DEPP/DEPP1/C10ORF10 部分通过 ROS 诱导的 FGF21 调节肝脏葡萄糖和脂肪代谢,The FASEB Journal

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DEPP/DEPP1/C10ORF10 部分通过 ROS 诱导的 FGF21 调节肝脏葡萄糖和脂肪代谢
The FASEB Journal ( IF 4.4 ) Pub Date : 2018-04-27 , DOI: 10.1096/fj.201800357r
Wenli Li ₁ , Meiling Ji ₁ , Yandie Lin ₁ , Yi Miao ₁ , Simin Chen ₁ , Hao Li ₁

Affiliation

黄体酮诱导的蜕膜蛋白 (DEPP/DEPP1/C10ORF10) 是通过拒绝获得食物而诱导的，并通过在体内胰岛素敏感器官中重新喂养而减少。胰岛素对 DEPP 的负调节也在几种细胞系中得到证实。然而，DEPP在胰岛素敏感器官中的功能仍然未知。在本研究中，我们研究了 DEPP 对肝脏能量代谢的影响并探讨了其潜在机制。在腺病毒介导的肝脏过表达小鼠中研究了 DEPP 的代谢作用。通过生化分析检测肝甘油三酯 (TG)、糖原和血清代谢物。通过间接量热法测量能量稳态。定量 PCR 用于检测参与脂肪酸氧化、生酮、脂肪生成和糖异生的基因的表达。为了评估成纤维细胞生长因子 21 (FGF21) 在介导 DEPP 代谢作用中的作用，在腺病毒递送后 24 小时将 FGF21 抗体腹膜内给药于小鼠，并检查代谢改变。通过过氧化氢酶活性测定、活细胞荧光或定量 PCR 测量活性氧 (ROS) 水平。还评估了 DEPP 对 db/db 小鼠表型的影响。DEPP 的急性肝脏过表达显着降低了血清葡萄糖和 TG 水平，显着升高了 β-羟基丁酸水平，并改善了葡萄糖清除率。与对照组相比，DEPP 过表达减少了食物摄入量、能量消耗率和呼吸商。DEPP 过表达显着增加了脂肪酸氧化和生酮，但抑制了脂质合成和糖新生。对潜在机制的研究表明，DEPP 通过诱导氧化应激来调节能量代谢。随着ROS清除系统的受损和ROS形成的促进，DEPP过表达导致ROS积累。FGF21 响应氧化应激而上调，并介导 DEPP 对脂肪酸氧化、生酮和脂质合成的影响，但不影响糖异生，事实证明 FGF21 抗体显着抑制了 DEPP 诱导的脂肪酸氧化和酮的增加‐ genesis，逆转了脂质合成的减少，但没有改变对糖异生的抑制。而且，DEPP 在 db/db 小鼠中的过度表达导致体重和血清葡萄糖水平显着降低，并显着改善胰岛素敏感性。小鼠肝脏中 DEPP 的过度表达促进脂肪酸氧化和酮生成，并抑制脂肪生成和糖异生，这部分是由细胞 ROS 水平升高诱导的 FGF21 介导的。 - Li, W., Ji, M., Lin, Y., Miao, Y ., Chen, S., Li, H. DEPP/DEPP1/C10ORF10 部分通过 ROS 诱导的 FGF21 调节肝脏葡萄糖和脂肪代谢。FASEB J. 32, 5459–5469 (2018)。www.fasebj.org Ji, M., Lin, Y., Miao, Y., Chen, S., Li, H. DEPP/DEPP1/C10ORF10 通过 ROS 诱导的 FGF21 部分调节肝脏葡萄糖和脂肪代谢。FASEB J. 32, 5459–5469 (2018)。www.fasebj.org Ji, M., Lin, Y., Miao, Y., Chen, S., Li, H. DEPP/DEPP1/C10ORF10 通过 ROS 诱导的 FGF21 部分调节肝脏葡萄糖和脂肪代谢。FASEB J. 32, 5459–5469 (2018)。www.fasebj.org

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DEPP/DEPP1/C10ORF10 regulates hepatic glucose and fat metabolism partly via ROS-induced FGF21

Decidual protein induced by progesterone (DEPP/DEPP1/C10ORF10) is induced by denying access to food and reduced by refeeding in insulin‐sensitive organs in vivo. The negative regulation of DEPP by insulin is also proven in several cell lines. However, the functions of DEPP in insulin‐sensitive organs remain unknown. In the present study, we investigated the impact of DEPP on hepatic energy metabolism and addressed the underlying mechanisms. The metabolic effects of DEPP were investigated in mice with adenovirus‐mediated hepatic overexpression. Liver triglyceride (TG), glycogen, and serum metabolites were detected by biochemical assays. Energy homeostasis was measured by indirect calorimetry. Quantitative PCR was used to examine expression of genes involved in fatty acid oxidation, ketogenesis, lipogenesis, and gluconeogenesis. To evaluate the role of fibroblast growth factor 21 (FGF21) mediating the metabolic effects of DEPP, FGF21 antibody was administrated intraperitoneally to mice at 24 h after the delivery of adenovirus, and the metabolic alterations were examined. Reactive oxygen species (ROS) levels were measured by catalase activity assay, live cell fluorescence, or quantitative PCR. Effects of DEPP on the phenotype of db/db mice were also assessed. Acute hepatic overexpression of DEPP significantly reduced serum glucose and TG levels, dramatically elevated β‐hydroxybutyrate levels, and improved glucose clearance. Compared with controls, DEPP overexpression reduced food intake, the energy expenditure rate, and the respiratory quotient. DEPP overexpression significantly increased fatty acid oxidation and ketogenesis but suppressed lipid synthesis and gluco‐ neogenesis. Investigations of the underlying mechanisms revealed that DEPP regulates energy metabolism by inducing oxidative stress. With the impairment of the ROS scavenging system and promotion of ROS formation, DEPP overexpression leads to ROS accumulation. FGF21 is upregulated in response to oxidative stress and mediates the effects of DEPP on fatty acid oxidation, ketogenesis, and lipid synthesis but not gluconeogenesis, as evidenced by the fact that the FGF21 antibody dramatically suppressed a DEPP‐induced increase of fatty acid oxidation and keto‐ genesis, reversed the reduction of lipid synthesis, but did not change the suppression of gluconeogenesis. Moreover, overexpression of DEPP in db/db mice led to a marked reduction in body weight and serum glucose levels and significantly improved insulin sensitivity. Hepatic overexpression of DEPP in mice promotes fatty acid oxidation and ketogenesis and suppresses lipogenesis and gluconeogenesis, which is partly mediated by FGF21 induced by elevated cellular ROS levels.—Li, W., Ji, M., Lin, Y., Miao, Y., Chen, S., Li, H. DEPP/DEPP1/C10ORF10 regulates hepatic glucose and fat metabolism partly via ROS‐induced FGF21. FASEB J. 32, 5459–5469 (2018). www.fasebj.org

更新日期：2018-04-27

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