Biochimica et biophysica acta. Molecular and cell biology of lipids最新文献_第7页

Control of ALOX5 expression in monocytic cells using a synthetic riboswitch 利用合成核糖开关控制ALOX5在单核细胞中的表达

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-25 DOI: 10.1016/j.bbalip.2025.159671

Robin W. Bruckhoff , Julia H. Oberlis , Dieter Steinhilber , Beatrix Suess

The human 5-lipoxygenase (5-LOX), which is encoded by the arachidonate 5-lipoxygenase (ALOX5) gene, has its canonical function in leukotriene (LT) biosynthesis, which controls inflammatory and allergic responses. Besides oxylipin formation from polyunsaturated fatty acids, 5-LOX has several noncanonical functions. It acts as transcriptional regulator in the nucleus but also interacts with Dicer and modulates microRNA expression and processing.

In this study, we employed a tetracycline riboswitch-controlled cassette-exon system to conditionally control ALOX5 expression in the monocytic leukemic cell line MonoMac6. Synthetic riboswitches are gaining increasing interest as a means of controlling transgene expression, with applications in functional genomics and potential therapeutic strategies. We designed an artificial ALOX5 gene that contains two cassette exons with premature termination codons (PTCs), thus only being expressed when both synthetic exons are skipped. The switchable ALOX5 gene was transduced into MonoMac6 5-LOX knock-out (KO) cells, thereby enabling the tetracycline-dependent re-expression of 5-LOX proteins. The newly established cell line was characterized in terms of tetracycline dose dependency and switching kinetics. Induction of ALOX5 exerted the non-canonical 5-LOX effects on prostaglandin-endoperoxide synthase 2 (PTGS2) and L-kynureninase (KYNU) gene expression. This allowed us to demonstrate the outstanding advantages of a riboswitch-controlled system in terms of time dependency and gene function. The novel MonoMac6 cell line now provides a perfect tool for further research into the non-canonical functions of 5-LOX.

人5-脂氧合酶（5-LOX）由花生四烯酸5-脂氧合酶（ALOX5）基因编码，在白三烯（LT）生物合成中具有典型功能，控制炎症和过敏反应。除了由多不饱和脂肪酸生成氧脂外，5-LOX还具有几种非规范功能。它在细胞核中作为转录调节剂，但也与Dicer相互作用并调节microRNA的表达和加工。在本研究中，我们采用四环素核素开关控制的盒式外显子系统来有条件地控制ALOX5在单核白血病细胞系MonoMac6中的表达。合成核糖开关作为一种控制转基因表达的手段，在功能基因组学和潜在的治疗策略中得到了越来越多的应用。我们设计了一个人工ALOX5基因，它包含两个带过早终止密码子（ptc）的盒式外显子，因此只有当两个合成外显子都被跳过时才表达。可切换的ALOX5基因被转导到MonoMac6 5-LOX敲除（KO）细胞中，从而使5-LOX蛋白的四环素依赖性重新表达。新建立的细胞系在四环素剂量依赖性和切换动力学方面进行了表征。ALOX5的诱导对前列腺素内过氧化物合成酶2 （PTGS2）和l -尿尿酶（KYNU）基因表达产生非规范5-LOX效应。这使我们能够证明核糖体开关控制系统在时间依赖性和基因功能方面的突出优势。新的MonoMac6细胞系现在为进一步研究5-LOX的非规范功能提供了一个完美的工具。

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引用次数: 0

Polyunsaturated fatty acids in kidney diseases: Navigating the fine line between healing and damage 多不饱和脂肪酸在肾脏疾病中：在愈合和损害之间的细线上导航。

IF 3.3 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-23 DOI: 10.1016/j.bbalip.2025.159668

Mehrdad Aghasizadeh , Ahmad Reza Bahrami , Maryam M. Matin

Polyunsaturated fatty acids (PUFAs) regulate renal inflammation through metabolites generated by COX, LOX, and CYP pathways. While prostaglandins, leukotrienes, and 20-hydroxyeicosatetraenoic acid (20-HETE) exacerbate kidney injury, epoxyeicosatrienoic acids (EETs), lipoxins, and other specialized pro-resolving mediators (SPMs) counteract inflammation and promote tissue repair. These lipid mediators also modulate nuclear receptors such as peroxisome proliferator-activated receptors (PPARs) and fibrotic pathways like TGF-β signaling. Disease-specific imbalances in PUFA metabolism have been implicated in nephrotic syndrome, glomerulonephritis, kidney transplantation, and renal cancer. This review integrates mechanistic insights with experimental and clinical data, highlighting therapeutic strategies including dietary ω-3 PUFA supplementation, synthetic SPM analogs, selective enzyme inhibitors, and nanocarrier-based delivery systems. We also address limitations, such as short half-life, off-target effects, and immunoregulatory risks. Lipidomic profiling may aid in patient stratification and treatment personalization. Collectively, targeting PUFA-derived lipid mediators offers a promising adjunct to conventional therapies for inflammatory and immune-mediated kidney diseases.

多不饱和脂肪酸（PUFAs）通过COX、LOX和CYP途径产生的代谢物调节肾脏炎症。虽然前列腺素、白三烯和20-羟基二十碳四烯酸（20-HETE）会加重肾损伤，但环氧二十碳三烯酸（EETs）、脂毒素和其他专门的促溶解介质（SPMs）会抵消炎症并促进组织修复。这些脂质介质也调节核受体，如过氧化物酶体增殖激活受体（ppar）和纤维化途径，如TGF-β信号传导。疾病特异性多聚脂肪酸代谢失衡与肾病综合征、肾小球肾炎、肾移植和肾癌有关。这篇综述结合了实验和临床数据的机制见解，强调了治疗策略，包括膳食ω-3 PUFA补充，合成SPM类似物，选择性酶抑制剂和基于纳米载体的递送系统。我们还讨论了局限性，如半衰期短、脱靶效应和免疫调节风险。脂质组学分析有助于患者分层和治疗个性化。总的来说，靶向pufa衍生的脂质介质为炎症和免疫介导的肾脏疾病的常规治疗提供了一个有希望的辅助疗法。

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引用次数: 0

Linarin alleviates high-fat diet-induced NAFLD via modulating the PI3K/Akt/mTOR pathway, autophagy, and gut microbiota Linarin通过调节PI3K/Akt/mTOR通路、自噬和肠道微生物群来缓解高脂肪饮食诱导的NAFLD。

IF 3.3 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-16 DOI: 10.1016/j.bbalip.2025.159666

Mengfan Lv , Yaxin Zhai , Hao Yu , Jiaqi Cheng , Yunfei Wei , Yibo Zhang , Yanmin Zhang , Haihua Feng

Linarin (Lin) is a flavonoid compound widely found in traditional herbal medicines and is recognized for its diverse biological properties, including anti-inflammatory, analgesic, antioxidant, hepatoprotective, and anti-apoptotic effects. Non-alcoholic fatty liver disease (NAFLD) is closely associated with autophagy and inflammation processes. However, the interaction between Lin and NAFLD remains underexplored. This study aimed to investigate the protective effects of Lin against NAFLD and its underlying pharmacological mechanisms. In vitro, we established a NAFLD model using AML12 cells stimulated with oleic acid (OA) and palmitic acid (PA). In vivo, we induced a chronic model in mice by feeding them a high-fat diet (HFD). Lipid metabolism markers, Oil Red O staining, and H&E staining were used to assess intracellular lipid accumulation. Inflammatory and autophagic markers were also measured. The 16S rRNA analysis was performed to evaluate the changes in the gut microbiota composition after Lin intervention in mice. Both in vitro and in vivo experiments demonstrated that Lin reduces lipid accumulation, which is mediated through the enhancement of autophagy and the inhibition of the release of inflammatory factors. 16S rRNA analysis revealed that Lin alleviates gut dysbiosis by reducing Firmicutes and Bacteroidetes phyla while increasing the abundance of Akkermansia and Bifidobacterium genera. Mechanistically, Lin activates autophagy via the PI3K/Akt/mTOR pathway, thereby alleviating lipid accumulation and inflammation. These findings suggest that Lin can mitigate NAFLD by inhibiting the activation of the PI3K/Akt/mTOR pathway, highlighting its potential as a promising therapeutic approach for NAFLD.

Linarin （Lin）是一种广泛存在于传统草药中的类黄酮化合物，具有多种生物学特性，包括抗炎、镇痛、抗氧化、保护肝脏和抗细胞凋亡等作用。非酒精性脂肪性肝病（NAFLD）与自噬和炎症过程密切相关。然而，Lin与NAFLD之间的相互作用仍未得到充分探讨。本研究旨在探讨林对NAFLD的保护作用及其潜在的药理学机制。在体外，我们用油酸（OA）和棕榈酸（PA）刺激AML12细胞建立NAFLD模型。在体内，我们通过高脂饮食（HFD）诱导小鼠慢性模型。脂质代谢标志物、油红O染色和H&E染色用于评估细胞内脂质积累。还测量了炎症和自噬标志物。采用16S rRNA分析来评估Lin干预后小鼠肠道菌群组成的变化。体外和体内实验均表明，Lin通过增强自噬和抑制炎症因子的释放来减少脂质积累。16S rRNA分析显示，Lin通过减少厚壁菌门（Firmicutes）和拟杆菌门（Bacteroidetes），增加Akkermansia和双歧杆菌属（Bifidobacterium）的丰度，缓解肠道生态失调。在机制上，Lin通过PI3K/Akt/mTOR途径激活自噬，从而减轻脂质积累和炎症。这些发现表明Lin可以通过抑制PI3K/Akt/mTOR通路的激活来缓解NAFLD，突出了其作为NAFLD治疗方法的潜力。

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引用次数: 0

Effect of α-ketoglutarate on maternal lipid homeostasis and mitochondrial status perturbed by gestational arsenic exposure α-酮戊二酸对妊娠期砷暴露扰乱的母体脂质稳态和线粒体状态的影响

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-16 DOI: 10.1016/j.bbalip.2025.159665

Tong Zhan , Shuang-Rui Bao , Ying Sun , Hong-Yan Wu , Wen-Kang Tao , Xin-Ru Liang , Zhi-Yan Wan , Qian Yang , Hua Wang , Yi-Chao Huang , Jian-Qing Wang , De-Xiang Xu , Cheng Zhang

Arsenic is a common environmental toxicant with known hepatotoxic effects, yet its impact on maternal lipid metabolism during pregnancy remains poorly understood. In this study, we established a pregnant mouse model to investigate the effects of gestational arsenic exposure and the potential protective role of α-ketoglutarate (α-KG), a key tricarboxylic acid (TCA) cycle intermediate. In the first experiment, arsenic exposure led to significant disruptions in maternal serum and hepatic lipid profiles. Mechanistically, arsenic reduced hepatic α-KG concentrations, impaired mitochondrial ultrastructure, altered mitochondria-related gene expression, induced oxidative stress, and decreased multiple TCA cycle intermediates, collectively indicating compromised mitochondrial function. In the second experiment, α-KG supplementation during gestation effectively restored hepatic α-KG levels and reversed arsenic-induced lipid metabolic imbalances. Moreover, α-KG preserved mitochondrial morphology, normalized the expression of mitochondrial genes, alleviated oxidative stress, and partially rescued the levels of disrupted TCA intermediates. These results suggest that arsenic disrupts maternal lipid homeostasis primarily through mitochondrial dysfunction and oxidative stress, and that α-KG supplementation can alleviate these disturbances by supporting mitochondrial function. Although the exact molecular mechanisms require further clarification, our findings highlight the potential therapeutic role of α-KG in maintaining maternal lipid metabolic health during arsenic exposure during pregnancy.

砷是一种常见的环境毒物，已知具有肝毒性作用，但其对怀孕期间母体脂质代谢的影响仍知之甚少。在这项研究中，我们建立了妊娠小鼠模型，研究妊娠期砷暴露的影响和α-酮戊二酸（α-KG）的潜在保护作用，α-酮戊二酸是三羧酸（TCA）循环的关键中间体。在第一个实验中，砷暴露导致母体血清和肝脏脂质谱的显著破坏。从机制上说，砷降低了肝脏α-KG浓度，破坏了线粒体超微结构，改变了线粒体相关基因表达，诱导氧化应激，减少了多个TCA循环中间体，共同表明线粒体功能受损。在第二个试验中，妊娠期补充α-KG可有效恢复肝脏α-KG水平，逆转砷诱导的脂质代谢失衡。此外，α-KG还能保持线粒体形态，使线粒体基因表达正常化，减轻氧化应激，部分恢复被破坏的TCA中间体水平。这些结果表明，砷主要通过线粒体功能障碍和氧化应激破坏母体脂质稳态，而α-KG的补充可以通过支持线粒体功能来缓解这些干扰。虽然确切的分子机制需要进一步澄清，但我们的研究结果强调了α-KG在维持妊娠期砷暴露期间母体脂质代谢健康方面的潜在治疗作用。

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引用次数: 0

Metformin promotes lipid droplet-mitochondria coupling and improves insulin secretion in pancreatic β-cells exposed to lipotoxicity 二甲双胍促进脂滴-线粒体偶联并改善脂肪毒性胰腺β细胞的胰岛素分泌。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-12 DOI: 10.1016/j.bbalip.2025.159664

Aneta M. Dobosz , Ewelina Krogulec , Nataniel Stefanowski , Maria Kendziorek , Magdalena Lebiedzinska-Arciszewska , Mariusz R. Wieckowski , Justyna Janikiewicz , Agnieszka Dobrzyn

Lipotoxicity that is caused by excess lipid accumulation is a major factor that contributes to gradual impairments of β-cell function and the development of type 2 diabetes. Metformin has shown protective effects against lipid-induced damage in β-cells, but its specific mechanisms of action within pancreatic islets remain unclear. The present study comprehensively examined direct effects of metformin on lipid metabolism pathways in INS-1E β-cells that were exposed to lipotoxic stress. Our results showed that metformin reduced both the number and size of lipid droplets in palmitate-treated INS-1E cells. This was followed by an increase in fatty acid utilization and the enhanced association between mitochondria and lipid droplets. Under conditions of palmitate overexposure, metformin limited the activity of adipose triglyceride lipase and lipogenic regulators, such as stearoyl-CoA desaturase, and suppressed fatty acid uptake into cells. Additionally, metformin alleviated triglyceride and free fatty acid accumulation and partially reversed palmitate-induced impairments in insulin secretion in INS-1E cells that were subjected to lipotoxicity. Notably, this beneficial effect of metformin on insulin secretion in INS-1E cells exposed to lipotoxic stress was less pronounced when the balance between mitochondrial fusion and fission was disturbed. These findings provide additional mechanistic insights into pleiotropic effects of metformin and its role in regulating β-cell function.

过量脂质积累引起的脂肪毒性是导致β细胞功能逐渐受损和2型糖尿病发展的主要因素。二甲双胍已显示出对β细胞脂质损伤的保护作用，但其在胰岛内的具体作用机制尚不清楚。本研究全面考察了二甲双胍对暴露于脂毒性应激的INS-1E β-细胞脂质代谢途径的直接影响。我们的研究结果表明，二甲双胍减少了棕榈酸处理的INS-1E细胞中脂滴的数量和大小。随后，脂肪酸利用率增加，线粒体和脂滴之间的关联增强。在棕榈酸过度暴露的条件下，二甲双胍限制了脂肪甘油三酯脂肪酶和脂肪生成调节因子（如硬脂酰辅酶a去饱和酶）的活性，并抑制了脂肪酸进入细胞的摄取。此外，二甲双胍减轻了甘油三酯和游离脂肪酸的积累，并部分逆转了棕榈酸引起的脂毒性INS-1E细胞胰岛素分泌的损伤。值得注意的是，当线粒体融合和裂变之间的平衡受到干扰时，二甲双胍对暴露于脂毒性应激的INS-1E细胞胰岛素分泌的有益作用就不那么明显了。这些发现为二甲双胍的多效作用及其在调节β细胞功能中的作用提供了额外的机制见解。

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引用次数: 0

Molecular mechanisms of cytochrome P450-derived epoxy-fatty acids neuroprotection 细胞色素p450衍生的环氧脂肪酸神经保护的分子机制。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-10 DOI: 10.1016/j.bbalip.2025.159663

Cynthia Navarro-Mabarak, Julio Morán

The epoxyeicosatrienoic acids (EETs) are metabolites that result from the oxidation of the arachidonic acid by cytochrome P450 (CYP) epoxygenases. EETs are known to exert anti-inflammatory, antioxidant, vasodilatory, pro-angiogenic and anti-apoptotic actions. In the nervous system, EETs have been found to be neuroprotective in different models of neuronal damage. However, the molecular mechanisms responsible for these effects are not yet fully understood. This article seeks to review what is known about the signaling pathways involved in the EETs mediated neuroprotection. The mechanisms responsible for these effects are complex and involve several biological pathways that often crosstalk, including an inhibition of NFκB pathway, the activation of PPARα/γ nuclear receptors, and the activation of the PI3K/Akt pathway, among others. We also review what is known about the production and the biological significance of the epoxyeicosatrienoic acid ethanolamides (EET-EAs) and the epoxyeicosatrienoic acid glycerols (EET-EGs), metabolites that result from the epoxidation of the anandamide (AEA) and 2-arachidonylglycerol (2-AG) by CYP epoxygenases, which show endocannabinoid features.

环氧二碳三烯酸（EETs）是花生四烯酸被细胞色素P450 （CYP）环氧合酶氧化的代谢物。已知eet具有抗炎、抗氧化、血管扩张、促血管生成和抗凋亡作用。在神经系统中，已发现eet在不同的神经元损伤模型中具有神经保护作用。然而，导致这些效应的分子机制尚未完全了解。本文旨在回顾脑电图介导的神经保护所涉及的信号通路。这些作用的机制是复杂的，涉及几种经常相互作用的生物学途径，包括NFκB途径的抑制、PPARα/γ核受体的激活和PI3K/Akt途径的激活等。我们还回顾了环氧二碳三烯酸乙醇酰胺（EET-EAs）和环氧二碳三烯酸甘油（EET-EGs）的生产和生物学意义，这些代谢产物是由CYP环氧化酶环氧化anandamide （AEA）和2-花生四烯酰基甘油（2-AG）产生的，具有内源性大麻素特征。

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引用次数: 0

Fatty acid binding protein 1 (FABP1) depletion promotes an oxidative metabolic shift in Caco-2 colorectal cancer cells 脂肪酸结合蛋白1 （FABP1）的缺失促进Caco-2结直肠癌细胞的氧化代谢转变。

IF 3.3 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-08 DOI: 10.1016/j.bbalip.2025.159661

Delfina Lucía Borús , Giorgia Zadra , Daniel Minsky , María Lucía Costa , Betina Córsico , Judith Storch , Natalia Scaglia

Lipid metabolism reprogramming is a well-established hallmark of many cancer types, including colorectal cancer (CRC). Nevertheless, a clear understanding on how fatty acid (FA) metabolism is fine-tuned during CRC development and progression is still missing. Given that CRC is the second leading cause of cancer-related death, addressing these critical aspects may provide the rationale for new therapeutic approaches and early biomarker identification. Fatty acid binding protein 1 (FABP1) is a small protein that binds FA and other lipophilic compounds, acting as a lipid transporter in the intestine. Little is currently known about the function of FABP1 in CRC. Here we show that the knockdown of FABP1 in CRC cells impairs de novo FA and cholesterol synthesis, specifically, via altering the transcriptional regulation of lipid metabolism genes. FABP1 depletion suppresses the expression of FA and cholesterol synthesis-associated genes while promoting that of FA oxidation genes and mitochondrial oxidative pathways. The latter is associated with increased oxygen consumption rate and activation of the energy sensor 5’ AMP-activated kinase (AMPK). Taken together, our results show that FABP1 orchestrates the balance between FA synthesis and oxidation, most likely to prevent the cytotoxic effects of circulating unbound free fatty acids. Thus, targeting FABP1 function may represent a potential therapeutic strategy in advanced CRC.

脂质代谢重编程是许多癌症类型的一个公认的标志，包括结直肠癌（CRC）。然而，在结直肠癌的发生和发展过程中，脂肪酸（FA）代谢是如何微调的，目前还没有明确的认识。鉴于结直肠癌是癌症相关死亡的第二大原因，解决这些关键问题可能为新的治疗方法和早期生物标志物鉴定提供基础。脂肪酸结合蛋白1 （FABP1）是一种结合FA和其他亲脂化合物的小蛋白，在肠道中起脂质转运体的作用。目前对FABP1在CRC中的作用知之甚少。本研究表明，在结直肠癌细胞中，FABP1的敲低会损害FA和胆固醇的新生合成，特别是通过改变脂质代谢基因的转录调节。FABP1缺失抑制FA和胆固醇合成相关基因的表达，同时促进FA氧化基因和线粒体氧化途径的表达。后者与氧气消耗率增加和能量传感器5' amp活化激酶（AMPK）的激活有关。综上所述，我们的研究结果表明，FABP1协调了FA合成和氧化之间的平衡，最有可能阻止循环未结合的游离脂肪酸的细胞毒性作用。因此，靶向FABP1功能可能是晚期结直肠癌的一种潜在治疗策略。

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引用次数: 0

LIMP-2 deficiency-associated glycolipid abnormalities in mice 小鼠中与LIMP-2缺乏相关的糖脂异常。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-08 DOI: 10.1016/j.bbalip.2025.159657

Paulo Gaspar , André R.A. Marques , Maria J. Ferraz , Markus Damme , Gertjan Kramer , Mina Mirzaian , Marion Gijbels , Roelof Ottenhoff , Cindy van Roomen , Herman S. Overkleeft , Michael Schwake , Saskia Heybrock , Maria Carmo Macário , Paul Saftig , Johannes M. Aerts

Glucocerebrosidase (GCase) catalyzes the lysosomal degradation of glucosylceramide (GlcCer). GCase deficiency results in Gaucher disease (GD), a lysosomal storage disorder with characteristic hepatosplenomegaly. Transport of GCase to lysosomes is mediated by the lysosomal integral membrane protein type 2 (LIMP-2). Deficiency of LIMP-2 leads to reduced cellular GCase levels and manifests as Action Myoclonic Renal Failure Syndrome (AMRF). We investigated the cause for the markedly different symptomatology of GD and AMRF. In tissues of Limp2 −/− mice no prominent abnormalities in lysosomal enzymes were noted except for variable deficiency of GCase, as measured with enzymatic activity assay and detection of active GCase molecules with an activity-based probe. Noteworthy, in LIMP-2-deficient mice, residual GCase is remarkably high in leukocytes. GCase deficiency in tissues does not correlate with increases in GlcCer, but rather with increases in glucosylsphingosine (GlcSph) and glucosylated cholesterol (GlcChol), both glucosylated metabolites derived from GlcCer. Isolated lysosomes from hepatocytes of Limp2 −/− mice revealed no prominent abnormalities in lysosomal matrix proteins except GCase. The Limp2 −/− tritosomes showed clear increases in GlcSph and GlcChol but not in GlcCer. In conclusion, our data imply a critical role of LIMP-2 in glycosphingolipid homeostasis. Despite low GCase levels striking GlcCer accumulation is avoided in tissues of LIMP-2 deficient mice.

葡萄糖脑苷酶（GCase）催化溶酶体降解葡萄糖神经酰胺（glcer）。GCase缺乏导致戈谢病（GD），一种伴有特征性肝脾肿大的溶酶体积存疾病。GCase转运到溶酶体是由溶酶体整体膜蛋白2 （LIMP-2）介导的。LIMP-2缺乏导致细胞GCase水平降低，表现为行动性肌阵挛性肾衰竭综合征（AMRF）。我们探讨了GD和AMRF明显不同症状的原因。在Limp2 -/-小鼠的组织中，除了GCase的可变缺陷外，没有发现明显的溶酶体酶异常，这是通过酶活性测定和活性探针检测活性GCase分子来测量的。值得注意的是，在limp -2缺陷小鼠中，白细胞中残留的GCase非常高。组织中GCase的缺乏与glcer的增加无关，而是与葡萄糖基鞘氨酸（GlcSph）和葡萄糖基化胆固醇（GlcChol）的增加有关，这两种糖基化代谢产物均来源于glcer。从Limp2 -/-小鼠肝细胞分离的溶酶体显示除GCase外，溶酶体基质蛋白无明显异常。Limp2 -/-三体GlcSph和GlcChol明显升高，glcer无明显升高。总之，我们的数据表明，在鞘糖脂稳态中，LIMP-2起着至关重要的作用。尽管GCase水平较低，但在LIMP-2缺陷小鼠的组织中避免了显著的glcer积累。

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引用次数: 0

Partial inhibition of adipose CIDEC improves insulin sensitivity and increases energy expenditure in high-fat diet-fed mice via activating ATGL-PPARα pathway 部分抑制脂肪CIDEC通过激活ATGL-PPARα途径改善高脂饮食小鼠的胰岛素敏感性和增加能量消耗

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-07 DOI: 10.1016/j.bbalip.2025.159659

Qinghua Fu , Peng Wang , Weilin Li , Zhenhua Cai , Shiji Zhao , Weidong Ling , Mingxun Li , Xiaochuan Tang , Ziyi Song

Obesity poses a significant risk for metabolic disorders, such as insulin resistance and metabolic-associated fatty liver disease (MAFLD), yet effective treatments remain limited. Cell Death-Inducing DNA Fragmentation Factor-α-Like Effector C (CIDEC), a lipid droplet membrane protein, facilitates lipid droplet fusion and is crucial for adipose tissue expansion, making it a key target for obesity and related metabolic diseases. However, previous research revealed that complete genetic deletion of Cidec in adipose tissues, while reducing fat accumulation, induced severe insulin resistance in high-fat diet (HFD)-fed mice, potentially due to ectopic fat storage in the liver. Given that complete knockout is an extreme approach, partial inhibition holds greater clinical relevance. Therefore, this study aimed to investigate the effects of partial inhibition of CIDEC in adipose tissues on fat accumulation and insulin sensitivity in mice. Using the Cre-LoxP system, we generated adipose Cidec haploinsufficient mice. Under a standard diet, these mice exhibited normal body weight, fat accumulation, and insulin sensitivity. Notably, under HFD conditions, mice with partial Cidec deficiency showed reduced fat accumulation in adipose tissues while hepatic fat accumulation remained unchanged, accompanied by improved insulin sensitivity and increased energy expenditure. Mechanistically, we found partial Cidec deficiency activated thermogenic program in adipocytes in vivo and in vitro through the ATGL-PPARα pathway. In conclusion, adipose CIDEC partial inhibition attenuates HFD-induced obesity and insulin resistance by enhancing ATGL-PPARα-mediated energy expenditure, establishing this approach as a promising therapeutic strategy for obesity and related metabolic diseases.

肥胖会导致代谢紊乱，如胰岛素抵抗和代谢相关脂肪性肝病（MAFLD），但有效的治疗方法仍然有限。细胞死亡诱导DNA碎片因子-α样效应因子C （Cell Death-Inducing DNA Fragmentation Factor-α-Like Effector C， CIDEC）是脂滴膜蛋白，促进脂滴融合，对脂肪组织扩张至关重要，是肥胖及相关代谢疾病的关键靶点。然而，先前的研究表明，脂肪组织中Cidec的完全基因缺失，在减少脂肪积累的同时，在高脂肪饮食（HFD）喂养的小鼠中诱导了严重的胰岛素抵抗，这可能是由于肝脏中的异位脂肪储存。考虑到完全敲除是一种极端的方法，部分抑制具有更大的临床意义。因此，本研究旨在探讨部分抑制脂肪组织中CIDEC对小鼠脂肪积累和胰岛素敏感性的影响。使用Cre-LoxP系统，我们产生了脂肪单倍体不足的小鼠。在标准饮食下，这些小鼠表现出正常的体重、脂肪积累和胰岛素敏感性。值得注意的是，在HFD条件下，部分Cidec缺乏的小鼠脂肪组织中的脂肪积累减少，而肝脏脂肪积累保持不变，并伴有胰岛素敏感性改善和能量消耗增加。在机制上，我们发现部分Cidec缺乏通过ATGL-PPARα途径激活体内和体外脂肪细胞的产热程序。综上所述，脂肪部分抑制CIDEC通过增强atgl - ppar α-介导的能量消耗来减轻hfd诱导的肥胖和胰岛素抵抗，使该方法成为肥胖和相关代谢疾病的一种有前景的治疗策略。

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引用次数: 0

Agonist- and stress-driven compartmentalized phosphoinositide signaling in cells 细胞中激动剂和应激驱动的区隔化磷酸肌苷信号。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-05 DOI: 10.1016/j.bbalip.2025.159662

Mo Chen , Jay Xiaojun Tan , Yue Sun , Narendra Thapa , Vincent L. Cryns , Richard A. Anderson

Phosphoinositides (PIPs) are essential lipid messengers that regulate cellular responses to external stimuli and stress through spatially organized signaling pathways. In recent years, compartment-specific mechanisms by which PIP signaling integrates diverse cellular processes have been extensively expanded. This review discusses the distinct roles of PIP signaling across cellular compartments, including the plasma membrane, endosomes, lysosomes, protein scaffolds, and the nucleus. PIPs coordinate key processes such as receptor trafficking, cytoskeletal remodeling, autophagy, and signal transduction. Dynamic lysosomal PIP switches regulate critical functions like nutrient sensing, mTORC1 activity, and membrane repair, emphasizing their adaptability in maintaining cellular homeostasis. Furthermore, emerging evidence highlights nuclear PIP signaling in transcriptional regulation, DNA repair, and oncogenic pathways. Dysregulation of PIP signaling pathways is implicated in diseases such as cancer, neurodegeneration, and lysosomal storage disorders, underscoring their therapeutic potential in various pathological conditions.

磷酸肌苷（PIPs）是一种重要的脂质信使，通过空间组织的信号通路调节细胞对外部刺激和应激的反应。近年来，PIP信号整合多种细胞过程的室特异性机制已被广泛扩展。本文讨论了PIP信号在细胞质膜、核内体、溶酶体、蛋白支架和细胞核中的不同作用。pip协调关键过程，如受体运输、细胞骨架重塑、自噬和信号转导。动态溶酶体PIP开关调节营养感知、mTORC1活性和膜修复等关键功能，强调其在维持细胞稳态中的适应性。此外，新出现的证据强调了核PIP信号在转录调控、DNA修复和致癌途径中的作用。PIP信号通路的失调与癌症、神经退行性变和溶酶体贮积障碍等疾病有关，强调了它们在各种病理条件下的治疗潜力。

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引用次数: 0