TAK1 regulates hepatic lipid homeostasis through SREBP.
TAK1 regulates hepatic lipid homeostasis through SREBP.
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DOI：
10.1038/onc.2015.453
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发表时间：
2016-07-21
期刊：
影响因子：
8
通讯作者：
Ninomiya-Tsuji J
中科院分区：
文献类型：
--
作者：
Morioka S;Sai K;Omori E;Ikeda Y;Matsumoto K;Ninomiya-Tsuji J
甾醇调节元件结合蛋白（SREBPs）是调节胆固醇和脂肪酸生物合成的关键转录因子。SREBP活性受到严格调控以维持脂质稳态，并受细胞外刺激（如生长因子）的调节。虽然稳态SREBP调控已经得到了很好的研究，但刺激依赖性调控机制仍然难以捉摸。在这里，我们证明SREBPs通过TGF-β活化激酶1 (TAK1)，一种炎症信号分子，受到一种以前未被表征的机制的调节。我们发现TAK1结合并抑制成熟形式的srebp。在体内环境中，肝细胞特异性Tak1缺失在小鼠模型中上调肝脏脂质沉积和脂质生成酶。此外，肝脏Tak1缺乏导致脂肪变性病理，包括血液甘油三酯和胆固醇水平升高，这是肝细胞癌（HCC）发展的既定危险因素，并且确实与Tak1缺乏诱导的HCC发展相关。药理抑制SREBPs可减轻脂肪变性，降低tak1缺陷肝脏中HCC标志物基因的表达水平。因此，TAK1调控SREBP对维持肝脏稳态以防止脂肪变性至关重要，这是预防HCC发展的潜在重要机制。
Sterol regulatory element-binding proteins (SREBPs) are key transcription factors regulating cholesterol and fatty acid biosynthesis. SREBP activity is tightly regulated to maintain lipid homeostasis, and is modulated upon extracellular stimuli such as growth factors. While the homeostatic SREBP regulation is well studied, stimuli-dependent regulatory mechanisms are still elusive. Here we demonstrate that SREBPs are regulated by a previously uncharacterized mechanism through TGF-β activated kinase 1 (TAK1), a signaling molecule of inflammation. We found that TAK1 binds to and inhibits mature forms of SREBPs. In an in vivo setting, hepatocyte-specific Tak1 deletion upregulates liver lipid deposition and lipogenic enzymes in the mouse model. Furthermore, hepatic Tak1 deficiency causes steatosis pathologies including elevated blood triglyceride and cholesterol levels, which are established risk factors for the development of hepatocellular carcinoma (HCC) and are indeed correlated with Tak1-deficiency-induced HCC development. Pharmacological inhibition of SREBPs alleviated the steatosis and reduced the expression level of the HCC marker gene in the Tak1-deficient liver. Thus, TAK1 regulation of SREBP critically contributes to the maintenance of liver homeostasis to prevent steatosis, which is a potentially important mechanism to prevent HCC development.