Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, China.
Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China.
Comp Biochem Physiol B Biochem Mol Biol. 2024 Jan;269:110894. doi: 10.1016/j.cbpb.2023.110894. Epub 2023 Aug 18.
Metabolic stress induces lipophagy, a crucial process in lipid catabolism, which is under the regulation of autophagy involving transcription factor EB (TFEB). However, the precise mechanisms underlying TFEB's control remain enigmatic. In this study, we focused on yellow catfish (Pelteobagrus fulvidraco) as the model to investigate lipophagy activation under high glucose-induced lipid deposition. We hypothesized that lipophagy mediates high glucose-induced lipid deposition and proposed the involvement of the SIRT1-NRF2-TFEB pathway in the activation of lipophagy. We found that there was a functional antioxidative responsive element (ARE) on the tfeb gene promoter; high glucose (HG) increased the nuclear translocation of nuclear factor E2-related factor 2 (NRF2) recruitment to the tfeb promoter; TFEB, whose expression is regulated by NRF2, mediated the HG-induced activation of lipophagy and lipolysis. Moreover, we found that HG increased the silencing information regulator 2 related enzymes 1 (SIRT1) expression, and that the SIRT1 mediates NRF2 translocation to the nucleus, increased TFEB expression and activated autophagy. In the glucose tolerance test, blood glucose increased rapidly and plateaued at 4-h glucose after injection and then declined until 48-h post-injection. Generally speaking, the transcript level and protein expression of SIRT1, NRF2, TFEB, microtubule-associated proteins 1A/1B light chain 3B (LC3B), and autophagy-related 6 (Beclin1) showed similar trend after glucose injection, and trends to increase and plateau at 4-h injection, then decline until 16-h post-injection, and finally increased until 48-h post-injection. These results indicated that the SIRT1-NRF2-TFEB axis-mediated lipophagy may be an adaptive response to glucose injection. Collectively, for the first time, we found that NRF2 was associated directly with TFEB-mediated transcriptional control of hepatic lipophagy, and that lipophagy helps to alleviate the HG-induced lipid deposition via SIRT1-NRF2-TFEB activation in yellow catfish.
代谢应激诱导脂噬作用，这是脂质分解代谢的关键过程，受自噬调节，涉及转录因子 EB（TFEB）。然而，TFEB 控制的精确机制仍然神秘。在这项研究中，我们以黄颡鱼（Pelteobagrus fulvidraco）为模型，研究高糖诱导脂质沉积下的脂噬作用激活。我们假设脂噬作用介导高糖诱导的脂质沉积，并提出 SIRT1-NRF2-TFEB 途径参与脂噬作用的激活。我们发现 tfeb 基因启动子上存在功能性抗氧化反应元件（ARE）；高葡萄糖（HG）增加核因子 E2 相关因子 2（NRF2）募集到 tfeb 启动子的核易位；TFEB 的表达受 NRF2 调节，介导 HG 诱导的脂噬作用和脂解作用的激活。此外，我们发现 HG 增加了沉默信息调节酶 2 相关酶 1（SIRT1）的表达，SIRT1 介导 NRF2 向核易位，增加 TFEB 表达并激活自噬。在葡萄糖耐量试验中，注射后 4 小时血糖迅速升高并达到平台，然后在 48 小时后下降。一般来说，SIRT1、NRF2、TFEB、微管相关蛋白 1A/1B 轻链 3B（LC3B）和自噬相关 6（Beclin1）的转录水平和蛋白表达在葡萄糖注射后呈现相似的趋势，在 4 小时注射时呈上升和平台趋势，然后在 16 小时后下降，最后在 48 小时后上升。这些结果表明，SIRT1-NRF2-TFEB 轴介导的脂噬作用可能是对葡萄糖注射的一种适应性反应。总的来说，我们首次发现 NRF2 直接与 TFEB 介导的肝脂噬作用的转录控制相关，脂噬作用通过 SIRT1-NRF2-TFEB 的激活有助于缓解黄颡鱼中 HG 诱导的脂质沉积。
