Metabolism: clinical and experimental最新文献_第5页

Unravelling the obesity paradox in cancer: An umbrella review of protective associations and evidence credibility across 13 malignancies 揭开癌症中的肥胖悖论：对13种恶性肿瘤的保护性关联和证据可信度的综合回顾。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-12-01 DOI: 10.1016/j.metabol.2025.156461

Lulin Yu , Jing Yuan , Mingxian Meng , Hejing Pan , Long Ge , Liaoyao Wang , Xuanlin Li

Background

The “obesity paradox” in cancer remains controversial amid inconsistent meta-analyses. This umbrella review re-analyses evidence across 13 malignancies using pre-specified credibility criteria to clarify associations.

Methods

We conducted an umbrella review of systematic reviews and meta-analyses investigating obesity and cancer incidence or prognosis. PubMed, Embase, and Cochrane Library were searched from inception to August 2025. Evidence credibility was graded using the following criteria: statistical significance, heterogeneity, 95 % prediction intervals, small-study effects, excess significance bias, and methodological quality assessment.

Findings

Based on 33 included articles (comprising 145 associations across 13 cancer types), only two associations met the convincing evidence criteria: higher BMI was associated with a reduced incidence of oral cancer (relative risk [RR] = 0.93, 95 % CI: 0.91–0.96), and excess weight was associated with a reduced incidence of lung cancer in the Chinese population (odds ratio [OR] = 0.68, 95 % CI: 0.59–0.79). Highly suggestive evidence has revealed associations in lung cancer (reduced incidence, fewer surgical complications and prolonged cancer-specific survival), breast cancer (reduced incidence and decreased likelihood of lymph node metastasis), renal cell carcinoma (prolonged overall survival) and prostate cancer (prolonged overall survival). Of the remaining associations, 20 were suggestive, 51 weak, and 53 non-significant.

Conclusions

Only 21 (14 %) meta-analyses provided convincing or highly suggestive evidence, demonstrating potential associations of obesity in specific oncological contexts pertaining to both reduced incidence risk and improved prognostic outcomes. This synthesis also highlights critical gaps in current evidence, emphasising the need for standardised adiposity metrics, more prudent stratification, and rigorous methodology.

背景：在不一致的荟萃分析中，癌症中的“肥胖悖论”仍然存在争议。本综述使用预先指定的可信度标准重新分析了13种恶性肿瘤的证据，以澄清相关关系。方法：我们对调查肥胖与癌症发病率或预后的系统综述和荟萃分析进行了综合综述。PubMed， Embase和Cochrane图书馆从成立到2025年8月被检索。使用以下标准对证据可信度进行分级：统计显著性、异质性、95% %预测区间、小研究效应、过度显著性偏差和方法学质量评估。结果：基于纳入的33篇文章（包括13种癌症类型的145个关联），只有两个关联符合令人信服的证据标准：高BMI与口腔癌发病率降低相关（相对风险[RR] = 0.93,95 % CI: 0.91-0.96），超重与中国人群肺癌发病率降低相关（优势比[OR] = 0.68,95 % CI: 0.59-0.79）。极具暗示意义的证据显示，肺癌（发病率降低，手术并发症减少，癌症特异性生存期延长）、乳腺癌（发病率降低，淋巴结转移可能性降低）、肾细胞癌（总生存期延长）和前列腺癌（总生存期延长）与肺癌（总生存期延长）存在关联。在剩下的关联中，20个具有暗示性，51个较弱，53个不显著。结论：只有21项（14% %）荟萃分析提供了令人信服或高度暗示的证据，证明肥胖在特定肿瘤背景下与降低发病率风险和改善预后结果有关的潜在关联。这一综合也强调了当前证据的关键差距，强调需要标准化的肥胖指标，更谨慎的分层和严格的方法。

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引用次数: 0

Meteorin-like protein inhibits vascular smooth muscle cell-derived foam cell formation and atherosclerosis via KIT- endoplasmic reticulum stress signaling 流星蛋白样蛋白通过KIT-内质网应激信号抑制血管平滑肌细胞衍生泡沫细胞形成和动脉粥样硬化。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-11-29 DOI: 10.1016/j.metabol.2025.156459

Xu Chen , Xueying Jiang , Siyu Hou , Fengling Lai , Keqing Hu , Jie Li , Ting Yang , Xinxin Shen , Huimin Chen , Shen Chen , Xianfei Guo , Yan Zheng , Tao Xu , Guohai Su , Rong Huang

Objective

Vascular smooth muscle cell (VSMC)-derived foam cell formation is a major contributor to atherosclerosis progression and plaque instability. Meteorin-like protein (METRNL), a secreted organokine with known metabolic and anti-inflammatory effects, has been linked to cardiovascular protection, but its role in atherosclerosis is not well defined. This study investigated the function of METRNL in VSMC-derived foam cell formation and atherosclerosis and explored the underlying signaling mechanisms.

Methods

ApoE^−/− mice were used to investigate the role of METRNL in atherosclerosis. VSMC-derived foam cell formation was evaluated in human VSMC treated with oxidized LDL with or without METRNL supplementation.

Results

METRNL levels declined during atherosclerosis progression and were restored during regression. METRNL selectively inhibited foam cell formation in VSMCs—but not in macrophages—by downregulating CD36-mediated cholesterol uptake and suppressing endoplasmic reticulum stress through KIT signaling. Deletion of KIT specifically in smooth muscle cells abolished these protective effects. The transcription factor SP1 was found to bind directly to the METRNL promoter and enhance its expression. Clinically, lower serum METRNL levels were independently associated with increased risk and severity of acute coronary syndrome.

Conclusion

METRNL protects against VSMC foam cell formation and atherosclerosis by enhancing KIT signaling, thereby reducing ER stress and subsequent cholesterol uptake. These findings position METRNL as a potential therapeutic target and biomarker for atherosclerotic cardiovascular disease.

目的：血管平滑肌细胞（VSMC）衍生泡沫细胞的形成是动脉粥样硬化进展和斑块不稳定的主要因素。流星蛋白样蛋白（METRNL）是一种已知具有代谢和抗炎作用的分泌性器官因子，与心血管保护有关，但其在动脉粥样硬化中的作用尚未明确。本研究探讨了METRNL在vsmc衍生泡沫细胞形成和动脉粥样硬化中的作用，并探讨了其潜在的信号机制。方法：采用ApoE-/-小鼠实验，研究METRNL在动脉粥样硬化中的作用。用氧化LDL加或不加METRNL处理的人VSMC，评估VSMC衍生泡沫细胞的形成。结果：METRNL水平在动脉粥样硬化过程中下降，在回归过程中恢复。METRNL通过下调cd36介导的胆固醇摄取和通过KIT信号抑制内质网应激，选择性地抑制vsmcs中的泡沫细胞形成，而不是巨噬细胞。在平滑肌细胞中特异性地删除KIT会消除这些保护作用。转录因子SP1可直接与METRNL启动子结合，增强其表达。在临床上，较低的血清METRNL水平与急性冠状动脉综合征的风险和严重程度增加独立相关。结论：METRNL通过增强KIT信号，从而减少内质网应激和随后的胆固醇摄取，从而防止VSMC泡沫细胞形成和动脉粥样硬化。这些发现将METRNL定位为动脉粥样硬化性心血管疾病的潜在治疗靶点和生物标志物。

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引用次数: 0

Molecular code of ferroptosis: emerging multi-dimensional modifications and therapeutic targets in hepatic disorders 铁下垂的分子密码：在肝脏疾病中出现的多维修饰和治疗靶点

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-11-26 DOI: 10.1016/j.metabol.2025.156457

Xiaotong Cai , Yinhao Zhang , Wenqing Qin , Xiaojiaoyang Li

Ferroptosis, a distinct form of iron-dependent cell death characterized by lipid peroxidation, has emerged as a pivotal regulator in the pathogenesis of liver diseases. It functions both as a driver of hepatocyte injury in chronic liver disorders and as a therapeutic vulnerability in hepatocellular carcinoma. This review provides a comprehensive analysis of the regulatory networks of ferroptosis, shaped by both epigenetic and post-translational modifications. Specifically, we detailed how RNA and DNA methylation, non-coding RNAs, histone acetylation and post-translational modifications dynamically modulated the expression, stability and activity of ferroptosis-related molecules, especially for glutathione peroxidase 4, solute carrier family 7 member 11, acyl-CoA synthetase long-chain family member 4 and transferrin receptor 1. By dissecting these multilayered regulatory mechanisms, we delineated how distinct modifications operated, either promoting or suppressing ferroptosis across various liver diseases. Furthermore, we summarized recent advances in therapeutic interventions targeting ferroptosis-related pathways, including their pharmacological mechanisms, efficacy in preclinical models and limitations in clinical translation. Special emphasis was also placed on the complexity of modifications, disease-stage specificity and the topology of modification sites in shaping ferroptosis sensitivity. Collectively, this review highlights ferroptosis as a dynamic and therapeutically actionable within liver pathology and underscores the potential of targeting regulatory modifications to refine strategies for disease intervention.

铁中毒是一种以脂质过氧化为特征的铁依赖性细胞死亡的独特形式，已成为肝脏疾病发病机制中的关键调节因子。它在慢性肝脏疾病中作为肝细胞损伤的驱动因素，在肝细胞癌中作为治疗易感性。这篇综述提供了对铁下垂的调控网络的全面分析，由表观遗传和翻译后修饰形成。具体而言，我们详细介绍了RNA和DNA甲基化，非编码RNA，组蛋白乙酰化和翻译后修饰如何动态调节与铁凋亡相关分子的表达，稳定性和活性，特别是谷胱甘肽过氧化物酶4，溶质载体家族7成员11，酰基辅酶a合成酶长链家族成员4和转铁蛋白受体1。通过剖析这些多层调控机制，我们描述了不同的修饰如何起作用，促进或抑制各种肝脏疾病的铁下垂。此外，我们总结了针对铁中毒相关途径的治疗干预措施的最新进展，包括其药理机制、临床前模型的疗效和临床转化的局限性。特别强调还放在修饰的复杂性，疾病阶段的特异性和修饰位点的拓扑结构在形成铁下垂敏感性。总的来说，这篇综述强调了铁下垂在肝脏病理中是一种动态的、可治疗的疾病，并强调了靶向调节修改以完善疾病干预策略的潜力。

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引用次数: 0

Imeglimin ameliorates MASLD by targeting PEN2 to activate AMPK pathway imimimin通过靶向PEN2激活AMPK通路来改善MASLD

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-11-25 DOI: 10.1016/j.metabol.2025.156458

Jinghe Li , Ruizhong Zhang , Xin Zeng , Weilong Xu , Ling Gao , Shuyun He , Bingbing Wu , Yanjie Ma , Yunzhong Nie , Jun Shirakawa , Huimin Xia , Wei Li

Background and Aims

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent and increasingly chronic liver disorder with increasing global incidence, closely linked to prolonged high-fat diet (HFD)-induced metabolic impairment. Although imeglimin, an antidiabetic agent known to improve insulin resistance, has demonstrated therapeutic potential in metabolic diseases, its effects and underlying molecular mechanism in MASLD remain unclear.

Approach and results

In this study, we employed a long-term (48-week) high-fat diet-induced murine model of MASLD to recapitulate human disease progression, then treated those mice with imeglimin for 6 months to investigate its therapeutic effects. Imeglimin treatment improved insulin resistance, restored liver function, attenuated hepatic inflammation, and promoted hepatocyte viability. PEN2, a component of the γ-secretase complex, is identified as the key target of imeglimin. The therapeutic effects of imeglimin are abrogated in liver-specific Pen2-deficient mice or upon pharmacologic inhibition of AMP-activated protein kinase (AMPK), indicating that activation of PEN2-AMPK signaling is required for its beneficial effects. Furthermore, we found that imeglimin also protected human pluripotent stem cell (hPSC)-derived hepatocyte-like cells from free fatty acid (FFA)-induced lipid accumulation.

Conclusion

Collectively, our findings indicate that imeglimin ameliorates hepatic lipotoxicity by targeting PEN2 to activate AMPK axis, suggesting its potential as a new drug for MASLD treatment in the near future.

背景和目的代谢功能障碍相关脂肪变性肝病（MASLD）是一种高度普遍且日益增长的慢性肝病，全球发病率不断上升，与长期高脂肪饮食（HFD）引起的代谢损伤密切相关。尽管已知可改善胰岛素抵抗的抗糖尿病药物伊米明已被证明在代谢性疾病中具有治疗潜力，但其在MASLD中的作用和潜在的分子机制尚不清楚。方法和结果在本研究中，我们采用长期（48周）高脂肪饮食诱导的MASLD小鼠模型来概括人类疾病的进展，然后用伊米霉素治疗这些小鼠6个月，观察其治疗效果。依米霉素治疗可改善胰岛素抵抗，恢复肝功能，减轻肝脏炎症，促进肝细胞活力。PEN2是γ-分泌酶复合物的一个组成部分，被认为是imimimin的关键靶点。在肝脏特异性的pen2缺陷小鼠或amp活化蛋白激酶（AMPK）的药理学抑制下，伊米霉素的治疗作用被取消，这表明其有益作用需要激活PEN2-AMPK信号。此外，我们发现伊米明还能保护人类多能干细胞（hPSC）衍生的肝细胞样细胞免受游离脂肪酸（FFA）诱导的脂质积累。综上所述，我们的研究结果表明，伊梅米明通过靶向PEN2激活AMPK轴来改善肝脂毒性，表明其在不久的将来可能成为治疗MASLD的新药。

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引用次数: 0

TMEM41B contributes to atherosclerosis by promoting lipid synthesis in vascular smooth muscle cells via fatty acid synthase stabilization TMEM41B通过脂肪酸合酶稳定促进血管平滑肌细胞的脂质合成，从而促进动脉粥样硬化

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-11-24 DOI: 10.1016/j.metabol.2025.156456

Gui-Yan Peng , Li-Tai Wei , Ye-Xiang Jing , Hao-Long Luo , Zi-Lun Liu , Run-Chen Wei , Jun-Jie Ning , Guang-Qi Chang , Mian Wang

Foam cell formation has traditionally been attributed to macrophages; however, emerging evidence highlights vascular smooth muscle cells (VSMCs) as another significant contributor. Here, we found that TMEM41B is significantly upregulated in VSMCs of both human atherosclerotic (AS) lesions and murine models. Silencing TMEM41B in VSMCs of apolipoprotein E–deficient (ApoE^−/−) mice markedly reduced plaque size and macrophage infiltration. Overexpressing TMEM41B in cultured VSMCs altered intracellular lipid profiles by stabilizing fatty acid synthase (FASN), a crucial enzyme in fatty acid synthesis, via inhibiting its ubiquitination and degradation. The TMEM41B–FASN axis drove lipid synthesis, promoted intracellular lipid storage, and facilitated the release of pro-inflammatory cytokines. Further, in cultured VSMCs, herpes simplex virus (HSV) infection amplified TMEM41B expression via OCT-1-mediated transcriptional activation, linking viral infection to lipid metabolic reprogramming in vitro. These findings expand the current understanding of VSMC-derived foam cell formation and suggest that targeting the TMEM41B–FASN axis may represent a promising therapeutic strategy for AS, particularly in the context of HSV infection.

泡沫细胞的形成传统上归因于巨噬细胞；然而，新的证据强调血管平滑肌细胞（VSMCs）是另一个重要的贡献者。在这里，我们发现TMEM41B在人类动脉粥样硬化（AS）病变和小鼠模型的VSMCs中都显着上调。在载脂蛋白e缺陷（ApoE−/−）小鼠的VSMCs中沉默TMEM41B可显著减少斑块大小和巨噬细胞浸润。在培养的VSMCs中过表达TMEM41B，通过抑制脂肪酸泛素化和降解来稳定脂肪酸合成酶（FASN），从而改变细胞内脂质谱。FASN是脂肪酸合成的关键酶。TMEM41B-FASN轴驱动脂质合成，促进细胞内脂质储存，促进促炎细胞因子的释放。此外，在体外培养的VSMCs中，单纯疱疹病毒（HSV）感染通过oct -1介导的转录激活放大了TMEM41B的表达，将病毒感染与脂质代谢重编程联系起来。这些发现扩大了目前对vsmc衍生泡沫细胞形成的理解，并表明靶向TMEM41B-FASN轴可能代表了一种有希望的AS治疗策略，特别是在HSV感染的背景下。

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引用次数: 0

Prenatal caffeine exposure impairs neurodevelopment via glucocorticoid-driven epigenetic cascade suppressing astrocytic ABCG1 and cholesterol transport 产前咖啡因暴露通过糖皮质激素驱动的表观遗传级联抑制星形细胞ABCG1和胆固醇运输损害神经发育。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-11-22 DOI: 10.1016/j.metabol.2025.156454

Gaole Dai , Mingcui Luo , Shiyun Dai , Xinli Zhou , Sen Zhu , Mengxi Lu , Xiaoyi Han , Fang Yang , Ying Yu , Hui Wang , Dan Xu

Prenatal caffeine exposure (PCE), stemming from widespread maternal intake of caffeine-containing substances, has emerged as a major pharmacological stressor affecting fetal neurodevelopment. Although epidemiological studies have consistently linked PCE to cognitive impairments and emotional deficits in offspring, the underlying mechanisms have long been confined to direct adenosine receptor antagonism, failing to explain the persistent neurodevelopmental consequences. Here, using cross-species models (rat PCE, astrocyte-specific Abcg1 knockout mice, and glucocorticoid-treated zebrafish) and multi-scale analyses, we demonstrate that PCE activates the maternal-fetal glucocorticoid axis, leading to dysregulation of the GR-miR-130b/301b-PPARγ signaling cascade in hippocampal astrocytes. This disrupts expression of the cholesterol transporter— ATP binding cassette subfamily G member 1 (ABCG1), impairing astrocytic cholesterol efflux and depriving neurons of cholesterol-rich microenvironments essential for synaptic development. Abcg1 knockout mice recapitulate PCE-induced synaptic defects, while astrocyte-specific ABCG1 overexpression or miR-130b/301b inhibition rescues neuronal cholesterol supply and synaptic structure. Luciferase assays confirm that miR-130b/301b directly suppress Pparγ-mediated Abcg1 transcription. Our findings identify the GR-miR-130b/301b-PPARγ-ABCG1 axis as a core mechanism of PCE-induced neurotoxicity, establishing astrocytic cholesterol transport as a potential intervention target and providing a shared molecular framework for evaluating central nervous system risks of glucocorticoid-disruptive agents.

产前咖啡因暴露（PCE）源于母体广泛摄入含咖啡因物质，已成为影响胎儿神经发育的主要药理学应激源。尽管流行病学研究一直将PCE与后代的认知障碍和情绪缺陷联系起来，但其潜在机制长期以来一直局限于直接的腺苷受体拮抗剂，未能解释持续的神经发育后果。通过跨物种模型（大鼠PCE、星形胶质细胞特异性Abcg1敲除小鼠和糖皮质激素处理的斑马鱼）和多尺度分析，我们证明PCE激活母胎糖皮质激素轴，导致海马星形胶质细胞中GR-miR-130b/301b-PPARγ信号级联失调。这破坏了胆固醇转运体- ATP结合盒亚家族G成员1 （ABCG1）的表达，损害星形胶质细胞胆固醇外溢，剥夺了神经元突触发育所必需的富含胆固醇的微环境。Abcg1敲除小鼠重现pce诱导的突触缺陷，而星形胶质细胞特异性Abcg1过表达或miR-130b/301b抑制可挽救神经元胆固醇供应和突触结构。荧光素酶检测证实miR-130b/301b直接抑制ppar γ介导的Abcg1转录。我们的研究结果确定了GR-miR-130b/301b-PPARγ-ABCG1轴是pce诱导的神经毒性的核心机制，建立了星形细胞胆固醇转运作为潜在的干预靶点，并为评估糖皮质激素破坏性药物的中枢神经系统风险提供了一个共享的分子框架。

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引用次数: 0

Metabolic reprogramming in diabetic foot ulcers: mechanisms, therapeutic implications and future perspectives 糖尿病足溃疡的代谢重编程：机制、治疗意义和未来展望。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-11-22 DOI: 10.1016/j.metabol.2025.156455

Li Jinyi , Ding Xianguang , Ding Yuhan , Huang Haoyue , Xia Zhongyu , Wang Lianhui , Jianda Xu

As a devastating complication, diabetic foot ulcer (DFU) is characterized by chronic, nonhealing wounds due to vasculopathy and neuropathy. It has emerged as a most challenging chronic disease worldwide, affecting millions of people worldwide. The higher mortality and disability rates urgently require innovative therapeutic strategies. Recently, different from nanotechnology, metabolic reprogramming is believed to be associated with the occurrence and progression of various diseases (including cancer, obesity and neurodegenerative diseases). They can alter their cellular metabolism (involving glucose, lipid, and amino acid metabolism) to cope with different external stimuli and pressures. As a novel potential strategy, metabolic reprogramming also exhibits great potential to improve the wound healing of DFU. This review aims to summarize the current knowledge, biological characteristics, and underlying mechanisms of metabolic reprogramming in DFU. And we propose their potential therapeutic implications to improve wound healing and prevent complications in DFU. In addition, we also highlight the current challenges and the future perspectives.

作为一种毁灭性的并发症，糖尿病足溃疡（DFU）的特点是由血管病变和神经病变引起的慢性，不愈合的伤口。它已成为全世界最具挑战性的慢性病，影响着全世界数百万人。较高的死亡率和残疾率迫切需要创新的治疗策略。最近，与纳米技术不同，代谢重编程被认为与各种疾病（包括癌症、肥胖和神经退行性疾病）的发生和进展有关。它们可以改变细胞代谢（包括葡萄糖、脂质和氨基酸代谢）以应对不同的外部刺激和压力。作为一种新的潜在策略，代谢重编程在促进DFU创面愈合方面也显示出巨大的潜力。本文综述了DFU中代谢重编程的相关知识、生物学特性和潜在机制。我们提出了它们在改善DFU伤口愈合和预防并发症方面的潜在治疗意义。此外，我们还强调了当前的挑战和未来的展望。

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引用次数: 0

DC-SIGN+ macrophages alleviate metabolic dysfunction-associated steatotic liver disease via fine-tuning TLR4 signaling and inflammatory secretory profiles DC-SIGN+巨噬细胞通过微调TLR4信号和炎症分泌谱来缓解代谢功能障碍相关的脂肪变性肝病

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-11-19 DOI: 10.1016/j.metabol.2025.156453

Jinxia Liu , Haifeng Wu , Ling Zhou , Qin Jin , Huoyan Ji , Baoying Hu , Hongpei Wu , Ting Chen , Xun Wang , Jianwei Hong , Rongwei Feng , Xiaojun Zhang , Jiali Zhou , Weiliang Zhang , Xu Wang , Lishuai Qu , Chunhua Wan

Background & aims

Innate immune receptors play a pivotal role in modulating immune responses during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to comprehensively investigate the role of the C-type lectin receptor DC-specific ICAM3-grabbing non-integrin (DC-SIGN) in MASLD progression.

Methods

DC-SIGN expression in liver tissues from patients with MASLD and healthy individuals was examined using immunohistochemical analyses. Immunofluorescence was used to determine DC-SIGN distribution across liver cell types. In vivo, adeno-associated virus (AAV)-mediated transduction of CD68 promoter-driven human DC-SIGN (hDC-SIGN) or a control construct was performed in mice fed either a high-fat, high-cholesterol (HFHC) diet or a normal chow diet (NCD). Additionally, THP-1-differentiated macrophages were used in vitro to investigate the molecular mechanisms by which DC-SIGN modulates Toll-like receptor 4 (TLR4) endocytosis and inflammatory cytokine secretion.

Results

DC-SIGN expression was significantly reduced in liver tissues from patients with MASLD and HFHC-fed mice compared to healthy controls and NCD-fed mice. DC-SIGN predominantly co-localized with the macrophage marker CD68. Delivery of CD68 promoter-specific hDC-SIGN markedly ameliorated HFHC-induced liver lipotoxicity, steatosis, inflammation, and fibrosis. Mechanistically, DC-SIGN facilitated macrophage TLR4 endocytosis via direct binding to TLR4, suppressing MyD88-dependent pro-inflammatory responses while activating TBK1-dependent IRF3 signaling. Accordingly, Lewis^X (Le^X)-DC-SIGN signaling reduced lipopolysaccharide (LPS)-induced pro-inflammatory cytokine secretion while simultaneously enhancing anti-inflammatory IL-10 secretion.

Conclusions

DC-SIGN plays a key role in modulating TLR4-dependent inflammation in MASLD, suggesting that targeting macrophage DC-SIGN may be a promising therapeutic approach.

背景和目的在代谢功能障碍相关脂肪变性肝病（MASLD）的进展过程中，辛酸免疫受体在调节免疫反应中起关键作用。本研究旨在全面探讨c型凝集素受体dc特异性icam3攫取非整合素（DC-SIGN）在MASLD进展中的作用。方法采用免疫组化方法检测MASLD患者和健康人肝组织中sdc - sign的表达。免疫荧光测定DC-SIGN在不同肝细胞类型间的分布。在体内，腺相关病毒（AAV）介导的CD68启动子驱动的人DC-SIGN （hdl - sign）或对照构建物的转导在喂食高脂高胆固醇（HFHC）饮食或正常食物（NCD）的小鼠中进行。此外，利用体外thp -1分化巨噬细胞，研究DC-SIGN调节toll样受体4 （TLR4）内吞和炎性细胞因子分泌的分子机制。结果与健康对照组和ncd喂养小鼠相比，MASLD患者和hfhc喂养小鼠肝组织中dc - sign的表达显著降低。DC-SIGN主要与巨噬细胞标志物CD68共定位。递送CD68启动子特异性hdl - sign可显著改善hfhc诱导的肝脂毒性、脂肪变性、炎症和纤维化。在机制上，DC-SIGN通过直接结合TLR4促进巨噬细胞TLR4内吞，抑制myd88依赖的促炎反应，同时激活tbk1依赖的IRF3信号。因此，LewisX (LeX)-DC-SIGN信号可以减少脂多糖（LPS）诱导的促炎细胞因子分泌，同时增强抗炎IL-10分泌。结论DC-SIGN在MASLD中调节tlr4依赖性炎症中起关键作用，提示靶向巨噬细胞DC-SIGN可能是一种很有前景的治疗方法。

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引用次数: 0

Emerging roles of arginine metabolism in skeletal health and disease 精氨酸代谢在骨骼健康和疾病中的新作用

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-11-19 DOI: 10.1016/j.metabol.2025.156451

Sibo Wang , Qian Ren , Yansheng Huang , Yibo Ma , Xuefang Zhang , Yuan Liu , Baorong He , Liang Yan

Arginine, as a semi-essential amino acid, plays a pivotal role in bone metabolism and orthopedic diseases. Beyond its function in protein synthesis, arginine serves as a crucial precursor for Nitric Oxide (NO), polyamines, and proline, profoundly influencing osteoblast differentiation, osteoclast activation, immune responses, and angiogenesis. Research indicates that abnormalities in arginine metabolism—such as imbalances in NO synthase activity, upregulation of arginase, or abnormal expression of protein arginine methyltransferases—are closely associated with the onset and progression of osteoporosis, rheumatoid arthritis, osteoarthritis, and bone tumors. Simultaneously, the arginine pathway intertwines with oxidative stress, inflammatory responses, and epigenetic regulation, forming a complex “metabolism-immunity-bone” network. In materials science, arginine has been integrated into various biomaterial systems, including Poly (lactic-co-glycolic acid) (PLGA) scaffolds, chitosan hydrogels, hydroxyapatite composites, and RGD-functionalized polymers, significantly enhancing osteogenic, angiogenic, and immunomodulatory capabilities. Despite ongoing research advancements, challenges persist in understanding the environment-dependent effects of arginine, optimizing dosage, and achieving clinical translation. This review systematically summarizes the mechanistic roles of arginine in bone metabolism regulation and its application progress in engineered materials, offering novel therapeutic insights and research directions for preventing and treating diseases such as osteoporosis, arthritis, and bone tumors.

精氨酸作为一种半必需氨基酸，在骨代谢和骨科疾病中起着关键作用。除了在蛋白质合成中的功能外，精氨酸还是一氧化氮（NO）、多胺和脯氨酸的重要前体，深刻影响成骨细胞分化、破骨细胞活化、免疫反应和血管生成。研究表明，精氨酸代谢异常（如NO合成酶活性失衡、精氨酸酶上调或蛋白精氨酸甲基转移酶表达异常）与骨质疏松症、类风湿关节炎、骨关节炎和骨肿瘤的发生和发展密切相关。同时，精氨酸途径与氧化应激、炎症反应和表观遗传调控交织在一起，形成了一个复杂的“代谢-免疫-骨”网络。在材料科学中，精氨酸已被整合到各种生物材料系统中，包括聚乳酸-羟基乙酸（PLGA）支架、壳聚糖水凝胶、羟基磷灰石复合材料和rgd功能化聚合物，显著增强了成骨、血管生成和免疫调节能力。尽管研究不断取得进展，但在了解精氨酸的环境依赖效应、优化剂量和实现临床转化方面仍然存在挑战。本文系统综述了精氨酸在骨代谢调节中的机制作用及其在工程材料中的应用进展，为骨质疏松症、关节炎、骨肿瘤等疾病的防治提供新的治疗思路和研究方向。

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Induction of Yin Yang 1 (YY1) overexpression in mature adipocytes promotes dysfunctional adipose tissue and systemic insulin resistance in mice 诱导成熟脂肪细胞中阴阳1 （YY1）过表达可促进小鼠脂肪组织功能失调和全身胰岛素抵抗。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-11-19 DOI: 10.1016/j.metabol.2025.156439

Line Pedersen , Christy M. Gliniak , Thomas Myhre Dale , Qingzhang Zhu , Chao Li , Jan-Bernd Funcke , Clair Crewe , Jiahui Luo , Lauren Palluth , Yi Zhu , Philipp E. Scherer

The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been linked to controlling mitochondrial gene expression and regulating cellular oxidative respiration, protecting against diet-induced obesity and alterations in energy balance. The role of YY1 in non-thermogenic, white adipose tissue, on the other hand, remains largely unknown. Here, we show that adipocyte-specific induction of YY1 promotes dysfunctional adipose tissue and systemic insulin resistance in mice. Long-term YY1 induction in mature adipocytes leads to reduced weight gain, systemic insulin resistance, and increased liver steatosis in comparison to control littermates. In contrast, brown adipose tissue-specific YY1 overexpression has little effect on mice fed a high-fat diet. In an obesogenic environment, acute ectopic adiponectin promoter-driven YY1 expression promotes weight loss, cell death, and adipose tissue inflammation. Underlying the observed reduction in adipose tissue mass, we find that YY1 controls gene networks related to adipose tissue expansion, lipid anabolic pathways (hypertrophy), and hyperplasia (adipogenesis). Taken together, our results demonstrate novel roles of Yy1 in white adipose tissue. This versatile transcription factor regulates central aspects of white adipose tissue biology that are essential for maintaining whole-body physiology.

无所不在的转录因子盈阳1 （YY1）在多种生物过程中起着重要作用，据信可调节高达10% %的人类基因。在产热棕色脂肪组织中，YY1与控制线粒体基因表达、调节细胞氧化呼吸、防止饮食引起的肥胖和能量平衡改变有关。另一方面，YY1在非产热的白色脂肪组织中的作用在很大程度上仍然未知。在这里，我们发现脂肪细胞特异性诱导YY1促进小鼠功能失调的脂肪组织和全身性胰岛素抵抗。与对照组相比，成熟脂肪细胞中YY1的长期诱导导致体重增加减少、全身胰岛素抵抗和肝脏脂肪变性增加。相比之下，棕色脂肪组织特异性YY1过表达对喂食高脂肪饮食的小鼠几乎没有影响。在致胖环境中，急性异位脂联素启动子驱动的YY1表达促进体重减轻、细胞死亡和脂肪组织炎症。在观察到的脂肪组织质量减少的基础上，我们发现YY1控制着与脂肪组织扩张、脂质合成代谢途径（肥大）和增生（脂肪生成）相关的基因网络。综上所述，我们的结果证明了Yy1在白色脂肪组织中的新作用。这种多功能转录因子调节白色脂肪组织生物学的中心方面，对维持全身生理至关重要。

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引用次数: 0