Rachelle Bishay , Sina Kianoush , April Kinninger , Keishi Ichikawa , Srikanth Krishnan , Jairo Aldana-Bitar , Travis Benzing , Nathan D. Wong , Erin D. Michos , Ahmed Ghanem , Marziyeh Bagheri , Hossein Hamidi , Matthew J. Budoff
{"title":"Role of Coronary Artery Calcium in the Association Between Hormone Replacement Therapy Status and Incident Death and Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis","authors":"Rachelle Bishay , Sina Kianoush , April Kinninger , Keishi Ichikawa , Srikanth Krishnan , Jairo Aldana-Bitar , Travis Benzing , Nathan D. Wong , Erin D. Michos , Ahmed Ghanem , Marziyeh Bagheri , Hossein Hamidi , Matthew J. Budoff","doi":"10.1016/j.metabol.2025.156209","DOIUrl":"10.1016/j.metabol.2025.156209","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156209"},"PeriodicalIF":10.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144185154","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":"Revisiting gender differences in obesity and type 2 diabetes: Response letter","authors":"Amparo Galán , Francisco García-García","doi":"10.1016/j.metabol.2025.156307","DOIUrl":"10.1016/j.metabol.2025.156307","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156307"},"PeriodicalIF":10.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192021","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}
Getachew Arage , Koen F. Dekkers , Luka Marko Rašo , Ulf Hammar , Ulrika Ericson , Susanna C. Larsson , Hanna Engel , Gabriel Baldanzi , Kamalita Pertiwi , Sergi Sayols-Baixeras , Rikard Landberg , Johan Sundström , J. Gustav Smith , Gunnar Engström , Johan Ärnlöv , Marju Orho-Melander , Lars Lind , Tove Fall , Shafqat Ahmad
{"title":"Response to letter to the editor regarding: “Plasma metabolite profiles of meat intake and their association with cardiovascular disease risk: A population-based study in Swedish cohorts” by Arage et al., Metabolism. 2025 Jul;168:156188","authors":"Getachew Arage , Koen F. Dekkers , Luka Marko Rašo , Ulf Hammar , Ulrika Ericson , Susanna C. Larsson , Hanna Engel , Gabriel Baldanzi , Kamalita Pertiwi , Sergi Sayols-Baixeras , Rikard Landberg , Johan Sundström , J. Gustav Smith , Gunnar Engström , Johan Ärnlöv , Marju Orho-Melander , Lars Lind , Tove Fall , Shafqat Ahmad","doi":"10.1016/j.metabol.2025.156309","DOIUrl":"10.1016/j.metabol.2025.156309","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156309"},"PeriodicalIF":11.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192020","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}
Jie Liu , Anna Oliverio , Grzegorz Godlewski , Radka Kočvarová , Muhammad Arif , Abhishek Basu , Yukun Guan , Dechun Feng , Henry L. Puhl , Malliga R. Iyer , Resat Cinar , Bin Gao , Joseph Tam , George Kunos
{"title":"Hepatic CB1 receptor signaling triggers Gi/oα-mediated lipolysis in lean mice but Gsα-mediated lipogenesis in obese mice","authors":"Jie Liu , Anna Oliverio , Grzegorz Godlewski , Radka Kočvarová , Muhammad Arif , Abhishek Basu , Yukun Guan , Dechun Feng , Henry L. Puhl , Malliga R. Iyer , Resat Cinar , Bin Gao , Joseph Tam , George Kunos","doi":"10.1016/j.metabol.2025.156308","DOIUrl":"10.1016/j.metabol.2025.156308","url":null,"abstract":"<div><h3>Objectives</h3><div>Obesity-induced steatotic liver disease (SLD) is driven by the uptake of adipocyte-derived fatty acids (FAs) into hepatocytes via the FA translocase CD36, which also prevents their consumption by inhibiting AMP kinase (AMPK)-mediated FA oxidation (FAO). We explored the role of hepatocyte CB1 receptors (hCB1R) in controlling hepatic triglyceride (TG) content by regulating CD36 and its downstream targets.</div></div><div><h3>Methods</h3><div>hCB1R knockout (hCB1Rko) mice and their control littermates kept on standard or high-fat diet were used to analyze hCB1R-mediated hepatic gene expression profile and lipid metabolism in intact mice and in cultured hepatocytes.</div></div><div><h3>Results</h3><div>Multi-omics data indicate that hCB1R target a distinct set of genes associated with SLD, including <em>Cd36.</em> In mice with diet-induced obesity, hCB1R signaling via CD36-AMPK-FAO pathway contributes to both the development of SLD and its reversal by CB1R blockade. But, in lean mice hCB1R signaling inhibits CD36 expression and activates AMPK-mediated FAO. These opposite effects were replicated in AML12 mouse hepatocytes incubated with or without oleic acid (OA). OA, an endogenous ligand of GPR3, induced a switch in hCB1R signaling from a G<sub>i/o</sub>α-mediated reduction in cAMP to a G<sub>s</sub>α-mediated increase in cAMP in a GPR3/G<sub>s</sub>α -dependent manner, facilitated by increasing the ratio of G<sub>s</sub>α:G<sub>i/o</sub>α proteins in the steatotic compared to lean liver.</div></div><div><h3>Conclusions</h3><div>In the lean state, endocannabinoid activation of hCB1R increases FAO, which mitigates SLD, as reported for chronic marihuana smokers, whereas in obese mice hCB1R tonically inhibit FAO, which promotes SLD and underlies the anti-steatotic effect of peripheral CB1R blockade.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156308"},"PeriodicalIF":10.8,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187384","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":"On the misinterpretation of metabolites as causal mediators between meat intake and cardiovascular risk","authors":"Yang Zhang, Fanwu Chi, Ren Zhu, Lian Hu","doi":"10.1016/j.metabol.2025.156305","DOIUrl":"10.1016/j.metabol.2025.156305","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156305"},"PeriodicalIF":11.9,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181205","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}
Min Yin , Yan Zhang , Suosi Liu , Qianrong Wang , Yu Zhang , Jiali Min , Jiahui Yang , Yuyan Zhao , Zhiguang Zhou , Xia Li , Shanshan Liu
{"title":"The chemokine CCL20 promotes hepatocyte cholesterol deposition during metabolic dysfunction-associated steatohepatitis by regulating OLR1 expression","authors":"Min Yin , Yan Zhang , Suosi Liu , Qianrong Wang , Yu Zhang , Jiali Min , Jiahui Yang , Yuyan Zhao , Zhiguang Zhou , Xia Li , Shanshan Liu","doi":"10.1016/j.metabol.2025.156301","DOIUrl":"10.1016/j.metabol.2025.156301","url":null,"abstract":"<div><h3>Background & aims</h3><div>Metabolic dysfunction-associated steatohepatitis (MASH) is becoming a leading driver of liver failure and transplantation. The specific pathogenic mechanisms driving MASH remain incompletely understood. In this study, we aimed to investigate the role of CCL20 in MASH progression.</div></div><div><h3>Methods</h3><div>Using RNA sequencing data and murine models of MASH, we analyzed the expression levels of CCL20 in liver tissues, as well as the correlation of CCL20 levels with liver function parameters. Hepatic CCL20-knockdown and hepatic progenitor cell (HPC)/cholangiocyte-specific CCL20-knockout mice were used to assess the role of CCL20 in hepatic steatosis and inflammation. The mechanisms by which CCL20 influences MASH were explored via in vitro and in vivo gain- and loss-of-function approaches.</div></div><div><h3>Results</h3><div>We observed that CCL20 is significantly upregulated in MASH livers from mice and humans and that hepatic CCL20 expression is positively correlated with MASH severity. CCL20, which is mainly produced by HPCs/cholangiocytes, is transcriptionally activated by RELB and SOX9. In mice, CCL20 knockout in HPCs/cholangiocytes attenuated pathological changes in the liver. Mechanistically, by binding to CCR6, CCL20 activates the JNK signaling pathway, which increases OLR1 expression, thereby promoting oxLDL uptake and cholesterol deposition in hepatocytes.</div></div><div><h3>Conclusion</h3><div>These findings implicate the CCL20-CCR6-JNK-OLR1 axis as a crucial determinant of MASH progression and highlight CCL20 inhibition as an attractive therapeutic strategy for MASH.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156301"},"PeriodicalIF":10.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174254","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}
Guo-Qiang Pan , Yu-Chuan Yan , Rui-Zhe Li , Chen Xiong , Shao-peng Zhang , Ying Qu , Rui Dong , Yu Zhou , Tuan-Song Zhang , Zhi-Qiang Chen , Xiao-Lu Zhang , Xiao-Feng Dong , Dong-Xu Wang , Zhao-Ru Dong , Tao Li
{"title":"Targeting SAMD1 enhances the effect of anti-PD-1 plus lenvatinib therapy in hepatocellular carcinoma by increasing ferroptosis sensitivity and immune response","authors":"Guo-Qiang Pan , Yu-Chuan Yan , Rui-Zhe Li , Chen Xiong , Shao-peng Zhang , Ying Qu , Rui Dong , Yu Zhou , Tuan-Song Zhang , Zhi-Qiang Chen , Xiao-Lu Zhang , Xiao-Feng Dong , Dong-Xu Wang , Zhao-Ru Dong , Tao Li","doi":"10.1016/j.metabol.2025.156304","DOIUrl":"10.1016/j.metabol.2025.156304","url":null,"abstract":"<div><h3>Background</h3><div>Combination therapy of anti-PD-1 plus lenvatinib has shown effective anti-tumour effects for unresectable hepatocellular carcinoma (HCC), but the overall prognosis of HCC is still unsatisfactory. Elucidating the molecular mechanism underlying HCC progression contributes to develop new effective treatment in order to enhances the response of anti-PD-1 plus lenvatinib therapy and improve the patients prognosis.</div></div><div><h3>Method and results</h3><div>Here, we reported that targeting SAMD1 in HCC cells via small interference RNA-containing ZIF-90@HA (ATP/acid-responsive) Nanoparticles (ZIF-90@siRNA@HA NPs, ZSH NPs) significantly enhanced the anti-tumour effects of anti-PD-1 plus lenvatinib in vivo. Targeting SAMD1 in HCC cells not only increased cellular ROS abundance by inhibiting glycolysis and enhancing oxidative phosphorylation (OXPHOS) to increase ferroptosis sensitivity, but also inhibited the expression of CCL28, thereby reducing the recruitment of Treg cells, and improving the immunosuppression of tumour microenvironment. Mechanistically, SAMD1 suppression inhibits the expression of NUAK2 via Hippo pathway, thereby decreasing the phosphorylation of PFKP Ser386 and promoting the ubiquitination degradation of PFKP in HCC. Further study demonstrated that SAMD1 inhibition increased the expression of ITIH5 by regulating H3K4me3 demethylation at the ITIH5 promoter and then regulates Hippo pathway.</div></div><div><h3>Conclusions</h3><div>Our study revealed the potential application of targeting SAMD1 in HCC treatment by enhancing ferroptosis sensitivity and immune response.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156304"},"PeriodicalIF":10.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143000","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}
Daniel J. Cuthbertson , Oliver J. Kennedy , Josh Bilson , Theresa J. Hydes , Giovanni Targher , Kate Glyn-Owen , Ryan Buchanan , Paul Roderick , Christopher D. Byrne
{"title":"Impact of metabolic dysfunction severity in steatotic liver disease and its interaction with liver fibrosis on all-cause mortality and multiple hepatic and extra-hepatic outcomes","authors":"Daniel J. Cuthbertson , Oliver J. Kennedy , Josh Bilson , Theresa J. Hydes , Giovanni Targher , Kate Glyn-Owen , Ryan Buchanan , Paul Roderick , Christopher D. Byrne","doi":"10.1016/j.metabol.2025.156306","DOIUrl":"10.1016/j.metabol.2025.156306","url":null,"abstract":"<div><h3>Background</h3><div>In metabolic dysfunction-associated steatotic liver disease (MASLD) and in MASLD with alcohol consumption (MetALD), we investigated the effect of severity of metabolic dysfunction on incident major adverse liver outcomes (MALO), major cardiovascular events (MACE), obesity-related cancers, and all-cause mortality (ACM).</div></div><div><h3>Methods</h3><div>SLD was identified among 502,381 UK Biobank participants using the Hepatic Steatosis Index (HSI) (>36 <em>vs.</em><30). Metabolic syndrome (MetS) traits and MetS (≥3 traits) using MASLD/MetALD criteria. Cox regression was used to estimate adjusted hazard ratios and 95%CIs [aHR(95%CIs)] of MASLD or MetALD <em>plus</em> 1 to 5 MetS traits with incident MALO, MACE, obesity-related cancers and 5-year/10-year incidence rates <em>versus</em> reference (no SLD/MetS traits).</div></div><div><h3>Results</h3><div>Median follow-up was 148 to 149 months. Comparing MASLD with one <em>versus</em> five MetS traits, respectively, to the reference; for MALO, [aHRs (95%CIs)] were 2.27 (1.03–5.00) and 9.19 (4.98–16.95); for MetALD, aHRs were 1.65 (0.53–5.11) and 8.54 (3.65–19.95) respectively. For MACE, with MASLD; aHRs were 1.51 (1.19–1.92) and 4.81 (4.06–5.69) respectively; with MetALD, aHRs were 1.46 (1.00–2.13) and 4.64 (3.51–6.14) respectively. For obesity-related cancers; with MASLD, aHRs were 1.04 (0.87–1.23) and 1.46 (1.29–1.66) respectively; with MetALD, aHRs were 1.01 (0.79–1.29) and 1.51 (1.24–1.83) respectively. 5-year and 10-year incidence rates also increased progressively with increasing MetS traits. Combining SLD, MetS and high liver fibrosis risk (defined by FIB-4 ≥ 2.67) was strongly associated with MALO in both MASLD and MetALD (aHRs 27.48, (17.72–42.61); 43.36, 20.53–91.58 respectively).</div></div><div><h3>Conclusion</h3><div>In MASLD or MetALD, the numbers of MetS traits markedly influence risk and incidence of liver-related outcomes, MACE, obesity-related cancers and ACM.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156306"},"PeriodicalIF":10.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142935","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}