Metabolism: clinical and experimental最新文献

{"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}

{"title":"Hepatocyte-specific SLC27A4 deletion ameliorates nonalcoholic fatty liver disease in mice via suppression of phosphatidylcholine-mediated PXR activation","authors":"Chuangpeng Shen ,&nbsp;Zhisen Pan ,&nbsp;Wenmin Xie ,&nbsp;Jian Zhao ,&nbsp;Deyu Miao ,&nbsp;Ling Zhao ,&nbsp;Min Liu ,&nbsp;Yanhua Zhong ,&nbsp;Chong Zhong ,&nbsp;Frank J. Gonzalez ,&nbsp;Wei Wang ,&nbsp;Yong Gao ,&nbsp;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}

{"title":"Letter to the editor: global burden of metabolic dysfunction-associated steatotic liver disease: results from the global burden of disease study 2021.","authors":"Yakun Li, Han Moshage","doi":"10.1016/j.metabol.2024.156055","DOIUrl":"10.1016/j.metabol.2024.156055","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156055"},"PeriodicalIF":10.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567316","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":"1,25-Dihydroxyvitamin D3 protects against placental inflammation by suppressing NLRP3-mediated IL-1β production via Nrf2 signaling pathway in preeclampsia","authors":"Xueqing Liu ,&nbsp;Xinyu Zhang ,&nbsp;Linlin Ma ,&nbsp;Na Qiang ,&nbsp;Jiao Wang ,&nbsp;Yujia Huang ,&nbsp;Xiaolei Yuan ,&nbsp;Chunmei Lu ,&nbsp;Yang Cao ,&nbsp;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 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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>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.</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}

{"title":"Leptin physiology and pathophysiology in energy homeostasis, immune function, neuroendocrine regulation and bone health","authors":"Konstantinos Stefanakis ,&nbsp;Jagriti Upadhyay ,&nbsp;Arantxa Ramirez-Cisneros ,&nbsp;Nihar Patel ,&nbsp;Akshat Sahai ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2024.156056","DOIUrl":"10.1016/j.metabol.2024.156056","url":null,"abstract":"<div><div>Since its discovery and over the past thirty years, extensive research has significantly expanded our understanding of leptin and its diverse roles in human physiology, pathophysiology and therapeutics. A prototypical adipokine initially identified for its critical function in appetite regulation and energy homeostasis, leptin has been revealed to also exert profound effects on the hypothalamic-pituitary-gonadal, thyroid, adrenal and growth hormone axis, differentially between animals and humans, as well as in regulating immune function. Beyond these roles, leptin plays a pivotal role in significantly affecting bone health by promoting bone formation and regulating bone metabolism both directly and indirectly through its neuroendocrine actions. The diverse actions of leptin are particularly notable in leptin-deficient animal models and in conditions characterized by low circulating leptin levels, such as lipodystrophies and relative energy deficiency. Conversely, the effectiveness of leptin is attenuated in leptin-sufficient states, such as obesity and other high-adiposity conditions associated with hyperleptinemia and leptin tolerance. This review attempts to consolidate 30 years of leptin research with an emphasis on its physiology and pathophysiology in humans, including its promising therapeutic potential. We discuss preclinical and human studies describing the pathophysiology of energy deficiency across organ systems and the significant role of leptin in regulating neuroendocrine, immune, reproductive and bone health. We finally present past proof of concept clinical trials of leptin administration in leptin-deficient subjects that have demonstrated positive neuroendocrine, reproductive, and bone health outcomes, setting the stage for future phase IIb and III randomized clinical trials in these conditions.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156056"},"PeriodicalIF":10.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558257","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":"The impact of weight loss on fat-free mass, muscle, bone and hematopoiesis health: Implications for emerging pharmacotherapies aiming at fat reduction and lean mass preservation","authors":"Konstantinos Stefanakis ,&nbsp;Michail Kokkorakis ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2024.156057","DOIUrl":"10.1016/j.metabol.2024.156057","url":null,"abstract":"<div><div>Similar to bariatric surgery, incretin receptor agonists have revolutionized the treatment of obesity, achieving up to 15–25 % weight loss in many patients, i.e., at a rate approaching that achieved with bariatric surgery. However, over 25 % of total weight lost from both surgery and pharmacotherapy typically comes from fat-free mass, including skeletal muscle mass, which is often overlooked and can impair metabolic health and increase the risk of subsequent sarcopenic obesity. Loss of muscle and bone as well as anemia can compromise physical function, metabolic rate, and overall health, especially in older adults. The myostatin-activin-follistatin-inhibin system, originally implicated in reproductive function and subsequently muscle regulation, appears to be crucial for muscle and bone maintenance during weight loss. Activins and myostatin promote muscle degradation, while follistatins inhibit their activity in states of negative energy balance, thereby preserving lean mass. Novel compounds in the pipeline, such as Bimagrumab, Trevogrumab, and Garetosmab—which inhibit activin and myostatin signaling—have demonstrated promise in preventing muscle loss while promoting fat loss. Either alone or combined with incretin receptor agonists, these medications may enhance fat loss while preserving or even increasing muscle and bone mass, offering a potential solution for improving body composition and metabolic health during significant weight loss. Since this dual therapeutic approach could help address the challenges of muscle and bone loss during weight loss, well-designed studies are needed to optimize these strategies and assess long-term benefits. For the time being, considerations like advanced age and prefrailty may affect the choice of suitable candidates in clinical practice for current and emerging anti-obesity medications due to the associated risk of sarcopenia.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156057"},"PeriodicalIF":10.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558258","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":"Evidence from clinical studies of leptin: current and future clinical applications in humans","authors":"Nikolaos Perakakis ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2024.156053","DOIUrl":"10.1016/j.metabol.2024.156053","url":null,"abstract":"<div><div>Leptin has been established as the prototype adipose tissue secreted hormone and as a major regulator of several human physiology functions. Here, we are primarily reviewing the findings from studies in humans involving leptin administration. We are describing the metabolic, endocrine and immunologic effects of leptin replacement in conditions of leptin deficiency, such as short-term fasting in healthy individuals, relative energy deficiency in sports (RED<img>S), congenital leptin deficiency (CLD), generalized (GL) and partial lipodystrophy (PL), HIV-associated lipodystrophy (HIV-L) and of leptin treatment in conditions of leptin excess (common obesity, type 2 diabetes, steatotic liver disease). We are comparing the results with the findings from preclinical models and present the main conclusions regarding the role of leptin in human physiology, pathophysiology and therapeutics. We conclude that, in conditions of energy deficiency, leptin substitution effectively reduces body weight and fat mass through reduction of appetite, it improves hypertriglyceridemia, insulin resistance and hepatic steatosis (especially in GL and PL), it restores neuroendocrine function (especially the gonadotropic axis), it regulates adaptive immune system cell populations and it improves bone health. On the contrary, leptin treatment in conditions of leptin excess, such as common obesity and type 2 diabetes, does not improve any metabolic abnormalities. Strategies to overcome leptin tolerance/resistance in obesity and type 2 diabetes have provided promising results in animal studies, which should though be tested in humans in randomized clinical trials.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156053"},"PeriodicalIF":10.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142554962","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":"Advances in body composition and gender differences in susceptibility to frailty syndrome: Role of osteosarcopenic obesity","authors":"Rosy Conforto ,&nbsp;Valeria Rizzo ,&nbsp;Raffaella Russo ,&nbsp;Elisa Mazza ,&nbsp;Samantha Maurotti ,&nbsp;Carmelo Pujia ,&nbsp;Elena Succurro ,&nbsp;Franco Arturi ,&nbsp;Yvelise Ferro ,&nbsp;Angela Sciacqua ,&nbsp;Arturo Pujia ,&nbsp;Tiziana Montalcini","doi":"10.1016/j.metabol.2024.156052","DOIUrl":"10.1016/j.metabol.2024.156052","url":null,"abstract":"<div><div>There is general consensus that an improper diet negatively impacts health and that nutrition is a primary tool for the prevention of non-communicable diseases. Unfortunately, the importance of studying body composition, which can reveal early predictors of gender-related diseases, is still not well understood in this context. Currently, individuals are still classified as obese based solely on their body mass index, without considering the amount of fat, its distribution, and the quantity of muscle and bone mass. In this regard, the body composition phenotype defined as “osteosarcopenic obesity” affects approximately 6–41 % of postmenopausal women, with prevalence increasing with age due to the hormonal and metabolic changes that occur during this period. This particular phenotype arises from the strong relationship between visceral fat, muscle, bone, and gut microbiota and predispose postmenopausal women to frailty<del>.</del> Frailty is a complex clinical phenomenon with significant care and economic implications for our society. Recent studies suggest that women have a higher prevalence of frailty syndrome and its individual components, such as osteoporosis, fractures and sarcopenia, compared to men. Here, we provide a comprehensive overview of recent advances regarding the impact of gender on body composition and frailty. Furthermore, we reflect on the crucial importance of personalized nutritional interventions, with a focus on reducing visceral fat, increasing protein intake and optimizing vitamin D levels. A review of the scientific literature on this topic highlights the importance of studying body composition for a personalized and gender-specific approach to nutrition and dietetics, in order to identify frailty syndrome early and establish personalized treatments. This new method of researching disease predictors could likely help clarify the controversial results of studies on vitamin D, calcium and proteins, translate into practical wellness promotion across diverse elderly populations.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156052"},"PeriodicalIF":10.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142561021","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":"CHK1 attenuates cardiac dysfunction via suppressing SIRT1-ubiquitination","authors":"Tong-Tong Yang ,&nbsp;Liu-Hua Zhou ,&nbsp;Ling-Feng Gu ,&nbsp;Ling-Ling Qian ,&nbsp;Yu-Lin Bao ,&nbsp;Peng Jing ,&nbsp;Jia-Teng Sun ,&nbsp;Chong Du ,&nbsp;Tian-Kai Shan ,&nbsp;Si-Bo Wang ,&nbsp;Wen-Jing Wang ,&nbsp;Jia-Yi Chen ,&nbsp;Ze-Mu Wang ,&nbsp;Hao Wang ,&nbsp;Qi-Ming Wang ,&nbsp;Ru-Xing Wang ,&nbsp;Lian-Sheng Wang","doi":"10.1016/j.metabol.2024.156048","DOIUrl":"10.1016/j.metabol.2024.156048","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondrial dysfunction is linked to myocardial ischemia-reperfusion (I/R) injury. Checkpoint kinase 1 (CHK1) could facilitate cardiomyocyte proliferation, however, its role on mitochondrial function in I/R injury remains unknown.</div></div><div><h3>Methods</h3><div>To investigate the role of CHK1 on mitochondrial function following I/R injury, cardiomyocyte-specific knockout/overexpression mouse models were generated. Adult mouse cardiomyocytes (AMCMs) were isolated for <em>in vitro</em> study. Mass spectrometry-proteomics analysis and protein co-immunoprecipitation assays were conducted to dissect the molecular mechanism.</div></div><div><h3>Results</h3><div>CHK1 was downregulated in myocardium post I/R and AMCMs post oxygen-glucose deprivation/re‑oxygenation (OGD/R). <em>In vivo</em>, CHK1 overexpression protected against I/R induced cardiac dysfunction, while heterogenous CHK1 knockout exacerbated cardiomyopathy. <em>In vitro</em>, CHK1 inhibited OGD/R-induced cardiomyocyte apoptosis and bolstered cardiomyocyte survival. Mechanistically, CHK1 attenuated oxidative stress and preserved mitochondrial metabolism in cardiomyocytes under I/R. Moreover, disrupted mitochondrial homeostasis in I/R myocardium was restored by CHK1 through the promotion of mitochondrial biogenesis and mitophagy. Through mass spectrometry analysis following co-immunoprecipitation, SIRT1 was identified as a direct target of CHK1. The 266–390 domain of CHK1 interacted with the 160–583 domain of SIRT1. Importantly, CHK1 phosphorylated SIRT1 at Thr530 residue, thereby inhibiting SMURF2-mediated degradation of SIRT1. The role of CHK1 in maintaining mitochondrial dynamics control and myocardial protection is abolished by SIRT1 inhibition, while inactivated mutation of SIRT1 Thr530 fails to reverse the impaired mitochondrial dynamics following CHK1 knockdown. CHK1 Δ390 amino acids (aa) mutant functioned similarly to full-length CHK1 in scavenging ROS and maintaining mitochondrial dynamics. Consistently, cardiac-specific SIRT1 knockdown attenuated the protective role of CHK1 in I/R injury.</div></div><div><h3>Conclusions</h3><div>Our findings revealed that CHK1 mitigates I/R injury and restores mitochondrial dynamics in cardiomyocytes through a SIRT1-dependent mechanism.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156048"},"PeriodicalIF":10.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504210","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}