Metabolism: clinical and experimental最新文献

{"title":"Accurate non-invasive detection of MASH with fibrosis F2-F3 using a lightweight machine learning model with minimal clinical and metabolomic variables.","authors":"Konstantinos Stefanakis, Geltrude Mingrone, Jacob George, Christos S Mantzoros","doi":"10.1016/j.metabol.2024.156082","DOIUrl":"https://doi.org/10.1016/j.metabol.2024.156082","url":null,"abstract":"<p><strong>Background: </strong>There are no known non-invasive tests (NITs) designed for accurately detecting metabolic dysfunction-associated steatohepatitis (MASH) with liver fibrosis stages F2-F3, excluding cirrhosis-the FDA-defined range for prescribing Resmetirom and other drugs in clinical trials. We aimed to validate and re-optimize known NITs, and most importantly to develop new machine learning (ML)-based NITs to accurately detect MASH F2-F3.</p><p><strong>Methods: </strong>Clinical and metabolomic data were collected from 443 patients across three countries and two clinic types (metabolic surgery, gastroenterology/hepatology) covering the entire spectrum of biopsy-proven MASLD, including cirrhosis and healthy controls. Three novel types of ML models were developed using a categorical gradient boosting machine pipeline. These were compared with 24 biomarker, imaging, and algorithm-based NITs with both known cutoffs for MASH F2-F4 and re-optimized cutoffs for MASH F2-F3.</p><p><strong>Results: </strong>NFS at a - 1.455 cutoff attained an AUC of 0.59, the highest sensitivity (90.9 %, 95 % CI 84.3-95.4), and NPV of 87.2 %. FIB4 risk stratification followed by elastography (8 kPa) had the best specificity (86.9 %) and PPV (63.3 %), with an AUC of 0.57. NFS followed by elastography improved the PPV to 65.3 % and AUC to 0.62. Re-optimized FibroScan-AST (FAST) at a 0.22 cutoff had the highest PPV (69.1 %). ML models using aminotransferases, metabolic syndrome components, BMI, and 3-ureidopropionate achieved an AUC of 0.89, which further increased to 0.91 following hyperparameter optimization and the addition of alpha-ketoglutarate. These new ML models outperformed all other NITs and displayed accuracy, sensitivity, specificity, PPV, and NPV up to 91.2 %, 85.3 %, 97.0 %, 92.4 %, and 90.7 % respectively. The models were reproduced and validated in a secondary sensitivity analysis, that used one of the cohorts as feature selection/training, and the rest as independent validation, likewise outperforming all other NITs.</p><p><strong>Conclusions: </strong>We report for the first time the diagnostic characteristics of non-invasive, metabolomics-based biomarker models to detect MASH with fibrosis F2-F3 required for Resmetirom treatment and inclusion in ongoing phase-III trials. These models may be used alone or in combination with other NITs to accurately determine treatment eligibility.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156082"},"PeriodicalIF":10.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682244","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":"Successful repurposing of empagliflozin to treat neutropenia in a severe congenital neutropenia patient with G6PC3 mutations.","authors":"Grigorios Tsaknakis, Erasmia Boutakoglou, Irene Mavroudi, Christos S Mantzoros, Maria Veiga-da Cunha, Helen A Papadaki","doi":"10.1016/j.metabol.2024.156077","DOIUrl":"10.1016/j.metabol.2024.156077","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156077"},"PeriodicalIF":10.8,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668470","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":"Metabolic dysfunction-associated steatotic liver disease and urinary system cancers: Mere coincidence or reason for concern?","authors":"Fernando Bril, Alicia Elbert","doi":"10.1016/j.metabol.2024.156066","DOIUrl":"https://doi.org/10.1016/j.metabol.2024.156066","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic disease characterized by insulin resistance and lipotoxicity. Its association with type 2 diabetes, cardiovascular disease, liver cirrhosis, and hepatocellular carcinoma are well described. However, the association of MASLD and extra-hepatic cancers has received significantly less attention. This narrative review will summarize the conflicting evidence regarding the association between MASLD and cancers of the urinary system, including renal cell carcinoma, urothelial carcinoma, and prostate adenocarcinoma. It will explore potential mechanisms that could be responsible for a higher risk of urinary system cancers in patients with MASLD. We hope that our comprehensive assessment of the literature will help the readers to better interpret the available evidence.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156066"},"PeriodicalIF":10.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648060","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":"PCSK9 in metabolism and diseases.","authors":"Amir Ajoolabady, Domenico Pratico, Mohsen Mazidi, Ian G Davies, Gregory Y H Lip, Nabil Seidah, Peter Libby, Guido Kroemer, Jun Ren","doi":"10.1016/j.metabol.2024.156064","DOIUrl":"https://doi.org/10.1016/j.metabol.2024.156064","url":null,"abstract":"<p><p>PCSK9 is a serine protease that regulates plasma levels of low-density lipoprotein (LDL) and cholesterol by mediating the endolysosomal degradation of LDL receptor (LDLR) in the liver. When PCSK9 functions unchecked, it leads to increased degradation of LDLR, resulting in elevated circulatory levels of LDL and cholesterol. This dysregulation contributes to lipid and cholesterol metabolism abnormalities, foam cell formation, and the development of various diseases, including cardiovascular disease (CVD), viral infections, cancer, and sepsis. Emerging clinical and experimental evidence highlights an imperative role for PCSK9 in metabolic anomalies such as hypercholesterolemia and hyperlipidemia, as well as inflammation, and disturbances in mitochondrial homeostasis. Moreover, metabolic hormones - including insulin, glucagon, adipokines, natriuretic peptides, and sex steroids - regulate the expression and circulatory levels of PCSK9, thus influencing cardiovascular and metabolic functions. In this comprehensive review, we aim to elucidate the regulatory role of PCSK9 in lipid and cholesterol metabolism, pathophysiology of diseases such as CVD, infections, cancer, and sepsis, as well as its pharmaceutical and non-pharmaceutical targeting for therapeutic management of these conditions.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156064"},"PeriodicalIF":10.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639261","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":"Engineering organoids-on-chips for drug testing and evaluation","authors":"Hui Wang ,&nbsp;Wan Zhu ,&nbsp;Cong Xu ,&nbsp;Wentao Su ,&nbsp;Zhongyu Li","doi":"10.1016/j.metabol.2024.156065","DOIUrl":"10.1016/j.metabol.2024.156065","url":null,"abstract":"<div><div>Organoids-on-chips is an emerging innovative integration of stem cell-derived organoids with advanced organ-on-chip technology, providing a novel platform for the in vitro construction of biomimetic micro-physiological systems. The synergistic merger transcends the limitations of traditional drug screening and safety assessment methodologies, such as 2D cell cultures and animal models. In this review, we examine the prevailing challenges and prerequisites of preclinical models utilized for drug screening and safety evaluations. We highlighted the salient features and merits of organoids-on-chip, elucidating their capability to authentically replicate human physiology, thereby addressing contemporary impediments. We comprehensively overviewed the recent endeavors where organoids-on-chips have been harnessed for drug screening and safety assessment and delved into potential opportunities and challenges for evolving sophisticated, near-physiological organoids-on-chips. Based on current achievements, we further discuss how to enhance the practicality of organoids-on-chips and accelerate the translation from preclinical to clinical stages in healthcare and industry by utilizing multidisciplinary convergent innovation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156065"},"PeriodicalIF":10.8,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623519","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":"Serum lipidomic signatures in patients with varying histological severity of metabolic-dysfunction associated steatotic liver disease.","authors":"Sneha Muralidharan, Jonathan W J Lee, Lim Yee Siang, Mark Muthiah, Eunice Tan, Deniz Demicioglu, Asim Shabbir, Loo Wai Mun, Koo Chieh Sian, Lee Yin Mei, Gwyneth Soon, Aileen Wee, Nur Halisah, Sakinah Abbas, Shanshan Ji, Alexander Triebl, Bo Burla, Hiromi W L Koh, Chan Yun Shen, Lee Mei Chin, Ng Huck Hui, Markus R Wenk, Federico Torta, Dan Yock Young","doi":"10.1016/j.metabol.2024.156063","DOIUrl":"https://doi.org/10.1016/j.metabol.2024.156063","url":null,"abstract":"<p><strong>Background & aims: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a spectrum of pathologies ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Patients with metabolic associated steatohepatitis (MASH) with and without fibrosis are at greatest risk of liver and cardiovascular complications. To identify such at-risk MASLD patients, physicians are still reliant on invasive liver biopsies. This study aimed to identify circulating lipidomic signatures to better identify patients with MASH in a multi-ethnic Asian cohort.</p><p><strong>Approach & results: </strong>A lipidomic approach was used to quantify a total of 481 serum lipids from 151 Singaporean patients paired with protocolized liver biopsies. Lipidomic signatures as diagnostic biomarkers for MASLD, MASH and advanced fibrosis were identified. 210 lipids showed significant differences for varying histological subtypes of MASLD. Majority of these lipids were associated with liver steatosis (198/210). We identified a panel of 13 lipids associated with lobular inflammation, ballooning and significant fibrosis. More specifically, dihexosylceramides were novel markers for significant fibrosis. Using the serum lipidome alone, we could stratify patients with MASLD (AUROC 0.863), as well as those with at-risk MASH (AUROC 0.912) and advanced fibrosis (AUROC 0.95). The lipidomic at-risk MASH predictor, using 14 markers, was independently validated (n = 105) with AUROC 0.76.</p><p><strong>Conclusions: </strong>The dynamic shift in blood lipid profile was associated with progressive histological stages of MASLD, providing surrogate markers for distinguishing stages of MASLD as well as identifying novel pathways in the pathogenesis.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156063"},"PeriodicalIF":10.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623621","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":"Wars1 downregulation in hepatocytes induces mitochondrial stress and disrupts metabolic homeostasis","authors":"Francesca Pontanari ,&nbsp;Hadrien Demagny ,&nbsp;Adrien Faure ,&nbsp;Xiaoxu Li ,&nbsp;Giorgia Benegiamo ,&nbsp;Antoine Jalil ,&nbsp;Alessia Perino ,&nbsp;Johan Auwerx ,&nbsp;Kristina Schoonjans","doi":"10.1016/j.metabol.2024.156061","DOIUrl":"10.1016/j.metabol.2024.156061","url":null,"abstract":"<div><div>Several laboratories, including ours, have employed the <em>Slc25a47</em>^{tm1c(EUCOMM)Hmgu} mouse model to investigate the role of SLC25A47, a hepatocyte-specific mitochondrial carrier, in regulating hepatic metabolism and systemic physiology. In this study, we reveal that the hepatic and systemic phenotypes observed following recombination of the <em>Slc25a47-Wars1</em> locus in hepatocytes are primarily driven by the unexpected downregulation of <em>Wars1</em>, the cytosolic tryptophan aminoacyl-tRNA synthetase located adjacent to <em>Slc25a47</em>. While the downregulation of <em>Wars1</em> predictably affects cytosolic translation, we also observed a significant impairment in mitochondrial protein synthesis within hepatocytes. This disturbance in mitochondrial function leads to an activation of the mitochondrial unfolded protein response (UPR^mt), a critical component of the mitochondrial stress response (MSR). Our findings clarify the distinct roles of <em>Slc25a47</em> and <em>Wars1</em> in maintaining both systemic and hepatic metabolic homeostasis. This study sheds new light on the broader implications of aminoacyl-tRNA synthetases in mitochondrial physiology and stress responses.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156061"},"PeriodicalIF":10.8,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605465","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}

{"title":"Body weight control via protein kinase CK2: diet-induced obesity counteracted by pharmacological targeting","authors":"Laura M. Buchwald ,&nbsp;Ditte Neess ,&nbsp;Daniel Hansen ,&nbsp;Thomas K. Doktor ,&nbsp;Vignesh Ramesh ,&nbsp;Lasse B. Steffensen ,&nbsp;Blagoy Blagoev ,&nbsp;David W. Litchfield ,&nbsp;Brage S. Andresen ,&nbsp;Kim Ravnskjaer ,&nbsp;Nils J. Færgeman ,&nbsp;Barbara Guerra","doi":"10.1016/j.metabol.2024.156060","DOIUrl":"10.1016/j.metabol.2024.156060","url":null,"abstract":"<div><h3>Background</h3><div>Protein kinase CK2 is a highly conserved enzyme implicated in the pathogenesis of various human illnesses including obesity. Despite compelling evidence for the involvement of this kinase in the pathophysiology of obesity, the molecular mechanisms by which CK2 might regulate fat metabolism are still poorly understood.</div></div><div><h3>Methods and results</h3><div>In this study, we aimed to elucidate the role of CK2 on lipid metabolism by employing both <em>in vitro</em> and <em>in vivo</em> approaches using mouse pre-adipocytes and a mouse model of diet-induced obesity. We show that pharmacological inhibition of CK2 by CX-4945 results in premature upregulation of p27^KIP1 preventing the progression of cells into mature adipocytes by arresting their development at the intermediate phase of adipogenic differentiation. Consistent with this, we show that <em>in vivo</em>, CK2 regulates the expression levels and ERK-mediated phosphorylation of C/EBPβ, which is one of the earliest transcription factors responsive to adipogenic stimuli. Furthermore, we demonstrate the functional implication of CK2 in the expression of late markers of adipogenesis and factors regulating lipogenesis in liver and white adipose tissue. Finally, we show that while mice subjected to high-fat diet increased their body weight, those additionally treated with CX-4945 gained considerably less weight. NMR-based body composition analysis revealed that this is linked to significant differences in body fat mass.</div></div><div><h3>Conclusions</h3><div>Taken together, our study provides novel insights into the role of CK2 in fat metabolism in response to chronic lipid overload and confirms CK2 pharmacological targeting as a potentially powerful strategy for body weight control and/or the treatment of obesity and related metabolic disorders.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156060"},"PeriodicalIF":10.8,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623622","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}

{"title":"Targeting endoplasmic reticulum stress as a potential therapeutic strategy for diabetic cardiomyopathy","authors":"Irem Congur ,&nbsp;Geltrude Mingrone ,&nbsp;Kaomei Guan","doi":"10.1016/j.metabol.2024.156062","DOIUrl":"10.1016/j.metabol.2024.156062","url":null,"abstract":"<div><div>Endoplasmic reticulum (ER) is an essential organelle involved in vesicular transport, calcium handling, protein synthesis and folding, and lipid biosynthesis and metabolism. ER stress occurs when ER homeostasis is disrupted by the accumulation of unfolded and/or misfolded proteins in the ER lumen. Adaptive pathways of the unfolded protein response (UPR) are activated to maintain ER homeostasis. In obesity and type 2 diabetes mellitus (T2DM), accumulating data indicate that persistent ER stress due to maladaptive UPR interacts with insulin/leptin signaling, which may be the potential and central mechanistic link between obesity-/T2DM-induced metabolic dysregulation (chronic hyperglycemia, dyslipidemia and lipotoxicity in cardiomyocytes), insulin/leptin resistance and the development of diabetic cardiomyopathy (DiabCM). Meanwhile, these pathological conditions further exacerbate ER stress. However, their interrelationships and the underlying molecular mechanisms are not fully understood. A deeper understanding of ER stress-mediated pathways in DiabCM is needed to develop novel therapeutic strategies. The aim of this review is to discuss the crosstalk between ER stress and leptin/insulin signaling and their involvement in the development of DiabCM focusing on mitochondria-associated ER membranes and chronic inflammation. We also present the current direction of drug development and important considerations for translational research into targeting ER stress for the treatment of DiabCM.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156062"},"PeriodicalIF":10.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605463","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}

{"title":"Role of glycogen in cardiac metabolic stress","authors":"Ke-Fa Xiang ,&nbsp;Jing-jing Wan ,&nbsp;Peng-yuan Wang ,&nbsp;Xia Liu","doi":"10.1016/j.metabol.2024.156059","DOIUrl":"10.1016/j.metabol.2024.156059","url":null,"abstract":"<div><div>Metabolic stress in the myocardium arises from a diverse array of acute and chronic pathophysiological contexts. Glycogen mishandling is a key feature of metabolic stress, while maladaptation in energy-stress situations confers functional deficits. Cardiac glycogen serves as a pivotal reserve for myocardial energy, which is classically described as an energy source and contributes to glucose homeostasis during hypoxia or ischemia. Despite extensive research activity, how glycogen metabolism affects cardiovascular disease remains unclear. In this review, we focus on its regulation across myocardial energy metabolism in response to stress, and its role in metabolism, immunity, and autophagy. We further summarize the cardiovascular-related drugs regulating glycogen metabolism. In this way, we provide current knowledge for the understanding of glycogen metabolism in the myocardium.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156059"},"PeriodicalIF":10.8,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583348","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}