Metabolism: clinical and experimental最新文献

{"title":"Hepatic aconitase 1 redirects citrate flux to suppress lipogenesis and ameliorate hypercholesterolemia","authors":"Linyi Li ,&nbsp;Yu Wang ,&nbsp;Zhiyong Du ,&nbsp;Huahui Yu ,&nbsp;Yunyun Yang ,&nbsp;Zihan Zhang ,&nbsp;Yanru Duan ,&nbsp;Lijie Han ,&nbsp;Chaowei Hu ,&nbsp;Yunhui Du ,&nbsp;Haili Sun ,&nbsp;Xuechun Sun ,&nbsp;Jingci Xing ,&nbsp;Xiaoqian Gao ,&nbsp;Dong Chen ,&nbsp;Yuhui Wang ,&nbsp;Xinwei Hua ,&nbsp;Jianping Li ,&nbsp;Yanwen Qin","doi":"10.1016/j.metabol.2025.156417","DOIUrl":"10.1016/j.metabol.2025.156417","url":null,"abstract":"<div><h3>Background and aims</h3><div>Targeting key enzymes in hepatic de novo lipogenesis (DNL) presents a promising strategy for treating hypercholesterolemia. However, the precise regulatory mechanisms governing hepatic DNL remain incompletely understood. Cytosolic citrate plays a crucial role in DNL, with aconitase 1 (ACO1), a key enzyme in citrate metabolism, potentially influencing lipid metabolism. The aim of this study was to clarify the role of hepatic ACO1 in regulating both hepatic and systemic lipid homeostasis.</div></div><div><h3>Methods</h3><div>ACO1 expression and activity were assessed in liver tissues from multiple hypercholesterolemic animal models. Using liver-specific genetic manipulation, we examined the effects of hepatic ACO1 knockout and overexpression on hypercholesterolemia and atherosclerosis. Targeted metabolomics and stable isotope-based flux analysis were used to profile hepatic substrate utilization patterns.</div></div><div><h3>Results</h3><div>Hepatic ACO1 expression was significantly reduced in both hypercholesterolemic patients and animal models. Hepatocyte-specific ACO1 deletion exacerbated dyslipidemia, while ACO1 overexpression improved hypercholesterolemia, hepatic steatosis, and atherosclerosis in mouse models. Mechanistically, ACO1 overexpression redirected cytosolic citrate metabolism toward α-ketoglutarate, thereby limiting acetyl-CoA availability for DNL and suppressing fatty acid and cholesterol synthesis. These lipid-lowering effects were dependent on ACO1 enzymatic activity, as catalytically inactive ACO1 mutants failed to replicate the observed benefits.</div></div><div><h3>Conclusion</h3><div>Our findings identify hepatic ACO1 as a critical regulator of lipid metabolism homeostasis. Promoting ACO1-mediated citrate redirection effectively mitigates hypercholesterolemia and atherosclerosis by suppressing hepatic DNL, highlighting ACO1 as a potential target for lipid-lowering therapies.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156417"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258780","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}

{"title":"METTL1-mediated m7G methylation of FoxO1 regulates lipid metabolism in metabolic dysfunction-associated fatty liver disease","authors":"Jiang Du ,&nbsp;Yujie Li ,&nbsp;Xinxing Zhu ,&nbsp;Jingwen Gao ,&nbsp;Yuxuan Zhang ,&nbsp;Chiheng Wang ,&nbsp;Di Han ,&nbsp;Liang Qiao ,&nbsp;Beilin Kou ,&nbsp;Rui Guo ,&nbsp;Hongen Zhang ,&nbsp;Juntang Lin","doi":"10.1016/j.metabol.2025.156420","DOIUrl":"10.1016/j.metabol.2025.156420","url":null,"abstract":"<div><div>Metabolic dysfunction-associated fatty liver disease (MASLD) is characterized by the accumulation and degeneration of lipids in hepatocytes, presenting a complex pathogenesis that complicates drug development. In this study, we found that methyltransferase-like 1 (METTL1) is upregulated in the livers of both MASLD mice and clinical samples. Hepatocyte-specific depletion of METTL1 inhibits lipid synthesis and promotes lipid oxidation, alleviating metabolic disorders in high-fat diet (HFD)-induced MASLD mice. Conversely, overexpression of METTL1 enhances lipid synthesis while suppressing lipid oxidation. Mechanistically, METTL1 regulates the stability and protein expression levels of FoxO1 mRNA by methylating the Exon1 region of FoxO1, as demonstrated by m7G sequencing. Additionally, we found that overexpression of FoxO1 counteracts the protective effects of METTL1 deficiency on metabolic disorders in MASLD mice. Moreover, we identified a potent small-molecule inhibitor of METTL1, specifically Homatropine Methylbromide (HtMBm), which significantly ameliorated HFD-induced MASLD. Overall, our study suggests that METTL1 plays a crucial role in the progression of MASLD and highlights the therapeutic potential of targeting METTL1 to modulate fatty acid metabolism in this condition.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156420"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308571","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}

{"title":"Mitochondrial phosphopantetheinylation is required for oxidative metabolism","authors":"Pieter R. Norden ,&nbsp;Riley J. Wedan ,&nbsp;Samuel E.J. Preston ,&nbsp;Morgan Canfield ,&nbsp;Naomi Graber ,&nbsp;Jacob Z. Longenecker ,&nbsp;Olivia A. Pentecost ,&nbsp;Elizabeth McLaughlin ,&nbsp;Madeleine L. Hart ,&nbsp;Sara M. Nowinski","doi":"10.1016/j.metabol.2025.156413","DOIUrl":"10.1016/j.metabol.2025.156413","url":null,"abstract":"<div><div>4′-Phosphopantetheinyl (4’PP) groups are essential co-factors added to target proteins by <u>p</u>hospho<u>p</u>antetheinyl <u>t</u>ransferase (PPTase) enzymes. Although mitochondrial 4’PP-modified proteins have been described for decades, a mitochondrially-localized PPTase has never been found in mammals. We discovered that the cytoplasmic PPTase <u>a</u>mino<u>a</u>dipate <u>s</u>emialdehyde <u>d</u>ehydrogenase <u>p</u>hospho<u>p</u>antetheinyl <u>t</u>ransferase (AASDHPPT) is required for mitochondrial respiration and oxidative metabolism. Loss of AASDHPPT results in failed 4’PP modification of the mitochondrial acyl carrier protein and blunted activity of the mitochondrial fatty acid synthesis (mtFAS) pathway. We found that in addition to its cytoplasmic localization, AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 20 amino acids of the protein. Our data show that this novel mitochondrial localization of AASDHPPT is required to support mtFAS activity and oxidative metabolism. We further identify five variants of uncertain significance in <em>AASDHPPT</em> that are likely pathogenic in humans due to loss of mtFAS activity.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156413"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251663","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}

{"title":"ALDH2 deficiency aggravates vascular injury-induced restenosis by enhancing vascular smooth muscle cell proliferation through SLC38A2-mediated upregulation of glutamine uptake","authors":"Dehui Hou ,&nbsp;Kehui Yang ,&nbsp;Yang Liu,&nbsp;Han Du,&nbsp;Hongwei Yue,&nbsp;Fengyang Xu,&nbsp;Wentao Sang,&nbsp;Xiangkai Zhao,&nbsp;Yijun Sun,&nbsp;Feng Xu,&nbsp;Yuguo Chen","doi":"10.1016/j.metabol.2025.156411","DOIUrl":"10.1016/j.metabol.2025.156411","url":null,"abstract":"<div><h3>Background and aims</h3><div>Vascular injury-induced restenosis is an important cause of poor long-term prognosis in patients with coronary artery disease (CAD). Although aldehyde dehydrogenase 2 (ALDH2) deficiency has been linked to poor outcomes in CAD patients, the precise mechanisms through which ALDH2 influences vascular injury-induced restenosis remain elusive. Herein, we attempted to explore the role of ALDH2 in modulating vascular smooth muscle cell (VSMC) proliferation and vascular injury-induced restenosis.</div></div><div><h3>Methods and results</h3><div>Immunofluorescence and immunoblotting revealed that ALDH2 expression was significantly decreased in VSMCs in human stenotic coronary segments and injured mouse femoral and carotid arteries. Global ALDH2 knockout and VSMC-specific ALDH2 knockout exacerbated injury-induced neointima formation, whereas VSMC-specific ALDH2 overexpression reduced neointima formation. Endothelial cell (EC)-specific ALDH2 knockout had little effect on injury-induced neointima formation. Mechanistic studies revealed that ALDH2 deficiency facilitated VSMC proliferation by upregulating the expression of the glutamine transporter SLC38A2, which is a novel ALDH2 target gene. Further bioinformatics analysis, luciferase assays, and ChIP–qPCR revealed that ALDH2 deficiency increased SLC38A2 expression <em>via</em> activating transcription factor 4 (ATF4) and that ATF4 knockdown largely reversed the ability of ALDH2 deficiency to promote VSMC proliferation. Moreover, ALDH2 deficiency promoted the accumulation of 4-HNE adducted proteins, thereby activating ATF4, which subsequently increased SLC28A2 transcriptional activity in VSMCs. Importantly, downregulation of SLC38A2 by adeno-associated virus serotype 2 (AAV2) shRNA or by the inhibitor MeAIB has promising therapeutic potential in limiting VSMC proliferation and neointima formation. Finally, we demonstrated that VSMC proliferation was aggravated and that neointima formation occurred in ALDH2^E506k mutant mice.</div></div><div><h3>Conclusion</h3><div>Our study elucidates a novel mechanism through which ALDH2 deficiency aggravates neointimal formation by enhancing VSMC proliferation through an increase in glutamine uptake, suggesting a promising translational strategy for the prevention of vascular injury-induced restenosis.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156411"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258767","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}

{"title":"Lysine potentiates insulin secretion via AASS-dependent catabolism and regulation of GABA content and signaling","authors":"Felipe Muñoz ,&nbsp;Qian Gao ,&nbsp;Matthias Mattanovich ,&nbsp;Kajetan Trost ,&nbsp;Ondřej Hodek ,&nbsp;Andreas Lindqvist ,&nbsp;Nils Wierup ,&nbsp;Malin Fex ,&nbsp;Thomas Moritz ,&nbsp;Hindrik Mulder ,&nbsp;Luis Rodrigo Cataldo","doi":"10.1016/j.metabol.2025.156423","DOIUrl":"10.1016/j.metabol.2025.156423","url":null,"abstract":"<div><div>Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane depolarization similar to arginine, the role of its intracellular metabolism in β-cell function remains unexplored.</div><div>Here, we show that lysine acutely potentiates GSIS and that genes encoding enzymes in the lysine degradation pathway, including AminoAdipate-Semialdehyde Synthase (AASS), a key mitochondrial enzyme catalysing the first two steps of lysine catabolism, were present in human pancreatic islets and INS1 832/13 β cells. Some of these genes including <em>AASS, ALDH7A1, DHTKD1</em>, and <em>HADH</em>, were downregulated in pancreatic islets from type 2 diabetes (T2D) versus non-diabetic (ND) donors. Silencing <em>AASS</em> in human islets and INS1 832/13 β cells led to reduced GSIS. Integrated transcriptomics and metabolomics revealed altered expression of GABA metabolism genes, reduced GABA content and accumulation of glutamate in <em>Aass</em>-KD cells. Mitochondrial TCA cycle and OXPHOS function was impaired, evidenced by decreased ATP/ADP ratio, diminished glucose-stimulated mitochondrial respiration, and elevated lactate/pyruvate ratio. Cytosolic calcium responses to glucose and GABA were also disrupted.</div><div>Pharmacological analyses demonstrated that inhibition of GABA synthesis or degradation did not account for the reduced GSIS, but providing substrates and activation of GDH partially restored insulin secretion, pointing to a diminished glutamate supply as a contributing factor. Remarkably, exogenous GABA restored insulin secretion in β cells and human islets with suppressed AASS-dependent lysine catabolism, supporting a role for GABA as both a metabolic substrate and signaling effector.</div><div>Together, these findings identify AASS-mediated lysine catabolism as a critical regulator of β-cell metabolic integrity, linking impaired lysine metabolism to GABA depletion, mitochondrial dysfunction, and secretory failure in T2D islets. They also underscore the nutritional importance of essential amino acids such as lysine in sustaining GSIS and glucose homeostasis, and support therapeutic strategies aimed at restoring lysine catabolism or GABA/glutamate balance to maintain β-cell function.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156423"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145409747","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}

{"title":"A melanocortin 4- and glucagon-like peptide 1 receptor multiple agonist for the treatment of diabetes and obesity","authors":"Emily F. Ashlaw ,&nbsp;Clinton T. Elfers ,&nbsp;Kylie S. Chichura ,&nbsp;Isabella Chavez Miranda ,&nbsp;Aelish McGivney ,&nbsp;Oleg G. Chepurny ,&nbsp;George G. Holz ,&nbsp;Ginger Mullins ,&nbsp;Laura J. den Hartigh ,&nbsp;Yongjun Liu ,&nbsp;Christian L. Roth ,&nbsp;Robert P. Doyle","doi":"10.1016/j.metabol.2025.156414","DOIUrl":"10.1016/j.metabol.2025.156414","url":null,"abstract":"<div><div>Obesity and its sequelae cause significant morbidity and mortality worldwide. Current glucagon-like peptide-1 (GLP-1) receptor agonist-based treatments have significant side-effects associated with high rates of treatment discontinuation. Such concerns are greater still in children and adolescents. Thus, there remains a clinical unmet need to develop obesity and/or T2D mellitus therapies with significantly improved tolerability. Herein, we examined a polypharmacy approach combining melanocortin (MC) 4-, and GLP-1-receptor agonism in a single monomeric peptide based on α-MSH and Exendin-4 to bind and stimulate different peptide receptors in vitro, and to drive reductions in body weight and food intake in up to 7 weeks of treatment in comparison to semaglutide and tirzepatide as standard of care positive controls in diet-induced obese rats. Despite the monomeric peptide GLP-1-/MC4-receptor multiple agonist (KCEM1) being a non-lipidated, weaker GLP-1R agonist compared to semaglutide and tirzepatide, reductions in calorie intake and body weight were similar in all three groups after daily subcutaneous injections of the three peptides. In addition, KCEM1 offered superior glycemic control during glucose tolerance testing. In gene expression analyses, KCEM1, but not semaglutide or tirzepatide, significantly increased expression of glucose transporter 4 (GLUT4) and key glycolysis enzyme Pgk1 in skeletal muscle, while it reduced genetic markers of inflammation in different tissues, including inflammatory markers IL-6 and TNF-α in liver tissue. Furthermore, KCEM1 lowered hepatic lipid content and improved metabolic dysfunction-associated steatohepatitis (MASH) scoring. Overall, these data extend emerging concepts around the use of multi-receptor polypharmacy to treat metabolic syndrome.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156414"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145301916","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}

{"title":"Emerging roles of TRIM in metabolic regulation","authors":"Jiaxing Wang ,&nbsp;Qiangzhou Wang ,&nbsp;Xinrui Li ,&nbsp;Qingqing Cai ,&nbsp;Yulin Bi ,&nbsp;Chenyang Xu ,&nbsp;Hao Bai ,&nbsp;Lihong Gu ,&nbsp;Guobin Chang ,&nbsp;Shihao Chen","doi":"10.1016/j.metabol.2025.156394","DOIUrl":"10.1016/j.metabol.2025.156394","url":null,"abstract":"<div><div>Recent findings have broadened our understanding of the tripartite motif (TRIM) protein family, positioning these proteins as pivotal regulators of cellular metabolism and cell fate. Primarily functioning as versatile E3 ubiquitin ligases, TRIM proteins orchestrate key metabolic pathways—including glucose, lipid, and amino acid metabolism—through both ubiquitination-dependent and -independent mechanisms such as oligomerization and epigenetic modification. For example, TRIM38, TRIM11, and TRIM24 have been reported to modulate glycolytic flux and insulin signaling by targeting key glucose transporters and glycolytic enzymes, with effects on cancer metabolism and insulin responses in model systems. Similarly, TRIM21 and TRIM56 have been implicated in fatty acid synthesis, oxidation, and cholesterol balance, with potential relevance to fatty-liver conditions and atherosclerosis. Moreover, TRIM-mediated regulation of amino acid metabolism-particularly through pathways involving glutamine and branched-chain amino acids-plays a central role in tumor metabolic reprogramming and survival. Beyond enzymatic regulation, TRIM proteins exert non-canonical functions through epigenetic modulation and interactions with signaling networks. This review synthesizes current insights into the multifaceted roles of TRIM proteins in metabolic control and cell death, suggesting that ferroptosis may link TRIM proteins to lipid and amino acid metabolism, and highlights the connection between TRIM proteins and metabolic stress as a key area for future research.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156394"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109903","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}

{"title":"Glucoprivation-induced nutrient preference relies on distinct NPY neurons that project to the paraventricular nucleus of the hypothalamus","authors":"Nawarat Rattanajearakul ,&nbsp;Kunio Kondoh ,&nbsp;Ou Fu ,&nbsp;Shiki Okamoto ,&nbsp;Kenta Kobayashi ,&nbsp;Ken-ichiro Nakajima ,&nbsp;Yasuhiko Minokoshi","doi":"10.1016/j.metabol.2025.156415","DOIUrl":"10.1016/j.metabol.2025.156415","url":null,"abstract":"<div><h3>Background</h3><div>Neural pathways related to total calorie intake have been extensively studied. However, it remains unclear how these mechanisms control food selection.</div></div><div><h3>Methods</h3><div>Male mice were subjected to glucoprivation through the intraperitoneal (i.p.) administration of 2-deoxy-<span>d</span>-glucose (2DG) and were examined for food selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) in a diet choice paradigm. This involved the chemogenetic or optogenetic modulation of the neural activity of AMP-activated protein kinase (AMPK)-regulated corticotropin-releasing hormone (CRH) neurons, melanocortin-4 receptor (MC4R) neurons in the paraventricular nucleus of the hypothalamus (PVH), and neuropeptide Y (NPY) neurons projecting to the PVH.</div></div><div><h3>Results</h3><div>Glucoprivation induced by 2DG administration in mice influenced two distinct neural pathways in the PVH that separately promote the intake of an HCD or an HFD. Injection of 2DG activated PVH-projecting NPY neurons in the nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM), resulting in a rapid increase in HCD intake through stimulation of PVH AMPK–regulated CRH neurons and recovery from glucoprivation. In contrast, PVH-projecting NPY neurons in the NTS, VLM, and arcuate nucleus of the hypothalamus (ARC) promoted HFD intake by inhibiting MC4R neurons in the PVH, reflecting the strong innate preference for an HFD in mice. The ARC NPY neurons specifically promoted HFD selection.</div></div><div><h3>Conclusion</h3><div>Our findings reveal a previously unrecognized mechanism for food selection between HCD and HFD during glucoprivation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156415"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280693","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}

{"title":"SRSF1 is essential for pancreatic β-cell proliferation and the maintenance of glucose homeostasis in mice","authors":"Xue You ,&nbsp;Qian Peng ,&nbsp;Wenju Qian ,&nbsp;Zhiqin Xie ,&nbsp;Yijun Lin ,&nbsp;Yikuo Gai ,&nbsp;Jingran Ye ,&nbsp;Ying Feng","doi":"10.1016/j.metabol.2025.156421","DOIUrl":"10.1016/j.metabol.2025.156421","url":null,"abstract":"<div><h3>Background</h3><div>β-Cell proliferation is vital for adapting to metabolic stress. Failure to expand β-cell mass during insulin resistance and aging contributes to dysfunction and diabetes. Understanding the mechanisms behind β-cell proliferation issues and dysfunction is crucial. SRSF1 is a central regulator of cell proliferation and survival, but its influence on β-cell proliferation and glucose control remains unclear. This study aims to investigate the role of SRSF1 in β-cell proliferation and its impact on glucose regulation. By examining the consequences of SRSF1 deficiency in pancreatic β-cells, we seek to elucidate the mechanisms linking SRSF1 to β-cell maintenance and function.</div></div><div><h3>Methods</h3><div>Mice with pancreatic β-cell-specific deletion of SRSF1 and a Rosa26-tdT lineage reporter were generated. Pancreatic sections were analyzed using immunostaining for insulin, glucagon, somatostatin, Ki67, tdT, proinsulin, TUNEL, and ER stress markers, as well as HE staining. Glucose tolerance tests, glucose and insulin measurements were performed in knockout and control mice. RNA-seq analyzed gene expression changes in 4-month-old islets, while scRNA-seq assessed cellular heterogeneity and gene expression profiles in 10-month-old mice islets. Knockdown assays and puromycin labeling experiments measured new protein synthesis.</div></div><div><h3>Results</h3><div>SRSF1 deficiency resulted in glucose intolerance and impaired insulin secretion, worsening with age. At early stages, knockout islets exhibited reduced β-cell proliferation accompanied by compensatory α-cell expansion. By 4 months, RNA-seq analysis showed downregulation of ribosome biogenesis and cell cycle genes, along with upregulation of α-cell determinants and progenitor-associated factors. Histological examination further revealed a decreased β-cell fraction, an increased α-cell fraction, and a small subset of α-cells co-expressing somatostatin, indicative of transient, stress-associated phenotypic plasticity. scRNA-seq identified ER stress and altered β-cell fate in knockout β-cells from 10-month-old mice. Notably, these changes were absent in 4-month-old knockout islets, indicating ER stress as a secondary response to proliferative defects from SRSF1 deficiency. Mechanistically, SRSF1 employs mechanisms similar to MYC to promote β-cell proliferation, with its effects on β-cells through the regulation of MYC expression.</div></div><div><h3>Conclusions</h3><div>SRSF1 is essential for β-cell proliferation and function through MYC-mediated pathways. Its deficiency disrupts β-cell homeostasis and contributes to metabolic dysfunction in mice, underscoring its importance in preserving functional β-cells and maintaining glucose balance.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156421"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370426","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}

{"title":"Sepsis-induced lipid droplet accumulation enhances antibacterial innate immunity through mechanisms dependent on DGAT-1 and interferon-beta","authors":"Filipe S. Pereira-Dutra ,&nbsp;Julia Cunha Santos ,&nbsp;Ellen Kiarely Souza ,&nbsp;Rodrigo Vieira Savi ,&nbsp;Tamyris S. Souza ,&nbsp;Helen Gil ,&nbsp;Hugo Espinheira-Silva ,&nbsp;Felipe Ferraro-Moreira ,&nbsp;Guilherme Iack ,&nbsp;Tamires Cunha-Fernandes ,&nbsp;Tathiany Igreja-Silva ,&nbsp;Lohanna Palhinha ,&nbsp;Mariana Macedo Campos ,&nbsp;Ester Fernanda Terra Souza ,&nbsp;Amanda França Cordeiro ,&nbsp;Pablo Andrade-dos-Santos ,&nbsp;Douglas Mathias Oliveira ,&nbsp;Vinicius Soares Cardoso ,&nbsp;Matheus A. Rajão ,&nbsp;Livia Teixeira ,&nbsp;Patrícia T. Bozza","doi":"10.1016/j.metabol.2025.156389","DOIUrl":"10.1016/j.metabol.2025.156389","url":null,"abstract":"<div><div>Lipid droplets (LDs) are lipid-rich organelles recognized as central players in lipid homeostasis, signaling, and inflammation. While their functions in inflammation are well-documented, the mechanisms of LDs in antibacterial immunity and infection resistance remain less understood. Our results show that <em>E. coli</em>-infection trigger immunometabolic reprogramming and LD accumulation in murine macrophages (BMDM). Moreover, purified LDs from LPS-stimulated and <em>E. coli-</em>infected macrophages exhibited direct <em>E. coli</em> anti-bacterial activity. Pharmacological inhibition or genetic knockdown of DGAT1, a key enzyme in triglyceride synthesis, reduced LD formation, bacterial clearance, and pro-inflammatory responses (nitric oxide, PGE₂, CCL2, IL-6). Notably, DGAT1 inhibition impaired the expression of IFN-β and interferon-stimulated genes (ISGs), including viperin, iNOS, cathelicidin and IGTP, in <em>E. coli</em>-infected macrophages. In a cecal-ligation and puncture model of sepsis in C57BL/6 mice, DGAT1 inhibition reduced sepsis-induced LD accumulation in peritoneal cells and decreased levels of IFN-β, CCL2, nitric oxide, and lipid mediators (PGE₂, LTB₄, and RvD1) in the peritoneum. Furthermore, DGAT1 inhibition accelerated sepsis-related mortality, coinciding with elevated bacterial loads in the peritoneum and bloodstream at 6- and 24-h post-sepsis. Our results demonstrate that LDs are critical regulators of innate immunity infection resistance, contributing to both bacterial clearance and the coordination of a protective proinflammatory response during sepsis through mechanisms dependent on DGAT-1 and Type I IFN.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156389"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091961","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}