Lipolysis Response to Endoplasmic Reticulum Stress in Adipose Cells
Lipolysis Response to Endoplasmic Reticulum Stress in Adipose Cells
复制标题
脂肪细胞内质网应激的脂解反应
DOI：
10.1074/jbc.m111.299115
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发表时间：
2012-02-24
影响因子：
4.8
通讯作者：
Xu, Guoheng
中科院分区：
文献类型：
--
作者：
Deng, Jingna;Liu, Shangxin;Xu, Guoheng
在肥胖和糖尿病中，脂肪细胞表现出显著的内质网（ER）应激，从而引发一系列反应。本研究旨在探讨内质网应激对大鼠脂肪细胞脂解的影响。Thapsigargin、tunicamycin和brefeldin A通过不同途径诱导内质网应激，有效地激活了时间依赖性的脂溶反应。内质网应激的溶脂作用伴随着cAMP的产生和蛋白激酶A （PKA）活性的升高。抑制PKA可减少PKA磷酸化底物并减弱脂解。虽然ERK1/2和JNK在内质网应激时都被激活，但通过抑制ERK1/2而不是JNK和p38 MAPK和PKC来部分抑制脂肪分解。因此，内质网应激通过激活cAMP/PKA和ERK1/2诱导脂肪分解。在下游的脂溶级联中，脂滴相关蛋白perilipin的磷酸化在内质网应激下显著增强，但在PKA抑制下减弱。此外，内质网应激刺激不会改变激素敏感脂肪酶和脂肪甘油三酯脂肪酶的水平，但会导致激素敏感脂肪酶的Ser-563和Ser-660磷酸化，并适度提高其从细胞质溶胶到脂滴的易位。随着这些变化，细胞脂肪酶的总活性被提高，导致脂肪分解。这些发现提示了脂肪细胞对内质网应激的脂解反应的新途径。这种脂溶激活可能是调节能量稳态的适应性反应，但持续的内质网应激挑战可能导致脂肪毒性、血脂异常和胰岛素抵抗，因为脂肪细胞向血液和其他组织的游离脂肪酸外流持续加速。
In obesity and diabetes, adipocytes show significant endoplasmic reticulum (ER) stress, which triggers a series of responses. This study aimed to investigate the lipolysis response to ER stress in rat adipocytes. Thapsigargin, tunicamycin, and brefeldin A, which induce ER stress through different pathways, efficiently activated a time-dependent lipolytic reaction. The lipolytic effect of ER stress occurred with elevated cAMP production and protein kinase A (PKA) activity. Inhibition of PKA reduced PKA phosphosubstrates and attenuated the lipolysis. Although both ERK1/2 and JNK are activated during ER stress, lipolysis is partially suppressed by inhibiting ERK1/2 but not JNK and p38 MAPK and PKC. Thus, ER stress induces lipolysis by activating cAMP/PKA and ERK1/2. In the downstream lipolytic cascade, phosphorylation of lipid droplet-associated protein perilipin was significantly promoted during ER stress but attenuated on PKA inhibition. Furthermore, ER stress stimuli did not alter the levels of hormone-sensitive lipase and adipose triglyceride lipase but caused Ser-563 and Ser-660 phosphorylation of hormone-sensitive lipase and moderately elevated its translocation from the cytosol to lipid droplets. Accompanying these changes, total activity of cellular lipases was promoted to confer the lipolysis. These findings suggest a novel pathway of the lipolysis response to ER stress in adipocytes. This lipolytic activation may be an adaptive response that regulates energy homeostasis but with sustained ER stress challenge could contribute to lipotoxicity, dyslipidemia, and insulin resistance because of persistently accelerated free fatty acid efflux from adipocytes to the bloodstream and other tissues.