博文
Nature Metabolism 10月刊代谢精选
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撰文 | 刘梓棋 张婷 郑宇含 王佳雯 李雨
编辑 | 孟美瑶
校对 | 张彦康
万圣节来临
宠物们也来凑凑热闹
不给糖就捣蛋！
近期Nature Metabolism研究发现
肝星状细胞(HSCs)又来“捣蛋”了
在肝脏纤维化过程中
TGF-β诱导HSCs中己糖激酶(HK1)
通过细胞外囊泡外泌到肝癌细胞
被其利用增强自身糖酵解促进增殖
Nature Metabolism
1、肝星状细胞来源的胞外囊泡中的HK1促进肝细胞癌的进展
肝癌隐藏帮凶—胞外囊泡中的HK1!
中文摘要
拓展阅读
细胞外囊泡（EVs）在代谢与肿瘤crosstalk中的功能
细胞外囊泡（EVs）根据囊泡直径大小可分为胞外小囊泡（sEVs，直径小于200nm）和胞外大囊泡（lEVs，直径大于200nm）。研究表明EV对于HCC恶性肿瘤的发生发展是至关重要的，并可作为早期HCC诊断的生物标志。近期研究发现HCC细胞分泌的包含PKM2的lEVs可促进单核细胞的葡萄糖代谢以及细胞核中STAT3的磷酸化修饰，从而上调与细胞分化相关的转录因子活性，导致单核细胞向巨噬细胞分化，重构肿瘤微环境，加剧HCC的发生发展。此外，也有研究发现由HCC分泌的EVs中含有致癌性microRNAs，可HSCs转化为致癌性HSCs，进而加剧HCC的发生发展。在本篇文章中，研究人员发现在肝纤维化进程中，TGF-β促进HSCs分泌包含HK1的lEVs，lEVs中的HK1被HCC摄取后，促进HCC中糖酵解过程，从而加剧HCC的发展。
HK1 from hepatic stellate cell–derived extracellular vesicles promotes progression of hepatocellular carcinoma 一作：Qi-tao Chen PI：Qiao Wu 发表单位：State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China Extracellular vesicles play crucial roles in intercellular communication in the tumor microenvironment. Here we demonstrate that in hepatic fibrosis, TGF-β stimulates the palmitoylation of hexokinase 1 (HK1) in hepatic stellate cells (HSCs), which facilitates the secretion of HK1 via large extracellular vesicles in a TSG101-dependent manner. The large extracellular vesicle HK1 is hijacked by hepatocellular carcinoma (HCC) cells, leading to accelerated glycolysis and HCC progression. In HSCs, the nuclear receptor Nur77 transcriptionally activates the expression of depalmitoylase ABHD17B to inhibit HK1 palmitoylation, consequently attenuating HK1 release. However, TGF-β-activated Akt functionally represses Nur77 by inducing Nur77 phosphorylation and degradation. We identify the small molecule PDNPA that binds Nur77 to generate steric hindrance to block Akt targeting, thereby disrupting Akt-mediated Nur77 degradation and preserving Nur77 inhibition of HK1 release. Together, this study demonstrates an overlooked function of HK1 in HCC upon its release from HSCs and highlights PDNPA as a candidate compound for inhibiting HCC progression. 原文链接：https://www.nature.com/articles/s42255-022-00642-5 看似花哨的手机外壳 其实每款设计的存在 都有其独特的功能 根据脂肪组织半胱氨酸双加氧酶1(Cdo1)
受到寒冷诱导上调这一现象
研究人员深入探究其独特功能
在Nature Metabolism发表研究揭示
Cdo1能够通过非酶作用
促进PPARγ/Med24/lipolysis信号通路
转录激活脂解基因ATGL和HSL的表达
进一步抵抗小鼠肥胖及代谢紊乱
Nature Metabolism
抵御肥胖新帮手—Cdo1帮你促进脂肪分解！
中文摘要
半胱氨酸双加氧酶1 (Cdo1)是牛磺酸合成的关键酶。本文中，研究人员发现Cdo1促进脂肪组织的脂解作用。且脂肪特异性敲除Cdo1后可降低小鼠的能量消耗、冷耐受和脂解作用，从而加剧饮食诱导肥胖(DIO)；此外，脂肪组织Cdo1的缺失也可抑制脂肪细胞中脂解相关基因如ATGL和HSL的表达，但并不影响牛磺酸水平。而在脂肪组织中特异性过表达ATGL和HSL可缓解由脂肪敲除Cdo1所引起的DIO。机制上，Cdo1可与PPAR-γ相互作用，促进中介复合体（mediator complex）的核心亚基Med24募集到ATGL和HSL基因启动子上，从而激活ATGL和HSL的表达。此外，在脂肪组织中过表达Cdo1可提高小鼠的冷耐受能力，缓解肥胖，并增强脂解作用。总之，本研究揭示了Cdo1调控脂解作用中发挥着重要作用。
拓展阅读
脂解对机体能量代谢的影响
Cdo1 promotes PPARγ-mediated adipose tissue lipolysis in male mice
一作：Ying-Ying Guo PI：Qi-Qun Tang
发表单位：Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China
Cysteine dioxygenase 1 (Cdo1) is a key enzyme in taurine synthesis. Here we show that Cdo1 promotes lipolysis in adipose tissue. Adipose-specific knockout of Cdo1 in mice impairs energy expenditure, cold tolerance and lipolysis, exacerbates diet-induced obesity (DIO) and decreases adipose expression of the key lipolytic genes encoding ATGL and HSL, with little effect on adipose taurine levels. White-adipose-specific overexpression of ATGL and HSL blunts the role of adipose Cdo1 deficiency in promoting DIO. Mechanistically, Cdo1 interacts with PPARγ and facilitates the recruitment of Med24, the core subunit of mediator complex, to ATGL and HSL gene promoters, thereby transactivating their expression. Further, mice with transgenic overexpression of Cdo1 show better cold tolerance, ameliorated DIO and higher lipolysis capacity. Thus, we uncover an unexpected and important role of Cdo1 in regulating adipose lipolysis.
原文链接：https://www.nature.com/articles/s42255-022-00644-3
喵星人只会卖萌？
只要你会开发
你就会拥有一只多功能猫
AMPK激动剂依旧功能多多
近期Nature Metabolism研究找到
新型AMPK激活剂——Aldometanib
不仅能够促进代谢健康、减轻肥胖
还能延长寿命和健康寿命，延缓衰老
3、醛缩酶抑制剂aldometanib可模拟葡萄糖饥饿过程来激活溶酶体AMPK
维持能量平衡，AMPK立大功！
中文摘要
拓展阅读
AMPK在能量代谢中的作用机制
当胞质中的能量受到限制时，溶酶体中的AMPK会通过AXIN/LKB1-AMPK轴的调控，其中AMPK的Thr172会被LKB1（肝激酶B1，一种丝氨酸/苏氨酸激酶）磷酸化从而被激活。AMPK被激活后，就会直接磷酸化下游的多个靶点例如乙酰-CoA羧化酶，SREBP-1蛋白等来抑制细胞内的合成代谢作用，促进分解代谢作用，从而减少ATP的消耗，增加ATP的产生，达到一个能量代谢的平衡。例如，AMPK可以在细胞处于葡萄糖饥饿/能量缺乏状态下使乙酰-CoA羧化酶（脂肪酸合成的限速酶）磷酸化，从而抑制乙酰-CoA羧化酶活性，进而抑制脂肪酸的合成过程，促进脂肪酸氧化过程，维持细胞的能量供应；此外也有研究发现在肝脏中，AMPK可通过磷酸化转录因子SREBP-1的Ser372位点，从而抑制SREBP-1的核转运，使得SREBP-1调控的脂肪酸合成相关基因转录减少，在转录水平抑制脂肪酸的合成，进而改善肝脏中脂质积累现象。本篇文章中，研究人员通过使用aldometanib抑制FBP和醛缩酶结合，从而激活AMPK活性，改善小鼠血糖稳态和脂肪肝现象，并延长小鼠寿命。
The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK
一作：Chen-Song Zhang PI：Sheng-Cai Lin
发表单位：State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Fujian, China
The activity of 5′-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. Here, we show that blocking FBP binding to aldolase with the small molecule aldometanib selectively activates the lysosomal pool of AMPK and has beneficial metabolic effects in rodents. We identify aldometanib in a screen for aldolase inhibitors and show that it prevents FBP from binding to v-ATPase-associated aldolase and activates lysosomal AMPK, thereby mimicking a cellular state of glucose starvation. In male mice, aldometanib elicits an insulin-independent glucose-lowering effect, without causing hypoglycaemia. Aldometanib also alleviates fatty liver and nonalcoholic steatohepatitis in obese male rodents. Moreover, aldometanib extends lifespan and healthspan in both Caenorhabditis elegans and mice. Taken together, aldometanib mimics and adopts the lysosomal AMPK activation pathway associated with glucose starvation to exert physiological roles, and might have potential as a therapeutic for metabolic disorders in humans.
原文链接：https://www.nature.com/articles/s42255-022-00640-7
https://m.sciencenet.cn/blog-3483272-1363507.html
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