3T3-L1 脂肪细胞中磷酸二酯酶的抑制来减弱 cAMP 诱导的脂肪分解
DOI：
10.1016/j.bbadis.2010.10.001
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发表时间：
2011-04-01
影响因子：
6.2
通讯作者：
Ning, Guang
中科院分区：
文献类型：
--
作者：
Zhou, Libin;Wang, Xiao;Ning, Guang
小檗碱是一种降血糖药，已被证明可以降低胰岛素抵抗大鼠的血浆游离脂肪酸 (FFA) 水平。在本研究中，我们探讨了小檗碱在 3T3-L1 脂肪细胞中抗脂肪分解作用的机制。结果表明，小檗碱可减弱儿茶酚胺、cAMP 升高剂和可水解 cAMP 类似物诱导的脂肪分解，但不能减弱肿瘤坏死因子 a 和不可水解 cAMP 类似物诱导的脂肪分解。与胰岛素不同，小檗碱对异丙肾上腺素响应的脂肪分解的抑制作用不会被磷脂酰肌醇3-激酶抑制剂渥曼青霉素消除，而是与细胞外信号调节激酶激酶抑制剂PD98059相加。脂肪细胞预先暴露于小檗碱可降低由异丙肾上腺素、毛喉素和 3-异丁基-1-甲基黄嘌呤 (IBMX) 以及激素敏感性脂肪酶 (HSL) Ser-563 和 Ser-660 去磷酸化诱导的细胞内 cAMP 产生，但对周脂蛋白磷酸化没有影响。小檗碱刺激 HSL Ser-565 以及单磷酸腺苷激活蛋白激酶 (AMPK) 磷酸化。然而，AMPK抑制剂化合物C并没有逆转小檗碱对HSL Ser-563、Ser-660和Ser-565磷酸化的调节作用，也没有逆转小檗碱的抗脂肪分解作用。使用 RNA 干扰敲除 AMPK 也未能恢复小檗碱抑制的脂肪分解。 cAMP 升高剂可增加 AMPK 活性，这不会与小檗碱的活性相加。用小檗碱刺激脂肪细胞会增加通过 (3)[H]cAMP 水解测量的磷酸二酯酶 (PDE) 3B 和 PDE4 活性。这些结果表明，小檗碱主要通过减少PDE的抑制来发挥抗脂解作用，导致cAMP和HSL磷酸化的减少，不依赖于AMPK途径。 (C) 2010 Elsevier B.V. 保留所有权利。
Berberine, a hypoglycemic agent, has been shown to decrease plasma free fatty acids (FFAs) level in insulinresistant rats. In the present study, we explored the mechanism responsible for the antilipolytic effect of berberine in 3T3-L1 adipocytes. It was shown that berberine attenuated lipolysis induced by catecholamines, cAMP-raising agents, and a hydrolyzable cAMP analog, but not by tumor necrosis factor a and a nonhydrolyzable cAMP analog. Unlike insulin, the inhibitory effect of berberine on lipolysis in response to isoproterenol was not abrogated by wortmannin, an inhibitor of phosphatidylinositol 3-kinase, but additive to that of PD98059, an extracellular signal-regulated kinase kinase inhibitor. Prior exposure of adipocytes to berberine decreased the intracellular cAMP production induced by isoproterenol, forskolin, and 3-isobutyl-1-methylxanthine (IBMX), along with hormone-sensitive lipase (HSL) Ser-563 and Ser-660 dephosphorylation, but had no effect on perilipin phosphorylation. Berberine stimulated HSL Ser-565 as well as adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. However, compound C, an AMPK inhibitor, did not reverse the regulatory effect of berberine on HSL Ser-563, Ser-660, and Ser-565 phosphorylation, nor the antilipolytic effect of berberine. Knockdown of AMPK using RNA interference also failed to restore berberine-suppressed lipolysis. cAMP-raising agents increased AMPK activity, which was not additive to that of berberine. Stimulation of adipocytes with berberine increased phosphodiesterase (PDE) 3B and PDE4 activity measured by hydrolysis of (3)[H]cAMP. These results suggest that berberine exerts an antilipolytic effect mainly by reducing the inhibition of PDE, leading to a decrease in cAMP and HSL phosphorylation independent of AMPK pathway. (C) 2010 Elsevier B.V. All rights reserved.