Metabolism: clinical and experimental最新文献

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Corrigendum to “Prolonged increase in glutamate whole body and intracellular production in older adults with COPD and healthy controls post-resistance exercise” [Metabolism, Volume 168, July 2025, 156185]

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-14 DOI: 10.1016/j.metabol.2025.156265

Robert H. Mbilinyi , Nicolaas E.P. Deutz , Clayton L. Cruthirds , Laura E. Ruebush , Tarun Sontam , Gabriella A.M. Ten Have , John J. Thaden , Mariëlle P.K.J. Engelen

引用次数: 0

Mechanical activation of adipose tissue macrophages mediated by Piezo1 protects against diet-induced obesity by regulating sympathetic activity

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-07 DOI: 10.1016/j.metabol.2025.156262

Shaoqiu Leng , Xiaoyu Zhang , Ruxia Zhao , Nan Jiang , Xinyue Liu , Xin Li , Qi Feng , Zi Sheng , Shuwen Wang , Jun Peng , Xiang Hu

Objective

Obesity-induced mechanical changes in white adipose tissue (WAT), including adipocyte hypertrophy and fibrosis, are hypothesized to alter adipose tissue macrophage (ATM) function through mechanosensitive pathways. This study aimed to determine whether the mechanosensor Piezo1 in ATMs regulates obesity-associated metabolic dysfunction and thermogenesis.

Methods

To investigate macrophage Piezo1 in obesity, myeloid-specific Piezo1-deficient mice (Piezo1^∆lyz2) and littermate controls (Piezo1^flox/+) were fed a high-fat diet (HFD) to induce obesity for 12 weeks. Metabolic assessments (GTT/ITT), tissue analyses (H&E staining, micro-CT), and RNA-seq were performed. Bone marrow transplantation and co-culture experiments (BMDMs with 3T3L1 adipocytes/PC12 neurons) were performed to evaluate macrophage-adipocyte/neuron crosstalk. Sympathetic activity was tested via cold exposure, NE measurement, and 6-OHDA/αMPT denervation. Molecular mechanisms were investigated using ChIP-qPCR.

Results

Piezo1^∆lyz2 mice exhibited aggravated HFD-induced obesity and insulin resistance despite reduced pro-inflammatory responses. Piezo1 deficiency in ATMs suppressed Slit3–ROBO1 signaling, leading to diminished NE secretion and impaired thermogenesis. Pharmacological inhibition of NE release (6-OHDA) or ROBO1 knockdown (shROBO1) abolished thermogenic disparities between Piezo1^∆lyz2 and control mice. Mechanistically, Piezo1 activation triggered SP1 nuclear translocation, directly binding to the Slit3 promoter to drive Slit3 transcription and secretion.

Conclusion

Piezo1 in ATMs mitigates obesity progression by promoting Slit3–ROBO1-dependent NE secretion and thermogenesis, independent of its pro-inflammatory role. This mechanosensitive pathway links WAT mechanical remodeling to metabolic regulation, which may offer a novel approach for managing obesity.

{"title":"Mechanical activation of adipose tissue macrophages mediated by Piezo1 protects against diet-induced obesity by regulating sympathetic activity","authors":"Shaoqiu Leng , Xiaoyu Zhang , Ruxia Zhao , Nan Jiang , Xinyue Liu , Xin Li , Qi Feng , Zi Sheng , Shuwen Wang , Jun Peng , Xiang Hu","doi":"10.1016/j.metabol.2025.156262","DOIUrl":"10.1016/j.metabol.2025.156262","url":null,"abstract":"<div><h3>Objective</h3><div>Obesity-induced mechanical changes in white adipose tissue (WAT), including adipocyte hypertrophy and fibrosis, are hypothesized to alter adipose tissue macrophage (ATM) function through mechanosensitive pathways. This study aimed to determine whether the mechanosensor Piezo1 in ATMs regulates obesity-associated metabolic dysfunction and thermogenesis.</div></div><div><h3>Methods</h3><div>To investigate macrophage Piezo1 in obesity, myeloid-specific Piezo1-deficient mice (<em>Piezo1</em><sup>∆lyz2</sup>) and littermate controls (<em>Piezo1</em><sup>flox/+</sup>) were fed a high-fat diet (HFD) to induce obesity for 12 weeks. Metabolic assessments (GTT/ITT), tissue analyses (H&E staining, micro-CT), and RNA-seq were performed. Bone marrow transplantation and co-culture experiments (BMDMs with 3T3L1 adipocytes/PC12 neurons) were performed to evaluate macrophage-adipocyte/neuron crosstalk. Sympathetic activity was tested via cold exposure, NE measurement, and 6-OHDA/αMPT denervation. Molecular mechanisms were investigated using ChIP-qPCR.</div></div><div><h3>Results</h3><div><em>Piezo1</em><sup>∆lyz2</sup> mice exhibited aggravated HFD-induced obesity and insulin resistance despite reduced pro-inflammatory responses. Piezo1 deficiency in ATMs suppressed Slit3–ROBO1 signaling, leading to diminished NE secretion and impaired thermogenesis. Pharmacological inhibition of NE release (6-OHDA) or ROBO1 knockdown (shROBO1) abolished thermogenic disparities between <em>Piezo1</em><sup>∆lyz2</sup> and control mice. Mechanistically, Piezo1 activation triggered SP1 nuclear translocation, directly binding to the Slit3 promoter to drive Slit3 transcription and secretion.</div></div><div><h3>Conclusion</h3><div>Piezo1 in ATMs mitigates obesity progression by promoting Slit3–ROBO1-dependent NE secretion and thermogenesis, independent of its pro-inflammatory role. This mechanosensitive pathway links WAT mechanical remodeling to metabolic regulation, which may offer a novel approach for managing obesity.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156262"},"PeriodicalIF":10.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143823272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reconsidering KLK7's role in adipose inflammation: letter to the editor. 重新考虑KLK7在脂肪炎症中的作用：致编辑的信。

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-05 DOI: 10.1016/j.metabol.2025.156255

Yaohui Zhong, Jiaqi Wei, Rui Jiang

引用次数: 0

Propagation of senescent phenotypes by extracellular HMGB1 is dependent on its redox state 细胞外 HMGB1 对衰老表型的传播取决于其氧化还原状态。

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-04 DOI: 10.1016/j.metabol.2025.156259

Ji-Won Shin , Dong-Hyun Jang , So Young Kim , Je-Jung Lee , Tae-Hwan Gil , Eunha Shim , Ji Yeon Kim , Hyeon Soo Kim , Michael J. Conboy , Irina M. Conboy , Christopher D. Wiley , Jeon-Soo Shin , Ok Hee Jeon

Background & purpose

Cellular senescence spreads systemically through blood circulation, but its mechanisms remain unclear. High mobility group box 1 (HMGB1), a multifunctional senescence-associated secretory phenotype (SASP) factor, exists in various redox states. Here, we investigate the role of redox-sensitive HMGB1 (ReHMGB1) in driving paracrine and systemic senescence.

Methods

We applied the paracrine senescence cultured model to evaluate the effect of ReHMGB1 on cellular senescence. Each redox state of HMGB1 was treated extracellularly to assess systemic senescence both in vitro and in vivo. Senescence was determined by SA-β-gal & EdU staining, p16^INK4a and p21 expression, RT-qPCR, and Western blot methods. Bulk RNA sequencing was performed to investigate ReHMGB1-driven transcriptional changes and underlying pathways. Cytokine arrays characterized SASP profiles from ReHMGB1-treated cells. In vivo, young mice were administered ReHMGB1 systemically to induce senescence across multiple tissues. A muscle injury model in middle-aged mice was used to assess the therapeutic efficacy of HMGB1 blockade.

Results

Extracellular ReHMGB1, but not its oxidized form, robustly induced senescence-like phenotypes across multiple cell types and tissues. Transcriptomic analysis revealed activation of RAGE-mediated JAK/STAT and NF-κB pathways, driving SASP expression and cell cycle arrest. Cytokine profiling confirmed paracrine senescence features induced by ReHMGB1. ReHMGB1 administration elevated senescence markers in vivo, while HMGB1 inhibition reduced senescence, attenuated systemic inflammation, and enhanced muscle regeneration.

Conclusion

ReHMGB1 is a redox-dependent pro-geronic factor driving systemic senescence. Targeting extracellular HMGB1 may offer therapeutic potential for preventing aging-related pathologies.

{"title":"Propagation of senescent phenotypes by extracellular HMGB1 is dependent on its redox state","authors":"Ji-Won Shin , Dong-Hyun Jang , So Young Kim , Je-Jung Lee , Tae-Hwan Gil , Eunha Shim , Ji Yeon Kim , Hyeon Soo Kim , Michael J. Conboy , Irina M. Conboy , Christopher D. Wiley , Jeon-Soo Shin , Ok Hee Jeon","doi":"10.1016/j.metabol.2025.156259","DOIUrl":"10.1016/j.metabol.2025.156259","url":null,"abstract":"<div><h3>Background & purpose</h3><div>Cellular senescence spreads systemically through blood circulation, but its mechanisms remain unclear. High mobility group box 1 (HMGB1), a multifunctional senescence-associated secretory phenotype (SASP) factor, exists in various redox states. Here, we investigate the role of redox-sensitive HMGB1 (ReHMGB1) in driving paracrine and systemic senescence.</div></div><div><h3>Methods</h3><div>We applied the paracrine senescence cultured model to evaluate the effect of ReHMGB1 on cellular senescence. Each redox state of HMGB1 was treated extracellularly to assess systemic senescence both <em>in vitro</em> and <em>in vivo</em>. Senescence was determined by SA-β-gal & EdU staining, p16<sup>INK4a</sup> and p21 expression, RT-qPCR, and Western blot methods. Bulk RNA sequencing was performed to investigate ReHMGB1-driven transcriptional changes and underlying pathways. Cytokine arrays characterized SASP profiles from ReHMGB1-treated cells. <em>In vivo</em>, young mice were administered ReHMGB1 systemically to induce senescence across multiple tissues. A muscle injury model in middle-aged mice was used to assess the therapeutic efficacy of HMGB1 blockade.</div></div><div><h3>Results</h3><div>Extracellular ReHMGB1, but not its oxidized form, robustly induced senescence-like phenotypes across multiple cell types and tissues. Transcriptomic analysis revealed activation of RAGE-mediated JAK/STAT and NF-κB pathways, driving SASP expression and cell cycle arrest. Cytokine profiling confirmed paracrine senescence features induced by ReHMGB1. ReHMGB1 administration elevated senescence markers <em>in vivo</em>, while HMGB1 inhibition reduced senescence, attenuated systemic inflammation, and enhanced muscle regeneration.</div></div><div><h3>Conclusion</h3><div>ReHMGB1 is a redox-dependent pro-geronic factor driving systemic senescence. Targeting extracellular HMGB1 may offer therapeutic potential for preventing aging-related pathologies.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156259"},"PeriodicalIF":10.8,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A complex multisystem disorder including hypopituitarism and hypoparathyroidism, associated with mutation in the gene encoding fatty acid synthase (FASN)

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-03 DOI: 10.1016/j.metabol.2025.156256

L.C. Gregory , S. Krywawych , S. Rahman , Carlos F. Lagos , S. Eaton , M.T. Dattani

Whole exome sequencing performed on a male patient with a complex phenotype including short stature associated with hypopituitarism, sensorineural deafness, hypoparathyroidism, retinal dystrophy, and developmental delay revealed a novel de novo variant in FASN (p.Ala2132Val), encoding fatty acid synthase. The patient failed to respond to growth-promoting treatment, only reaching a height of 128.3 cm (−6.98 SDS) at 24.7 years of age, and was prepubertal with a delayed bone age (13.6 years). Subsequent metabolic investigations demonstrated high triglyceride concentrations throughout an 18 h fast with a failure to increase 3-hydroxybutyrate, suggesting a defect in fatty acid oxidation or ketone body synthesis.

Human embryonic brain analysis revealed FASN expression in the diencephalon, hypothalamus and Rathke's pouch. Following the labelling of glucose with carbon-13 (C13) in cultured fibroblasts, mass spectrometry data revealed that more C13-glucose was incorporated into de novo synthesised palmitic acid in controls compared to patient cells, suggesting reduced fatty acid synthesis in the patient.

Our data suggest that the FASN p.Ala2132Val variant is associated with a complex phenotype including hypothalamo-pituitary dysfunction, consistent with previous studies showing that rodent neural/progenitor brain stem cells are governed by Fasn-dependent de novo lipogenesis (fatty acid synthesis) for proliferation.

{"title":"A complex multisystem disorder including hypopituitarism and hypoparathyroidism, associated with mutation in the gene encoding fatty acid synthase (FASN)","authors":"L.C. Gregory , S. Krywawych , S. Rahman , Carlos F. Lagos , S. Eaton , M.T. Dattani","doi":"10.1016/j.metabol.2025.156256","DOIUrl":"10.1016/j.metabol.2025.156256","url":null,"abstract":"<div><div>Whole exome sequencing performed on a male patient with a complex phenotype including short stature associated with hypopituitarism, sensorineural deafness, hypoparathyroidism, retinal dystrophy, and developmental delay revealed a novel <em>de novo</em> variant in <em>FASN</em> (p.Ala2132Val), encoding fatty acid synthase. The patient failed to respond to growth-promoting treatment, only reaching a height of 128.3 cm (−6.98 SDS) at 24.7 years of age, and was prepubertal with a delayed bone age (13.6 years). Subsequent metabolic investigations demonstrated high triglyceride concentrations throughout an 18 h fast with a failure to increase 3-hydroxybutyrate, suggesting a defect in fatty acid oxidation or ketone body synthesis.</div><div>Human embryonic brain analysis revealed <em>FASN</em> expression in the diencephalon, hypothalamus and Rathke's pouch. Following the labelling of glucose with carbon-13 (C13) in cultured fibroblasts, mass spectrometry data revealed that more C13-glucose was incorporated into <em>de novo</em> synthesised palmitic acid in controls compared to patient cells, suggesting reduced fatty acid synthesis in the patient.</div><div>Our data suggest that the <em>FASN</em> p.Ala2132Val variant is associated with a complex phenotype including hypothalamo-pituitary dysfunction, consistent with previous studies showing that rodent neural/progenitor brain stem cells are governed by Fasn-dependent <em>de novo</em> lipogenesis (fatty acid synthesis) for proliferation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156256"},"PeriodicalIF":10.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prediction models for the implementation of precision medicine in the real world. Some critical issues.

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-03 DOI: 10.1016/j.metabol.2025.156257

Claudia Menzaghi, Massimiliano Copetti, Christos S Mantzoros, Vincenzo Trischitta

引用次数: 0

Revisiting gender differences in obesity and type 2 diabetes: Letter to the editor.

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-03 DOI: 10.1016/j.metabol.2025.156260

Yaohui Zhong, Jiaqi Wei, Rui Jiang

引用次数: 0

Unraveling sphingolipid complexity in liver fibrosis: Perspectives for future research. 揭示肝纤维化中鞘磷脂的复杂性：未来研究的前景

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-02 DOI: 10.1016/j.metabol.2025.156254

Jiaqi Wei, Yaohui Zhong, Yaling Li, Jun Li

引用次数: 0

Hexosamine biosynthesis dysfunction-induced LIFR N-glycosylation deficiency exacerbates steatotic liver ischemia/reperfusion injury

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-02 DOI: 10.1016/j.metabol.2025.156258

Ran Liu , Gengqiao Wang , Yongbing Qian , Zhengting Jiang , Weimin Wang , Mao Cai , Shuhua Zhang , Guoliang Wang , Chuanzheng Wang , Tianhao Zou , Huan Cao , Di Zhang , Xueling Wang , Shenghe Deng , Tongxi Li , Jinyang Gu

Background

More and more steatotic livers undergo resection or transplantation but they exhibit higher susceptibility to ischemia-reperfusion injury (IRI), which results in increased perioperative complication morbidity and mortality. IRI is driven by various cytokines and receptors, both of which are extensively modified by N-glycosylation. We aim to elucidate susceptibility of steatotic livers to IRI from the perspective of N-glycosylation.

Methods

Differentially expressed genes and glycoproteins were identified with RNA-seq and N-glycoproteomics. Myeloid LIF or hepatocyte LIFR knockout mice were developed to examine the function of LIF and LIFR. Modalities including phosphoproteomics, ChIP-seq, single cell RNA-seq, metabolomics and immunoblotting were utilized to investigate underlying mechanisms.

Results

LIF transcription in myeloid cells and LIFR N-glycosylation in hepatocytes were substantially induced by IRI of normal livers. LIF and LIFR protected normal livers from IRI through activating STAT3 and promoting downstream TNFAIP3 expression, which was facilitated by LIFR N-glycosylation. Mechanistically, N-glycosylation at N238 stabilized LIFR protein by disrupting TRIM28-mediated K48 ubiquitination at LIFR K254. Furthermore, N-glycosylation at N358/N658/N675 of LIFR facilitated LIF/LIFR/gp130 complex formation and subsequent signal transduction. However, in steatotic livers, myeloid cell LIF transcription was partially inhibited due to hepatic microenvironment L-arginine insufficiency, while hepatocyte LIFR N-glycosylation was defective due to intracellular UDP-GlcNAc exhaustion. Importantly, combined L-arginine and GlcNAc treatment reversed LIF expression and LIFR N-glycosylation insufficiency, which represents potential therapeutic strategy to protect steatotic livers.

Conclusions

LIF expression and LIFR N-glycosylation insufficiency aggravates steatotic liver IRI, which can be reversed by combined L-arginine and GlcNAc treatment.

{"title":"Hexosamine biosynthesis dysfunction-induced LIFR N-glycosylation deficiency exacerbates steatotic liver ischemia/reperfusion injury","authors":"Ran Liu , Gengqiao Wang , Yongbing Qian , Zhengting Jiang , Weimin Wang , Mao Cai , Shuhua Zhang , Guoliang Wang , Chuanzheng Wang , Tianhao Zou , Huan Cao , Di Zhang , Xueling Wang , Shenghe Deng , Tongxi Li , Jinyang Gu","doi":"10.1016/j.metabol.2025.156258","DOIUrl":"10.1016/j.metabol.2025.156258","url":null,"abstract":"<div><h3>Background</h3><div>More and more steatotic livers undergo resection or transplantation but they exhibit higher susceptibility to ischemia-reperfusion injury (IRI), which results in increased perioperative complication morbidity and mortality. IRI is driven by various cytokines and receptors, both of which are extensively modified by N-glycosylation. We aim to elucidate susceptibility of steatotic livers to IRI from the perspective of N-glycosylation.</div></div><div><h3>Methods</h3><div>Differentially expressed genes and glycoproteins were identified with RNA-seq and N-glycoproteomics. Myeloid LIF or hepatocyte LIFR knockout mice were developed to examine the function of LIF and LIFR. Modalities including phosphoproteomics, ChIP-seq, single cell RNA-seq, metabolomics and immunoblotting were utilized to investigate underlying mechanisms.</div></div><div><h3>Results</h3><div>LIF transcription in myeloid cells and LIFR N-glycosylation in hepatocytes were substantially induced by IRI of normal livers. LIF and LIFR protected normal livers from IRI through activating STAT3 and promoting downstream TNFAIP3 expression, which was facilitated by LIFR N-glycosylation. Mechanistically, N-glycosylation at N238 stabilized LIFR protein by disrupting TRIM28-mediated K48 ubiquitination at LIFR K254. Furthermore, N-glycosylation at N358/N658/N675 of LIFR facilitated LIF/LIFR/gp130 complex formation and subsequent signal transduction. However, in steatotic livers, myeloid cell LIF transcription was partially inhibited due to hepatic microenvironment L-arginine insufficiency, while hepatocyte LIFR N-glycosylation was defective due to intracellular UDP-GlcNAc exhaustion. Importantly, combined L-arginine and GlcNAc treatment reversed LIF expression and LIFR N-glycosylation insufficiency, which represents potential therapeutic strategy to protect steatotic livers.</div></div><div><h3>Conclusions</h3><div>LIF expression and LIFR N-glycosylation insufficiency aggravates steatotic liver IRI, which can be reversed by combined L-arginine and GlcNAc treatment.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156258"},"PeriodicalIF":10.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

L-Kynurenine activates the AHR-PCSK9 pathway to mediate the lipid metabolic and ovarian dysfunction in polycystic ovary syndrome

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-03-31 DOI: 10.1016/j.metabol.2025.156238

Yujiao Wang , Yifan Wu , Hongwei Jiang , Shang Li , Jingjing Li , Cong Wang , Lexin Yang , Xiying Zhou , Juanjuan Yu , Junyu Zhai , Zi-Jiang Chen , Yanzhi Du

Dysregulated amino acid metabolism is a key contributor to polycystic ovary syndrome (PCOS). This cross-sectional study revealed that serum levels of L-kynurenine (L-Kyn) were significantly elevated in women with PCOS, whereas pyridoxal 5′-phosphate (PLP) levels were markedly reduced. Moreover, human serum L-Kyn levels exhibited a positive correlated with low-density lipoprotein cholesterol (LDL-C) and a negative correlation with high-density lipoprotein cholesterol (HDL-C). Additionally, letrozole (LET) induced PCOS-like mice displayed increased hepatic L-Kyn levels. Mechanistically, both in vivo and in vitro experiments demonstrated that the upregulation of indoleamine 2,3-dioxygenase (IDO1) activates the aryl hydrocarbon receptor (AHR) - proprotein convertase subtilisin/kexin type 9 (PCSK9) pathway in the liver of PCOS-like mice, thereby contributing to dyslipidemia. Treatment with epacadostat, an inhibitor of the enzyme IDO1, or PLP, a cofactor for L-Kyn catabolism, effectively restored ovarian function, improved glucose tolerance, and ameliorated lipid profile abnormalities in PCOS-like mice.

{"title":"L-Kynurenine activates the AHR-PCSK9 pathway to mediate the lipid metabolic and ovarian dysfunction in polycystic ovary syndrome","authors":"Yujiao Wang , Yifan Wu , Hongwei Jiang , Shang Li , Jingjing Li , Cong Wang , Lexin Yang , Xiying Zhou , Juanjuan Yu , Junyu Zhai , Zi-Jiang Chen , Yanzhi Du","doi":"10.1016/j.metabol.2025.156238","DOIUrl":"10.1016/j.metabol.2025.156238","url":null,"abstract":"<div><div>Dysregulated amino acid metabolism is a key contributor to polycystic ovary syndrome (PCOS). This cross-sectional study revealed that serum levels of L-kynurenine (L-Kyn) were significantly elevated in women with PCOS, whereas pyridoxal 5′-phosphate (PLP) levels were markedly reduced. Moreover, human serum L-Kyn levels exhibited a positive correlated with low-density lipoprotein cholesterol (LDL-C) and a negative correlation with high-density lipoprotein cholesterol (HDL-C). Additionally, letrozole (LET) induced PCOS-like mice displayed increased hepatic L-Kyn levels. Mechanistically, both in vivo and in vitro experiments demonstrated that the upregulation of indoleamine 2,3-dioxygenase (IDO1) activates the aryl hydrocarbon receptor (AHR) - proprotein convertase subtilisin/kexin type 9 (PCSK9) pathway in the liver of PCOS-like mice, thereby contributing to dyslipidemia. Treatment with epacadostat, an inhibitor of the enzyme IDO1, or PLP, a cofactor for L-Kyn catabolism, effectively restored ovarian function, improved glucose tolerance, and ameliorated lipid profile abnormalities in PCOS-like mice.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156238"},"PeriodicalIF":10.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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