β-hydroxybutyrate (BHB), the predominant ketone body in human circulation, is synthesized in liver mitochondria and rises markedly during fasting, caloric restriction, ketogenic diets, and high-intensity exercise. Once considered a mere metabolic intermediate, BHB is now recognized as a potent signaling molecule that links nutrient status to gene regulation, inflammation, and cellular stress responses. In fact, beyond serving as an energy substrate, BHB functions as a versatile signaling metabolite that integrates environmental cues to epigenetic regulation, gene expression, and cellular physiology. Accumulating evidence highlights its protective and disease-modifying effects, positioning BHB as a promising therapeutic candidate for diverse conditions associated with energy deficits or metabolic imbalances. Nevertheless, the precise mechanisms underlying these benefits remain incompletely defined. This review discusses recently identified molecular pathways regulated by BHB, with a focus on its roles in cellular signaling, inflammation, transcriptional control, and post-translational protein modifications. For the first time, we also explore the translational relevance of BHB in endocrine pancreas biology, drawing mechanistic parallels with the nervous system. Although neurons and β-cells share remarkable functional similarities, the impact of BHB on β-cell survival and function remains unexplored. Clarifying these effects may uncover new strategies to harness ketosis for the treatment of diabetes.
{"title":"Pancreas meets brain: β-hydroxybutyrate as a novel “β-cellular” metabolism therapy","authors":"Caroline Lopa , Donatella Pietrangelo , Gaetano Santulli , Jessica Gambardella , Speranza Rubattu , Mihaela Stefan-Lifshitz , Crystal Nieves Garcia , Stanislovas S. Jankauskas , Angela Lombardi","doi":"10.1016/j.metabol.2025.156419","DOIUrl":"10.1016/j.metabol.2025.156419","url":null,"abstract":"<div><div>β-hydroxybutyrate (BHB), the predominant ketone body in human circulation, is synthesized in liver mitochondria and rises markedly during fasting, caloric restriction, ketogenic diets, and high-intensity exercise. Once considered a mere metabolic intermediate, BHB is now recognized as a potent signaling molecule that links nutrient status to gene regulation, inflammation, and cellular stress responses. In fact, beyond serving as an energy substrate, BHB functions as a versatile signaling metabolite that integrates environmental cues to epigenetic regulation, gene expression, and cellular physiology. Accumulating evidence highlights its protective and disease-modifying effects, positioning BHB as a promising therapeutic candidate for diverse conditions associated with energy deficits or metabolic imbalances. Nevertheless, the precise mechanisms underlying these benefits remain incompletely defined. This review discusses recently identified molecular pathways regulated by BHB, with a focus on its roles in cellular signaling, inflammation, transcriptional control, and post-translational protein modifications. For the first time, we also explore the translational relevance of BHB in endocrine pancreas biology, drawing mechanistic parallels with the nervous system. Although neurons and β-cells share remarkable functional similarities, the impact of BHB on β-cell survival and function remains unexplored. Clarifying these effects may uncover new strategies to harness ketosis for the treatment of diabetes.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156419"},"PeriodicalIF":11.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318588","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}
Pub Date : 2025-10-14DOI: 10.1016/j.metabol.2025.156420
Jiang Du , Yujie Li , Xinxing Zhu , Jingwen Gao , Yuxuan Zhang , Chiheng Wang , Di Han , Liang Qiao , Beilin Kou , Rui Guo , Hongen Zhang , Juntang Lin
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.
{"title":"METTL1-mediated m7G methylation of FoxO1 regulates lipid metabolism in metabolic dysfunction-associated fatty liver disease","authors":"Jiang Du , Yujie Li , Xinxing Zhu , Jingwen Gao , Yuxuan Zhang , Chiheng Wang , Di Han , Liang Qiao , Beilin Kou , Rui Guo , Hongen Zhang , 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":"2025-10-14","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}
Pub Date : 2025-10-13DOI: 10.1016/j.metabol.2025.156414
Emily F. Ashlaw , Clinton T. Elfers , Kylie S. Chichura , Isabella Chavez Miranda , Aelish McGivney , Oleg G. Chepurny , George G. Holz , Ginger Mullins , Laura J. den Hartigh , Yongjun Liu , Christian L. Roth , Robert P. Doyle
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.
{"title":"A melanocortin 4- and glucagon-like peptide 1 receptor multiple agonist for the treatment of diabetes and obesity","authors":"Emily F. Ashlaw , Clinton T. Elfers , Kylie S. Chichura , Isabella Chavez Miranda , Aelish McGivney , Oleg G. Chepurny , George G. Holz , Ginger Mullins , Laura J. den Hartigh , Yongjun Liu , Christian L. Roth , 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":"2025-10-13","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}
Pub Date : 2025-10-10DOI: 10.1016/j.metabol.2025.156415
Nawarat Rattanajearakul , Kunio Kondoh , Ou Fu , Shiki Okamoto , Kenta Kobayashi , Ken-ichiro Nakajima , Yasuhiko Minokoshi
Background
Neural pathways related to total calorie intake have been extensively studied. However, it remains unclear how these mechanisms control food selection.
Methods
Male mice were subjected to glucoprivation through the intraperitoneal (i.p.) administration of 2-deoxy-d-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.
Results
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.
Conclusion
Our findings reveal a previously unrecognized mechanism for food selection between HCD and HFD during glucoprivation.
{"title":"Glucoprivation-induced nutrient preference relies on distinct NPY neurons that project to the paraventricular nucleus of the hypothalamus","authors":"Nawarat Rattanajearakul , Kunio Kondoh , Ou Fu , Shiki Okamoto , Kenta Kobayashi , Ken-ichiro Nakajima , 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":"2025-10-10","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}
Pub Date : 2025-10-10DOI: 10.1016/j.metabol.2025.156416
Yuan Qiao , Yijia Zhang , Cuiting Sun , Qi Jin , Peng Qu , Zecheng Li , Yang Qiu , Hua Meng , Dantao Peng , Liang Peng
Objectives
Impaired autophagy is increasingly recognized as a key contributor to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, its underlying molecular mechanisms remain largely undefined. Emerging evidence implicates epigenetic regulators in modulating autophagic pathways in metabolic diseases. Therefore, this study aimed to elucidate the role of a histone methyltransferase, nuclear receptor binding SET domain protein 2 (NSD2), in regulating autophagy and its contribution to MASLD progression.
Methods
NSD2 expression levels were evaluated in liver tissues from patients with MASLD and mouse models. Functional studies were conducted using hepatocyte-specific Nsd2 knockout and overexpression mouse models, along with cleavage under targets and tagmentation analysis in hepatocyte cell lines. Additionally, the effects of pharmacological NSD2 inhibition using NSC663284 were evaluated in human liver organoids. Autophagy, hepatic steatosis, and related epigenetic changes were assessed through molecular and histological techniques.
Results
NSD2 expression was markedly elevated in both patient livers and murine models, correlating positively with disease severity. Hepatic NSD2 deficiency alleviated diet-induced autophagy impairment and steatosis, while NSD2 overexpression exacerbated these pathologies. Mechanistically, NSD2 epigenetically suppressed TFEB transcription by promoting trimethylation of histone H4 at lysine 20, impairing autophagy. Pharmacological inhibition of NSD2 with NSC663284 similarly alleviated hepatic steatosis in human liver organoids.
Conclusion
NSD2 acts as a key epigenetic suppressor of TFEB-mediated autophagy in the liver, promoting lipid accumulation and MASLD progression. Targeting NSD2 represents a promising therapeutic strategy for MASLD.
{"title":"NSD2 exacerbates metabolic dysfunction-associated steatotic liver disease progression by suppressing TFEB-mediated autophagy-lysosomal pathway","authors":"Yuan Qiao , Yijia Zhang , Cuiting Sun , Qi Jin , Peng Qu , Zecheng Li , Yang Qiu , Hua Meng , Dantao Peng , Liang Peng","doi":"10.1016/j.metabol.2025.156416","DOIUrl":"10.1016/j.metabol.2025.156416","url":null,"abstract":"<div><h3>Objectives</h3><div>Impaired autophagy is increasingly recognized as a key contributor to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, its underlying molecular mechanisms remain largely undefined. Emerging evidence implicates epigenetic regulators in modulating autophagic pathways in metabolic diseases. Therefore, this study aimed to elucidate the role of a histone methyltransferase, nuclear receptor binding SET domain protein 2 (NSD2), in regulating autophagy and its contribution to MASLD progression.</div></div><div><h3>Methods</h3><div>NSD2 expression levels were evaluated in liver tissues from patients with MASLD and mouse models. Functional studies were conducted using hepatocyte-specific <em>Nsd2</em> knockout and overexpression mouse models, along with cleavage under targets and tagmentation analysis in hepatocyte cell lines. Additionally, the effects of pharmacological NSD2 inhibition using NSC663284 were evaluated in human liver organoids. Autophagy, hepatic steatosis, and related epigenetic changes were assessed through molecular and histological techniques.</div></div><div><h3>Results</h3><div>NSD2 expression was markedly elevated in both patient livers and murine models, correlating positively with disease severity. Hepatic NSD2 deficiency alleviated diet-induced autophagy impairment and steatosis, while NSD2 overexpression exacerbated these pathologies. Mechanistically, NSD2 epigenetically suppressed TFEB transcription by promoting trimethylation of histone H4 at lysine 20, impairing autophagy. Pharmacological inhibition of NSD2 with NSC663284 similarly alleviated hepatic steatosis in human liver organoids.</div></div><div><h3>Conclusion</h3><div>NSD2 acts as a key epigenetic suppressor of TFEB-mediated autophagy in the liver, promoting lipid accumulation and MASLD progression. Targeting NSD2 represents a promising therapeutic strategy for MASLD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156416"},"PeriodicalIF":11.9,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275315","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}
Pub Date : 2025-10-09DOI: 10.1016/j.metabol.2025.156417
Linyi Li , Yu Wang , Zhiyong Du , Huahui Yu , Yunyun Yang , Zihan Zhang , Yanru Duan , Lijie Han , Chaowei Hu , Yunhui Du , Haili Sun , Xuechun Sun , Jingci Xing , Xiaoqian Gao , Dong Chen , Yuhui Wang , Xinwei Hua , Jianping Li , Yanwen Qin
Background and aims
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.
Methods
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.
Results
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.
Conclusion
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.
{"title":"Hepatic aconitase 1 redirects citrate flux to suppress lipogenesis and ameliorate hypercholesterolemia","authors":"Linyi Li , Yu Wang , Zhiyong Du , Huahui Yu , Yunyun Yang , Zihan Zhang , Yanru Duan , Lijie Han , Chaowei Hu , Yunhui Du , Haili Sun , Xuechun Sun , Jingci Xing , Xiaoqian Gao , Dong Chen , Yuhui Wang , Xinwei Hua , Jianping Li , 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":"2025-10-09","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}
Pub Date : 2025-10-09DOI: 10.1016/j.metabol.2025.156411
Dehui Hou , Kehui Yang , Yang Liu, Han Du, Hongwei Yue, Fengyang Xu, Wentao Sang, Xiangkai Zhao, Yijun Sun, Feng Xu, Yuguo Chen
Background and aims
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.
Methods and results
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 via 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 ALDH2E506k mutant mice.
Conclusion
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.
{"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 , Kehui Yang , Yang Liu, Han Du, Hongwei Yue, Fengyang Xu, Wentao Sang, Xiangkai Zhao, Yijun Sun, Feng Xu, 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<sup>E506k</sup> 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":"2025-10-09","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}
Pub Date : 2025-10-06DOI: 10.1016/j.metabol.2025.156413
Pieter R. Norden , Riley J. Wedan , Samuel E.J. Preston , Morgan Canfield , Naomi Graber , Jacob Z. Longenecker , Olivia A. Pentecost , Elizabeth McLaughlin , Madeleine L. Hart , Sara M. Nowinski
4′-Phosphopantetheinyl (4’PP) groups are essential co-factors added to target proteins by phosphopantetheinyl transferase (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 aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (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 AASDHPPT that are likely pathogenic in humans due to loss of mtFAS activity.
{"title":"Mitochondrial phosphopantetheinylation is required for oxidative metabolism","authors":"Pieter R. Norden , Riley J. Wedan , Samuel E.J. Preston , Morgan Canfield , Naomi Graber , Jacob Z. Longenecker , Olivia A. Pentecost , Elizabeth McLaughlin , Madeleine L. Hart , 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":"2025-10-06","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}
Pub Date : 2025-10-03DOI: 10.1016/j.metabol.2025.156412
Jin Dai , Wen Dai , Yoriko Heianza , Lu Qi
Objective
Coffee is one of the most widely consumed beverages globally and has been linked to favorable health outcomes. However, its system-wide relationships with human biology and the underlying mechanisms remain poorly characterized. This study aimed to investigate the relationship between coffee consumption and continuous glucose monitoring (CGM) metrics and other biological systems in healthy adults.
Research design and methods
In the Human Phenotype Project, 8666 generally healthy Israeli adults provided two weeks of real-time dietary logs, from which coffee intake was estimated. Participants wore CGM devices throughout this period, and multimodal data spanning 11 additional systems (e.g., gut microbiome, serum lipidomics, and body composition) were collected. We employed machine learning approaches to quantify the extent to which each system reflected coffee intake. We performed linear regression to identify individual traits associated with coffee intake, with false discovery rates < 0.05 considered significant.
Results
This cross-sectional study identified continuously-monitored glucose regulation and gut microbial composition as the most reflective systems of coffee intake, with further analyses revealing favorable glycemic profiles spanning diverse aspects of glucose regulation with increasing coffee intake, and Clostridium phoceensis (i.e., Lawsonibacter asaccharolyticus) as the most significant species positively associated with coffee intake. Additionally, coffee intake was favorably associated with traits across body composition, serum lipidomics, and hepatic, hematopoietic, and renal systems.
Conclusions
This study found that habitual coffee intake was linked to multifaceted favorable glucose control captured by CGM and favorable profiles across multiple biological systems, providing mechanistic insights that may guide precision nutrition strategies for diabetes prevention.
{"title":"Phenome-wide associations of coffee intake in the human phenotype project","authors":"Jin Dai , Wen Dai , Yoriko Heianza , Lu Qi","doi":"10.1016/j.metabol.2025.156412","DOIUrl":"10.1016/j.metabol.2025.156412","url":null,"abstract":"<div><h3>Objective</h3><div>Coffee is one of the most widely consumed beverages globally and has been linked to favorable health outcomes. However, its system-wide relationships with human biology and the underlying mechanisms remain poorly characterized. This study aimed to investigate the relationship between coffee consumption and continuous glucose monitoring (CGM) metrics and other biological systems in healthy adults.</div></div><div><h3>Research design and methods</h3><div>In the Human Phenotype Project, 8666 generally healthy Israeli adults provided two weeks of real-time dietary logs, from which coffee intake was estimated. Participants wore CGM devices throughout this period, and multimodal data spanning 11 additional systems (e.g., gut microbiome, serum lipidomics, and body composition) were collected. We employed machine learning approaches to quantify the extent to which each system reflected coffee intake. We performed linear regression to identify individual traits associated with coffee intake, with false discovery rates < 0.05 considered significant.</div></div><div><h3>Results</h3><div>This cross-sectional study identified continuously-monitored glucose regulation and gut microbial composition as the most reflective systems of coffee intake, with further analyses revealing favorable glycemic profiles spanning diverse aspects of glucose regulation with increasing coffee intake, and <em>Clostridium phoceensis</em> (i.e., <em>Lawsonibacter asaccharolyticus</em>) as the most significant species positively associated with coffee intake. Additionally, coffee intake was favorably associated with traits across body composition, serum lipidomics, and hepatic, hematopoietic, and renal systems.</div></div><div><h3>Conclusions</h3><div>This study found that habitual coffee intake was linked to multifaceted favorable glucose control captured by CGM and favorable profiles across multiple biological systems, providing mechanistic insights that may guide precision nutrition strategies for diabetes prevention.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156412"},"PeriodicalIF":11.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232946","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}
Pub Date : 2025-10-03DOI: 10.1016/j.metabol.2025.156397
Chrysoula Boutari , Michael A. Hill , Christos S. Mantzoros
{"title":"Semaglutide, the first approved GLP-1 receptor agonist for the management of metabolic dysfunction-associated steatohepatitis","authors":"Chrysoula Boutari , Michael A. Hill , Christos S. Mantzoros","doi":"10.1016/j.metabol.2025.156397","DOIUrl":"10.1016/j.metabol.2025.156397","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156397"},"PeriodicalIF":11.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232989","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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