Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
J Lipid Res. 2013 Oct;54(10):2697-707. doi: 10.1194/jlr.M038802. Epub 2013 Aug 7.
Adipose tissue lipogenesis is paradoxically impaired in human obesity, promoting ectopic triglyceride (TG) deposition, lipotoxicity, and insulin resistance. We previously identified mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4), a sterile 20 protein kinase reported to be upstream of c-Jun NH2-terminal kinase (JNK) signaling, as a novel negative regulator of insulin-stimulated glucose transport in adipocytes. Using full-genome microarray analysis we uncovered a novel role for Map4k4 as a suppressor of lipid synthesis. We further report here the surprising finding that Map4k4 suppresses adipocyte lipogenesis independently of JNK. Thus, while Map4k4 silencing in adipocytes enhances the expression of lipogenic enzymes, concomitant with increased conversion of (14)C-glucose and (14)C-acetate into TGs and fatty acids, JNK1 and JNK2 depletion causes the opposite effects. Furthermore, high expression of Map4k4 fails to activate endogenous JNK, while Map4k4 depletion does not attenuate JNK activation by tumor necrosis factor α. Map4k4 silencing in cultured adipocytes elevates both the total protein expression and cleavage of sterol-regulated element binding protein-1 (Srebp-1) in a rapamycin-sensitive manner, consistent with Map4k4 signaling via mechanistic target of rapamycin complex 1 (mTORC1). We show Map4k4 depletion requires Srebp-1 upregulation to increase lipogenesis and further show that Map4k4 promotes AMP-protein kinase (AMPK) signaling and the phosphorylation of mTORC1 binding partner raptor (Ser792) to inhibit mTORC1. Our results indicate that Map4k4 inhibits adipose lipogenesis by suppression of Srebp-1 in an AMPK- and mTOR-dependent but JNK-independent mechanism.
脂肪组织的脂肪生成在人类肥胖中反常地受损，促进异位甘油三酯（TG）沉积、脂毒性和胰岛素抵抗。我们之前鉴定了丝裂原活化蛋白激酶激酶激酶激酶 4（Map4k4），一种报道为 c-Jun N 端激酶（JNK）信号上游的无菌 20 蛋白激酶，是脂肪细胞中胰岛素刺激的葡萄糖转运的新型负调控因子。使用全基因组微阵列分析，我们揭示了 Map4k4 作为脂质合成抑制剂的新作用。我们在此进一步报告了一个令人惊讶的发现，即 Map4k4 独立于 JNK 抑制脂肪细胞的脂肪生成。因此，虽然 Map4k4 在脂肪细胞中的沉默增强了脂肪生成酶的表达，伴随着（14）C-葡萄糖和（14）C-乙酸转化为 TG 和脂肪酸的增加，但 JNK1 和 JNK2 的耗竭会产生相反的效果。此外，Map4k4 的高表达未能激活内源性 JNK，而 Map4k4 的耗竭不会减弱肿瘤坏死因子 α 引起的 JNK 激活。在培养的脂肪细胞中沉默 Map4k4 会以雷帕霉素敏感的方式升高固醇调节元件结合蛋白-1（Srebp-1）的总蛋白表达和切割，这与 Map4k4 通过雷帕霉素靶蛋白复合物 1（mTORC1）信号传递一致。我们表明 Map4k4 的耗竭需要 Srebp-1 的上调以增加脂肪生成，并且进一步表明 Map4k4 促进 AMP-蛋白激酶（AMPK）信号和 mTORC1 结合伴侣 raptor（Ser792）的磷酸化以抑制 mTORC1。我们的结果表明，Map4k4 通过 AMPK 和 mTOR 依赖性但 JNK 独立性机制抑制 Srebp-1 来抑制脂肪组织的脂肪生成。
