Pub Date : 2024-11-19DOI: 10.1016/j.metabol.2024.156080
Angelo Armandi, Chiara Rosso, Gian Paolo Caviglia , Elisabetta Bugianesi
Hepatocellular carcinoma (HCC) is a relevant complication occurring in individuals with advanced Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). Recent epidemiological data suggest an alarming increase in the HCC burden worldwide, with a relevant proportion attributable to MASLD (up to 38 %), either in cirrhotic or non-cirrhotic livers. In view of the changing landscape of metabolic syndrome as “silent pandemic”, this narrative review aims to provide an updated picture of the burden of HCC in individuals with MASLD. In the complex pathophysiological pathways linking insulin resistance to MASLD and cardiometabolic syndrome, metabolic inflammation appears a relevant driver of systemic as well as organ-specific complications. Novel insights from the field of immunology, gut-derived liver damage, and association with extra-hepatic cancers will be discussed. Finally, strategies for risk-based HCC surveillance (circulating biomarkers, prognostic models and polygenic risk scores) will be provided and the potential impact of novel drug targeting fibrosing Metabolic dysfunction-Associated Steatohepatitis (MASH) on incident HCC will be discussed.
{"title":"An updated overview on hepatocellular carcinoma in patients with Metabolic dysfunction-Associated Steatotic Liver Disease: Trends, pathophysiology and risk-based surveillance","authors":"Angelo Armandi, Chiara Rosso, Gian Paolo Caviglia , Elisabetta Bugianesi","doi":"10.1016/j.metabol.2024.156080","DOIUrl":"10.1016/j.metabol.2024.156080","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a relevant complication occurring in individuals with advanced Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). Recent epidemiological data suggest an alarming increase in the HCC burden worldwide, with a relevant proportion attributable to MASLD (up to 38 %), either in cirrhotic or non-cirrhotic livers. In view of the changing landscape of metabolic syndrome as “silent pandemic”, this narrative review aims to provide an updated picture of the burden of HCC in individuals with MASLD. In the complex pathophysiological pathways linking insulin resistance to MASLD and cardiometabolic syndrome, metabolic inflammation appears a relevant driver of systemic as well as organ-specific complications. Novel insights from the field of immunology, gut-derived liver damage, and association with extra-hepatic cancers will be discussed. Finally, strategies for risk-based HCC surveillance (circulating biomarkers, prognostic models and polygenic risk scores) will be provided and the potential impact of novel drug targeting fibrosing Metabolic dysfunction-Associated Steatohepatitis (MASH) on incident HCC will be discussed.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156080"},"PeriodicalIF":10.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687695","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}
Pub Date : 2024-11-17DOI: 10.1016/j.metabol.2024.156066
Fernando Bril , Alicia Elbert
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.
{"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":"10.1016/j.metabol.2024.156066","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156066"},"PeriodicalIF":10.8,"publicationDate":"2024-11-17","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}
Pub Date : 2024-11-09DOI: 10.1016/j.metabol.2024.156065
Hui Wang , Wan Zhu , Cong Xu , Wentao Su , Zhongyu Li
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.
{"title":"Engineering organoids-on-chips for drug testing and evaluation","authors":"Hui Wang , Wan Zhu , Cong Xu , Wentao Su , 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}
Pub Date : 2024-11-08DOI: 10.1016/j.metabol.2024.156063
Sneha Muralidharan , Jonathan W.J. Lee , Yee Siang Lim , Mark Muthiah , Eunice Tan , Deniz Demicioglu , Asim Shabbir , Wai Mun Loo , Chieh Sian Koo , Yin Mei Lee , Gwyneth Soon , Aileen Wee , Nur Halisah , Sakinah Abbas , Shanshan Ji , Alexander Triebl , Bo Burla , Hiromi W.L. Koh , Yun Shen Chan , Mei Chin Lee , Yock Young Dan
Background & aims
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 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.
Approach & results
A lipidomic approach was used to quantify a total of 481 serum lipids from 151 Singaporean patients paired with protocolized liver biopsies. Lipidomic signatures for MASLD, at-risk 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. Of note, 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.
Conclusions
The dynamic shift in serum 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.
{"title":"Serum lipidomic signatures in patients with varying histological severity of metabolic-dysfunction associated steatotic liver disease","authors":"Sneha Muralidharan , Jonathan W.J. Lee , Yee Siang Lim , Mark Muthiah , Eunice Tan , Deniz Demicioglu , Asim Shabbir , Wai Mun Loo , Chieh Sian Koo , Yin Mei Lee , Gwyneth Soon , Aileen Wee , Nur Halisah , Sakinah Abbas , Shanshan Ji , Alexander Triebl , Bo Burla , Hiromi W.L. Koh , Yun Shen Chan , Mei Chin Lee , Yock Young Dan","doi":"10.1016/j.metabol.2024.156063","DOIUrl":"10.1016/j.metabol.2024.156063","url":null,"abstract":"<div><h3>Background & aims</h3><div>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 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.</div></div><div><h3>Approach & results</h3><div>A lipidomic approach was used to quantify a total of 481 serum lipids from 151 Singaporean patients paired with protocolized liver biopsies. Lipidomic signatures for MASLD, at-risk 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. Of note, 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.</div></div><div><h3>Conclusions</h3><div>The dynamic shift in serum 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.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 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}
Pub Date : 2024-11-07DOI: 10.1016/j.metabol.2024.156061
Francesca Pontanari , Hadrien Demagny , Adrien Faure , Xiaoxu Li , Giorgia Benegiamo , Antoine Jalil , Alessia Perino , Johan Auwerx , Kristina Schoonjans
Several laboratories, including ours, have employed the Slc25a47tm1c(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 Slc25a47-Wars1 locus in hepatocytes are primarily driven by the unexpected downregulation of Wars1, the cytosolic tryptophan aminoacyl-tRNA synthetase located adjacent to Slc25a47. While the downregulation of Wars1 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 (UPRmt), a critical component of the mitochondrial stress response (MSR). Our findings clarify the distinct roles of Slc25a47 and Wars1 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.
{"title":"Wars1 downregulation in hepatocytes induces mitochondrial stress and disrupts metabolic homeostasis","authors":"Francesca Pontanari , Hadrien Demagny , Adrien Faure , Xiaoxu Li , Giorgia Benegiamo , Antoine Jalil , Alessia Perino , Johan Auwerx , 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><sup>tm1c(EUCOMM)Hmgu</sup> 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<sup>mt</sup>), 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}
Pub Date : 2024-11-07DOI: 10.1016/j.metabol.2024.156060
Laura M. Buchwald , Ditte Neess , Daniel Hansen , Thomas K. Doktor , Vignesh Ramesh , Lasse B. Steffensen , Blagoy Blagoev , David W. Litchfield , Brage S. Andresen , Kim Ravnskjaer , Nils J. Færgeman , Barbara Guerra
Background
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.
Methods and results
In this study, we aimed to elucidate the role of CK2 on lipid metabolism by employing both in vitro and in vivo 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 p27KIP1 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 in vivo, 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.
Conclusions
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.
{"title":"Body weight control via protein kinase CK2: diet-induced obesity counteracted by pharmacological targeting","authors":"Laura M. Buchwald , Ditte Neess , Daniel Hansen , Thomas K. Doktor , Vignesh Ramesh , Lasse B. Steffensen , Blagoy Blagoev , David W. Litchfield , Brage S. Andresen , Kim Ravnskjaer , Nils J. Færgeman , 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<sup>KIP1</sup> 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}
Pub Date : 2024-11-06DOI: 10.1016/j.metabol.2024.156062
Irem Congur , Geltrude Mingrone , Kaomei Guan
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.
内质网（ER）是一个重要的细胞器，参与囊泡运输、钙处理、蛋白质合成和折叠以及脂质的生物合成和代谢。当未折叠和/或折叠错误的蛋白质在ER腔内积累而破坏ER平衡时，就会发生ER应激。未折叠蛋白反应（UPR）的适应途径被激活，以维持ER平衡。在肥胖和 2 型糖尿病（T2DM）中，不断积累的数据表明，不适应性 UPR 导致的持续性 ER 应激与胰岛素/瘦素信号传导相互作用，这可能是肥胖/T2DM 导致的代谢失调（心肌细胞中的慢性高血糖、血脂异常和脂毒性）、胰岛素/瘦素抵抗和糖尿病心肌病（DiabCM）发展之间潜在的核心机制联系。同时，这些病理条件进一步加剧了ER应激。然而，它们之间的相互关系和潜在的分子机制尚未完全明了。要开发新的治疗策略，就需要更深入地了解 DiabCM 中ER 应激介导的途径。本综述旨在讨论 ER 应激与瘦素/胰岛素信号之间的相互影响，以及它们在 DiabCM 发病过程中的参与，重点关注线粒体相关 ER 膜和慢性炎症。我们还介绍了当前药物开发的方向，以及针对治疗 DiabCM 的 ER 应激进行转化研究的重要考虑因素。
{"title":"Targeting endoplasmic reticulum stress as a potential therapeutic strategy for diabetic cardiomyopathy","authors":"Irem Congur , Geltrude Mingrone , 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}
Pub Date : 2024-11-03DOI: 10.1016/j.metabol.2024.156059
Ke-Fa Xiang , Jing-jing Wan , Peng-yuan Wang , Xia Liu
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.
{"title":"Role of glycogen in cardiac metabolic stress","authors":"Ke-Fa Xiang , Jing-jing Wan , Peng-yuan Wang , 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}
Pub Date : 2024-11-01DOI: 10.1016/j.metabol.2024.156054
Chuangpeng Shen , Zhisen Pan , Wenmin Xie , Jian Zhao , Deyu Miao , Ling Zhao , Min Liu , Yanhua Zhong , Chong Zhong , Frank J. Gonzalez , Wei Wang , Yong Gao , Changhui Liu
Background
The protein Solute carrier family 27 member 4 (SLC27A4) is crucial for fatty acid synthesis and β-oxidation, but its role in hepatic steatosis and nonalcoholic fatty liver disease (NAFLD) progression is not fully understood.
Methods
Mice with AAV-mediated overexpression of Slc27a4 in liver and hepatocytes-specific deletion of Slc27a4 were fed a standard chow diet, a high-fat diet (HFD), or a methionine and choline-deficient diet (MCD). Serum and liver tissues were collected and analyzed by biochemical assay, histology, lipidomic analysis, RNA-seq analysis, qPCR, western blot and immunofluorescence.
Results
This study found elevated expression of SLC27A4 in individuals with NAFLD and OAPA-treated MPHs cells, leading to increased lipid accumulation and diet-induced liver steatosis, inflammation, and fibrosis. Conversely, hepatocyte-specific deletion of Slc27a4 improved the development of both NAFLD and NASH. SLC27A4 overexpression resulted in increased hepatic pregnane X receptor (PXR) expression and accumulation of phosphatidylcholine (PC), which activates PXR signaling and inducing SLC27A4 expression. PXR overexpression hinders the protective impact of Slc27a4 deletion on lipid accumulation and inflammation, whereas its deficiency in mice reduces the effect of Slc27a4 overexpression on NAFLD development.
Conclusion
These results indicate that SLC27A4 plays a critical role of lipid accumulation and inflammation, and is implicated in the development of NAFLD progression, rendering it potentially actionable target for NAFLD treatment.
{"title":"Hepatocyte-specific SLC27A4 deletion ameliorates nonalcoholic fatty liver disease in mice via suppression of phosphatidylcholine-mediated PXR activation","authors":"Chuangpeng Shen , Zhisen Pan , Wenmin Xie , Jian Zhao , Deyu Miao , Ling Zhao , Min Liu , Yanhua Zhong , Chong Zhong , Frank J. Gonzalez , Wei Wang , Yong Gao , Changhui Liu","doi":"10.1016/j.metabol.2024.156054","DOIUrl":"10.1016/j.metabol.2024.156054","url":null,"abstract":"<div><h3>Background</h3><div>The protein Solute carrier family 27 member 4 (SLC27A4) is crucial for fatty acid synthesis and β-oxidation, but its role in hepatic steatosis and nonalcoholic fatty liver disease (NAFLD) progression is not fully understood.</div></div><div><h3>Methods</h3><div>Mice with AAV-mediated overexpression of <em>Slc27a4</em> in liver and hepatocytes-specific deletion of <em>Slc27a4</em> were fed a standard chow diet, a high-fat diet (HFD), or a methionine and choline-deficient diet (MCD). Serum and liver tissues were collected and analyzed by biochemical assay, histology, lipidomic analysis, RNA-seq analysis, qPCR, western blot and immunofluorescence.</div></div><div><h3>Results</h3><div>This study found elevated expression of SLC27A4 in individuals with NAFLD and OAPA-treated MPHs cells, leading to increased lipid accumulation and diet-induced liver steatosis, inflammation, and fibrosis. Conversely, hepatocyte-specific deletion of <em>Slc27a4</em> improved the development of both NAFLD and NASH. SLC27A4 overexpression resulted in increased hepatic pregnane X receptor (PXR) expression and accumulation of phosphatidylcholine (PC), which activates PXR signaling and inducing SLC27A4 expression. PXR overexpression hinders the protective impact of <em>Slc27a4</em> deletion on lipid accumulation and inflammation, whereas its deficiency in mice reduces the effect of <em>Slc27a4</em> overexpression on NAFLD development.</div></div><div><h3>Conclusion</h3><div>These results indicate that SLC27A4 plays a critical role of lipid accumulation and inflammation, and is implicated in the development of NAFLD progression, rendering it potentially actionable target for NAFLD treatment.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156054"},"PeriodicalIF":10.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567293","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 : 2024-10-31DOI: 10.1016/j.metabol.2024.156058
Xueqing Liu , Xinyu Zhang , Linlin Ma , Na Qiang , Jiao Wang , Yujia Huang , Xiaolei Yuan , Chunmei Lu , Yang Cao , Jie Xu
Background
Maternal vitamin D deficiency is associated with an increased risk of preeclampsia, a potentially life-threatening multi-system disorder specific to human pregnancy. Placental trophoblast dysfunction is a key factor in the development of preeclampsia, and the activation of NOD-like receptor protein 3 (NLRP3) inflammasome may play a crucial role in this process. Previous studies have suggested that vitamin D can exert beneficial effects by suppressing inflammasome activation, but the underlying mechanism has not been fully elucidated. This study aims to explore the protective effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on the placenta and to investigate the mechanisms by which 1,25(OH)2D3 attenuates NLRP3 inflammasome activation in a rat model of preeclampsia and hypoxia-cultured placental trophoblast cells.
Results
Our findings demonstrated that supplementation of rats with 1,25(OH)2D3 mitigated placental inflammation and prevented multi-organ dysfunction associated with preeclampsia. Treatment with 1,25(OH)2D3 inhibited inflammasome-mediated inflammation in trophoblast cells via its receptor VDR by reducing the expression of NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), decreasing IL-1β production, reducing mitochondrial reactive oxygen species generation, and enhancing the expression and enzymatic activity of Cu/Zn-superoxide dismutase (SOD). Mechanistically, 1,25(OH)2D3 upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, subsequently suppressing NLRP3-mediated IL-1β overproduction in trophoblast cells.
Conclusions
Our study indicates that 1,25(OH)2D3 inhibits NLRP3-mediated inflammation in trophoblast cells during preeclampsia by stimulating the Nrf2 signaling pathway and inhibiting oxidative stress.
{"title":"1,25-Dihydroxyvitamin D3 protects against placental inflammation by suppressing NLRP3-mediated IL-1β production via Nrf2 signaling pathway in preeclampsia","authors":"Xueqing Liu , Xinyu Zhang , Linlin Ma , Na Qiang , Jiao Wang , Yujia Huang , Xiaolei Yuan , Chunmei Lu , Yang Cao , Jie Xu","doi":"10.1016/j.metabol.2024.156058","DOIUrl":"10.1016/j.metabol.2024.156058","url":null,"abstract":"<div><h3>Background</h3><div>Maternal vitamin D deficiency is associated with an increased risk of preeclampsia, a potentially life-threatening multi-system disorder specific to human pregnancy. Placental trophoblast dysfunction is a key factor in the development of preeclampsia, and the activation of NOD-like receptor protein 3 (NLRP3) inflammasome may play a crucial role in this process. Previous studies have suggested that vitamin D can exert beneficial effects by suppressing inflammasome activation, but the underlying mechanism has not been fully elucidated. This study aims to explore the protective effects of 1,25-dihydroxyvitamin D<sub>3</sub> [1,25(OH)<sub>2</sub>D<sub>3</sub>] on the placenta and to investigate the mechanisms by which 1,25(OH)<sub>2</sub>D<sub>3</sub> attenuates NLRP3 inflammasome activation in a rat model of preeclampsia and hypoxia-cultured placental trophoblast cells.</div></div><div><h3>Results</h3><div>Our findings demonstrated that supplementation of rats with 1,25(OH)<sub>2</sub>D<sub>3</sub> mitigated placental inflammation and prevented multi-organ dysfunction associated with preeclampsia. Treatment with 1,25(OH)<sub>2</sub>D<sub>3</sub> inhibited inflammasome-mediated inflammation in trophoblast cells via its receptor VDR by reducing the expression of NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), decreasing IL-1β production, reducing mitochondrial reactive oxygen species generation, and enhancing the expression and enzymatic activity of Cu/Zn-superoxide dismutase (SOD). Mechanistically, 1,25(OH)<sub>2</sub>D<sub>3</sub> upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, subsequently suppressing NLRP3-mediated IL-1β overproduction in trophoblast cells.</div></div><div><h3>Conclusions</h3><div>Our study indicates that 1,25(OH)<sub>2</sub>D<sub>3</sub> inhibits NLRP3-mediated inflammation in trophoblast cells during preeclampsia by stimulating the Nrf2 signaling pathway and inhibiting oxidative stress.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156058"},"PeriodicalIF":10.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564686","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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