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Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling 焦磷酸法呢醇酯通过线粒体重塑促进自身免疫中树突状细胞的迁移
IF 20.8 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-18 DOI: 10.1038/s42255-024-01149-x
Xiaomin Zhang, Yali Chen, Geng Sun, Yankang Fei, Ha Zhu, Yanfang Liu, Junyan Dan, Chunzhen Li, Xuetao Cao, Juan Liu

Cellular metabolism modulates dendritic cell (DC) maturation and activation. Migratory dendritic cells (mig-DCs) travelling from the tissues to draining lymph nodes (dLNs) are critical for instructing adaptive immune responses. However, how lipid metabolites influence mig-DCs in autoimmunity remains elusive. Here, we demonstrate that farnesyl pyrophosphate (FPP), an intermediate of the mevalonate pathway, accumulates in mig-DCs derived from mice with systemic lupus erythematosus (SLE). FPP promotes mig-DC survival and germinal centre responses in the dLNs by coordinating protein geranylgeranylation and mitochondrial remodelling. Mechanistically, FPP-dependent RhoA geranylgeranylation promotes mitochondrial fusion and oxidative respiration through mitochondrial RhoA–MFN interaction, which subsequently facilitates the resolution of endoplasmic reticulum stress in mig-DCs. Simvastatin, a chemical inhibitor of the mevalonate pathway, restores mitochondrial function in mig-DCs and ameliorates systemic pathogenesis in SLE mice. Our study reveals a critical role for FPP in dictating mig-DC survival by reprogramming mitochondrial structure and metabolism, providing new insights into the pathogenesis of DC-dependent autoimmune diseases.

细胞代谢可调节树突状细胞(DC)的成熟和活化。从组织到引流淋巴结(dLNs)的迁移树突状细胞(mig-DCs)对于指导适应性免疫反应至关重要。然而,脂质代谢物如何影响自身免疫中的移行树突状细胞仍是个谜。在这里,我们证明了甲羟戊酸途径的中间产物焦磷酸法尼酯(FPP)会在系统性红斑狼疮(SLE)小鼠的mig-DCs中积累。FPP通过协调蛋白的geranylgeranylation和线粒体重塑,促进mig-DC在dLNs中的存活和生殖中心反应。从机理上讲,FPP 依赖的 RhoAeranylgeranylation 可通过线粒体 RhoA-MFN 相互作用促进线粒体融合和氧化呼吸,进而促进 mig-DCs 中内质网应激的解决。辛伐他汀是一种甲羟戊酸通路的化学抑制剂,它能恢复mig-DCs的线粒体功能,并改善系统性红斑狼疮小鼠的全身发病机制。我们的研究揭示了FPP通过重编程线粒体结构和新陈代谢在决定mig-DC存活中的关键作用,为DC依赖性自身免疫性疾病的发病机制提供了新的见解。
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引用次数: 0
Farnesyl pyrophosphate modulates dendritic cell migration in lupus autoimmunity 焦磷酸法呢醇酯调节狼疮自身免疫中树突状细胞的迁移
IF 20.8 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-18 DOI: 10.1038/s42255-024-01148-y
Farnesyl pyrophosphate (FPP), an intermediate of cholesterol biosynthesis in the mevalonate pathway, prolongs the survival of migratory dendritic cells (mig-DCs) by remodelling mitochondrial structure and metabolism. Treating a mouse model of systemic lupus erythematosus with simvastatin (an inhibitor of this pathway) led to recovery from dysregulation in mig-DCs and ameliorated systemic autoimmune pathogenesis.
焦磷酸法尼酯(FPP)是甲羟戊酸途径中胆固醇生物合成的中间体,它通过重塑线粒体结构和新陈代谢来延长移行树突状细胞(mig-DCs)的存活时间。用辛伐他汀(这一途径的抑制剂)治疗系统性红斑狼疮小鼠模型,可恢复迁移树突状细胞的失调,并改善系统性自身免疫发病机制。
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引用次数: 0
Genetic architecture of oral glucose-stimulated insulin release provides biological insights into type 2 diabetes aetiology 口服葡萄糖刺激胰岛素释放的基因结构为 2 型糖尿病病因提供了生物学启示
IF 18.9 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-17 DOI: 10.1038/s42255-024-01140-6
A. L. Madsen, S. Bonàs-Guarch, S. Gheibi, R. Prasad, J. Vangipurapu, V. Ahuja, L. R. Cataldo, O. Dwivedi, G. Hatem, G. Atla, M. Guindo-Martínez, A. M. Jørgensen, A. E. Jonsson, I. Miguel-Escalada, S. Hassan, A. Linneberg, Tarunveer S. Ahluwalia, T. Drivsholm, O. Pedersen, T. I. A. Sørensen, A. Astrup, D. Witte, P. Damm, T. D. Clausen, E. Mathiesen, T. H. Pers, R. J. F. Loos, L. Hakaste, M. Fex, N. Grarup, T. Tuomi, M. Laakso, H. Mulder, J. Ferrer, T. Hansen
The genetics of β-cell function (BCF) offer valuable insights into the aetiology of type 2 diabetes (T2D)1,2. Previous studies have expanded the catalogue of BCF genetic associations through candidate gene studies3–7, large-scale genome-wide association studies (GWAS) of fasting BCF8,9 or functional islet studies on T2D risk variants10–14. Nonetheless, GWAS focused on BCF traits derived from oral glucose tolerance test (OGTT) data have been limited in sample size15,16 and have often overlooked the potential for related traits to capture distinct genetic features of insulin-producing β-cells17,18. We reasoned that investigating the genetic basis of multiple BCF estimates could provide a broader understanding of β-cell physiology. Here, we aggregate GWAS data of eight OGTT-based BCF traits from ~26,000 individuals of European descent, identifying 55 independent genetic associations at 44 loci. By examining the effects of BCF genetic signals on related phenotypes, we uncover diverse disease mechanisms whereby genetic regulation of BCF may influence T2D risk. Integrating BCF-GWAS data with pancreatic islet transcriptomic and epigenomic datasets reveals 92 candidate effector genes. Gene silencing in β-cell models highlights ACSL1 and FAM46C as key regulators of insulin secretion. Overall, our findings yield insights into the biology of insulin release and the molecular processes linking BCF to T2D risk, shedding light on the heterogeneity of T2D pathophysiology. In a genome-wide association study for traits related to pancreatic beta-cell function in 26,000 individuals, 55 independent associations mapping to 44 genetic loci are identified.
β细胞功能(BCF)的遗传学为 2 型糖尿病(T2D)的病因学提供了宝贵的见解1,2。以往的研究通过候选基因研究3,4,5,6,7、空腹 BCF 的大规模全基因组关联研究(GWAS)8,9 或有关 T2D 风险变异的功能性胰岛研究10,11,12,13,14,扩大了 BCF 遗传关联的目录。然而,以口服葡萄糖耐量试验(OGTT)数据得出的 BCF 特质为重点的全基因组关联研究(GWAS)样本量有限15,16,而且往往忽略了相关特质捕捉胰岛素分泌 β 细胞不同遗传特征的潜力17,18。我们认为,研究多个 BCF 估计值的遗传基础可以更广泛地了解 β 细胞生理学。在这里,我们汇总了来自约 26,000 名欧洲后裔的八个基于 OGTT 的 BCF 特质的 GWAS 数据,在 44 个位点上发现了 55 个独立的遗传关联。通过研究 BCF 遗传信号对相关表型的影响,我们发现了 BCF 遗传调控可能影响 T2D 风险的多种疾病机制。将 BCF-GWAS 数据与胰岛转录组和表观基因组数据集整合,发现了 92 个候选效应基因。β细胞模型中的基因沉默突显出 ACSL1 和 FAM46C 是胰岛素分泌的关键调控因子。总之,我们的研究结果深入揭示了胰岛素释放的生物学特性以及将 BCF 与 T2D 风险联系起来的分子过程,揭示了 T2D 病理生理学的异质性。
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引用次数: 0
Genetics brings new insight to β-cell function 遗传学为了解β细胞功能提供了新视角
IF 18.9 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-17 DOI: 10.1038/s42255-024-01131-7
Amélie Bonnefond, Philippe Froguel
A meta-analysis of genome-wide association study for eight traits related to pancreatic β-cell function, based on 26,000 individuals, identified 55 independent association signals mapping to 44 loci. This study highlighted new effectors of β-cell function.
一项针对与胰腺β细胞功能相关的八个性状的全基因组关联研究的荟萃分析以 26,000 个个体为基础,发现了映射到 44 个位点的 55 个独立关联信号。这项研究强调了β细胞功能的新效应因子。
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引用次数: 0
Itaconate modulates mitochondria for antiviral IFN-β 伊塔康酸调节线粒体,促进 IFN-β 的抗病毒作用
IF 20.8 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-15 DOI: 10.1038/s42255-024-01146-0
Thekla Cordes, Karsten Hiller
Itaconate is an immunomodulatory metabolite that influences the outcome of infections and inflammatory diseases. New evidence indicates that itaconate-induced inhibition of succinate dehydrogenase regulates type 1 interferon production via the release of mitochondrial RNA, linking TCA cycle modulation to antiviral interferon responses.
伊塔康酸是一种免疫调节代谢物,可影响感染和炎症性疾病的结果。新证据表明,伊塔康酸诱导的琥珀酸脱氢酶抑制通过线粒体 RNA 的释放调节 1 型干扰素的产生,从而将 TCA 循环调节与抗病毒干扰素反应联系起来。
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引用次数: 0
Cytosolic acetyl-CoA synthesis shields mitochondria from stress in brown adipocytes 细胞膜乙酰-CoA 合成保护线粒体免受棕色脂肪细胞压力的影响
IF 20.8 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-15 DOI: 10.1038/s42255-024-01152-2
Brown adipose tissue (BAT) facilitates thermogenesis through fatty acid oxidation (FAO). Paradoxically, BAT simultaneously increases anabolic fatty acid synthesis (FAS), the reason for which is unclear. We provide evidence that thermogenic mitochondria within brown adipocytes export TCA cycle intermediates that fuel de novo lipid synthesis, in part to protect against metabolic stress.
棕色脂肪组织(BAT)通过脂肪酸氧化(FAO)促进产热。矛盾的是,棕色脂肪组织同时增加了合成代谢脂肪酸(FAS),其原因尚不清楚。我们提供的证据表明,棕色脂肪细胞内的产热线粒体会输出 TCA 循环中间产物,以促进脂质的从头合成,这在一定程度上是为了抵御代谢压力。
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引用次数: 0
Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase 伊塔康酸通过抑制琥珀酸脱氢酶驱动 mtRNA 介导的 I 型干扰素产生
IF 20.8 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-15 DOI: 10.1038/s42255-024-01145-1
Shane M. O’Carroll, Christian G. Peace, Juliana E. Toller-Kawahisa, Yukun Min, Alexander Hooftman, Sara Charki, Louise Kehoe, Maureen J. O’Sullivan, Aline Zoller, Anne F. Mcgettrick, Emily A. Day, Maria Simarro, Neali Armstrong, Justin P. Annes, Luke A. J. O’Neill

Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages and has been shown to have immunomodulatory properties. Here, we show that itaconate promotes type I interferon production through inhibition of succinate dehydrogenase (SDH). Using pharmacological and genetic approaches, we show that SDH inhibition by endogenous or exogenous itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1. In addition, the double-stranded RNA sensors MDA5 and RIG-I are required for IFNβ production in response to SDH inhibition by itaconate. Collectively, our data indicate that inhibition of SDH by itaconate links TCA cycle modulation to type I interferon production through mtRNA release.

伊塔康酸是炎症巨噬细胞中最高调的代谢物之一,已被证明具有免疫调节特性。在这里,我们发现伊塔康酸可通过抑制琥珀酸脱氢酶(SDH)来促进 I 型干扰素的产生。通过药理学和遗传学方法,我们发现内源性或外源性伊它康酸对 SDH 的抑制会导致双链线粒体 RNA(mtRNA)的释放,而这种释放依赖于 VDAC1 形成的线粒体孔。此外,双链 RNA 传感器 MDA5 和 RIG-I 也是 IFNβ 在伊塔康酸对 SDH 的抑制作用下产生的必要条件。总之,我们的数据表明,伊塔康酸对 SDH 的抑制通过 mtRNA 的释放将 TCA 循环调节与 I 型干扰素的产生联系起来。
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引用次数: 0
Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress 棕色脂肪 ATP-柠檬酸裂解酶将碳水化合物的供应与产热联系起来,并抵御代谢压力
IF 20.8 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-14 DOI: 10.1038/s42255-024-01143-3
Ekaterina D. Korobkina, Camila Martinez Calejman, John A. Haley, Miranda E. Kelly, Huawei Li, Maria Gaughan, Qingbo Chen, Hannah L. Pepper, Hafsah Ahmad, Alexander Boucher, Shelagh M. Fluharty, Te-Yueh Lin, Anoushka Lotun, Jessica Peura, Sophie Trefely, Courtney R. Green, Paula Vo, Clay F. Semenkovich, Jason R. Pitarresi, Jessica B. Spinelli, Ozkan Aydemir, Christian M. Metallo, Matthew D. Lynes, Cholsoon Jang, Nathaniel W. Snyder, Kathryn E. Wellen, David A. Guertin

Brown adipose tissue (BAT) engages futile fatty acid synthesis–oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY’s role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis–oxidation paradox in BAT.

棕色脂肪组织(BAT)进行着徒劳的脂肪酸合成-氧化循环,其目的一直难以捉摸。在这里,我们发现,ATP-柠檬酸裂解酶(ACLY)可生成用于脂肪酸合成的乙酰-CoA,并通过减轻代谢压力来促进产热。如果没有 ACLY,BAT 就会使三羧酸循环超负荷,激活综合应激反应(ISR)并抑制产热。当小鼠断奶后食用富含碳水化合物的食物时,ACLY 在防止 BAT 应激方面的作用就变得至关重要,而去除食物中的碳水化合物则可防止 ACLY 缺乏的 BAT 发生应激反应。缺失 ACLY 还能上调脂肪酸合成酶(Fasn);然而,虽然 ISR 激活本身并不是由脂肪酸合成受损引起的,但删除 Fasn 和 Acly 却能开启另一种代谢程序,从而克服三羧酸循环过载、防止 ISR 激活并挽救产热。总之,我们发现了 ACLY 在减轻线粒体压力方面以前未被认识到的作用,这种作用将膳食碳水化合物与解偶联蛋白 1 依赖性产热联系起来,并为了解 BAT 中脂肪酸合成-氧化悖论提供了基本见解。
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引用次数: 0
David H. Wasserman (1958–2024) 戴维-H-瓦瑟曼(1958-2024)
IF 20.8 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-14 DOI: 10.1038/s42255-024-01151-3
Julio E. Ayala, Owen P. McGuinness, Antentor Hinton
We have lost a distinguished scientist who made indelible contributions to our knowledge of exercise physiology and diabetes and was an advocate for mentoring and transparency in research.
我们失去了一位杰出的科学家,他为我们对运动生理学和糖尿病的了解做出了不可磨灭的贡献,他还是指导和研究透明度的倡导者。
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引用次数: 0
Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis 抑制肝脏草酸盐过度生成可改善代谢功能障碍相关性脂肪性肝炎
IF 18.9 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-27 DOI: 10.1038/s42255-024-01134-4
Sandeep Das, Alexandra C. Finney, Sumit Kumar Anand, Sumati Rohilla, Yuhao Liu, Nilesh Pandey, Alia Ghrayeb, Dhananjay Kumar, Kelley Nunez, Zhipeng Liu, Fabio Arias, Ying Zhao, Brenna H. Pearson-Gallion, M. Peyton McKinney, Koral S. E. Richard, Jose A. Gomez-Vidal, Chowdhury S. Abdullah, Elizabeth D. Cockerham, Joseph Eniafe, Andrew D. Yurochko, Tarek Magdy, Christopher B. Pattillo, Christopher G. Kevil, Babak Razani, Md. Shenuarin Bhuiyan, Erin H. Seeley, Gretchen E. Galliano, Bo Wei, Lin Tan, Iqbal Mahmud, Ida Surakka, Minerva T. Garcia-Barrio, Philip L. Lorenzi, Eyal Gottlieb, Eduardo Salido, Jifeng Zhang, A. Wayne Orr, Wanqing Liu, Monica Diaz-Gavilan, Y. Eugene Chen, Nirav Dhanesha, Paul T. Thevenot, Ari J. Cohen, Arif Yurdagul Jr, Oren Rom
The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C–C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid β-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-β targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH. Genetic and pharmacological inhibition of the overproduction of oxalate in the liver alleviates metabolic dysfunction-associated steatohepatitis in male mice.
代谢功能障碍相关性脂肪性肝炎(MASH)的发病率呈上升趋势,由于药物治疗效果有限,因此迫切需要确定新的代谢靶点。草酸盐是肝脏乳酸脱氢酶(LDHA)从乙醛酸生成的终末代谢产物。肝脏特异性丙氨酸-乙醛酸氨基转移酶(AGXT)能对乙醛酸进行解毒,防止草酸盐的积累。在这里,我们发现在 MASH 患者和小鼠的肝脏中,AGXT 被抑制,LDHA 被激活,导致草酸盐过度生成。反过来,草酸盐通过抑制过氧化物酶体增殖激活受体-α(PPARα)转录和脂肪酸β氧化,促进肝细胞脂肪变性,并通过 C-C motif 趋化因子配体 2 诱导单核细胞趋化。在饮食诱导的雄性 MASH 小鼠中,通过肝细胞特异性 AGXT 过表达或药物抑制 LDHA 来靶向草酸盐过量产生,可通过诱导 PPARα 驱动的脂肪酸 β 氧化和抑制单核细胞趋化、核因子-κB 和转化生长因子-β 靶点,有效减轻脂肪性肝炎和纤维化。这些研究结果突出表明,肝脏草酸盐过度分泌是治疗 MASH 的一个靶点。
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引用次数: 0
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Nature metabolism
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