Metabolism: clinical and experimental最新文献

{"title":"Membrane tension sensing formin-binding protein 1 is a neuronal nutrient stress-responsive Golgiphagy receptor","authors":"Smita Saha ,&nbsp;Anirban Mandal ,&nbsp;Akash Ranjan ,&nbsp;Debasish Kumar Ghosh","doi":"10.1016/j.metabol.2024.156040","DOIUrl":"10.1016/j.metabol.2024.156040","url":null,"abstract":"<div><h3>Background</h3><div>Nutrient stress-responsive neuronal homeostasis relies on intricate autophagic mechanisms that modulate various organelle integrity and function. The selective autophagy of the Golgi, known as Golgiphagy, regulates secretory processes by modulating vesicle trafficking during nutrient starvation.</div></div><div><h3>Results</h3><div>In this study, we explored a genetic screen of BAR-domain-containing proteins to elucidate the role of formin-binding protein 1 (FNBP1) as a Golgiphagy receptor in modulating Golgi dynamics in response to varying nutrient availability in neurons. Mapping the systems network of FNBP1 and its interacting proteins reveals the putative involvement of FNBP1 in autophagy and Golgi-associated processes. While nutrient depletion causes Golgi fragmentation, FNBP1 preferentially localizes to the fragmented Golgi membrane through its ²⁸⁴FEDYTQ²⁸⁹ motif during nutrient stress. Simultaneously, FNBP1 engages in molecular interactions with LC3B through a conserved ¹³¹WKQL¹³⁴ LC3 interacting region, thereby sequestering the fragmented Golgi membrane in neuronal autophagosomes. Increased aggregation of GM130, abnormal clumping of RAB11-positive secretory granules, and enhanced senescent death of FNBP1-depleted starved neurons indicate disruptions of neuronal homeostasis under metabolic stress.</div></div><div><h3>Conclusion</h3><div>The identification of FNBP1 as a nutrient stress-responsive Golgiphagy receptor expands our insights into the molecular mechanisms underlying Golgiphagy, establishing the crosstalk between nutrient sensing and membrane tension-sensing regulatory autophagic processes of Golgi turnover in neurons.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156040"},"PeriodicalIF":10.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350221","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 ,&nbsp;Erasmia Boutakoglou ,&nbsp;Irene Mavroudi ,&nbsp;Christos S. Mantzoros ,&nbsp;Maria Veiga-da Cunha ,&nbsp;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":"162 ","pages":"Article 156077"},"PeriodicalIF":10.8,"publicationDate":"2025-01-01","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":"Fam3a-mediated prohormone convertase switch in α-cells regulates pancreatic GLP-1 production in an Nr4a2-Foxa2-dependent manner","authors":"Dandan Wang ,&nbsp;Tianjiao Wei ,&nbsp;Xiaona Cui ,&nbsp;Li Xia ,&nbsp;Yafei Jiang ,&nbsp;Deshan Yin ,&nbsp;Xinyue Liao ,&nbsp;Fei Li ,&nbsp;Jian Li ,&nbsp;Qi Wu ,&nbsp;Xiafang Lin ,&nbsp;Shan Lang ,&nbsp;Yunyi Le ,&nbsp;Jichun Yang ,&nbsp;Jin Yang ,&nbsp;Rui Wei ,&nbsp;Tianpei Hong","doi":"10.1016/j.metabol.2024.156042","DOIUrl":"10.1016/j.metabol.2024.156042","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Fam3a has been demonstrated to regulate pancreatic β-cell function and glucose homeostasis. However, the role and mechanism of Fam3a in regulating α-cell function remain unexplored.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Glucagon and glucagon-like peptide-1 (GLP-1) levels in pancreas and plasma were measured in global &lt;em&gt;Fam3a&lt;/em&gt; knockout (&lt;em&gt;Fam3a&lt;/em&gt;&lt;sup&gt;−/−&lt;/sup&gt;) mice. Human islet single-cell RNA sequencing (scRNA-seq) datasets were utilized to analyze gene expression correlations between &lt;em&gt;FAM3A&lt;/em&gt; and &lt;em&gt;PCSK1&lt;/em&gt; (encoding PC1/3, which processes proglucagon into GLP-1). Mouse pancreatic α-cell line αTC1.9 cells were transfected with &lt;em&gt;Fam3a&lt;/em&gt; siRNA or plasmid for &lt;em&gt;Fam3a&lt;/em&gt; knockdown or overexpression to explore the effects of Fam3a on PC1/3 expression and GLP-1 production. The downstream mediator (including Nr4a2) was identified by transcriptomic analysis, and its role was confirmed by &lt;em&gt;Fam3a&lt;/em&gt; knockdown or overexpression in αTC1.9 cells. Based on the interacted protein of Nr4a2 and the direct binding to &lt;em&gt;Pcsk1&lt;/em&gt; promoter, the transcription factor Foxa2 was selected for further verification. Nuclear translocation assay and dual-luciferase reporter assay were used to clarify the involvement of Fam3a-Nr4a2-Foxa2 pathway in PC1/3 expression and GLP-1 production. Moreover, α-cell-specific &lt;em&gt;Fam3a&lt;/em&gt; knockout (&lt;em&gt;Fam3a&lt;/em&gt;&lt;sup&gt;α−/−&lt;/sup&gt;) mice were constructed to evaluate the metabolic variables and hormone levels under normoglycemic, high-fat diet (HFD)-fed and streptozotocin (STZ)-induced diabetic conditions. Exendin 9–39 (Ex9), a GLP-1 receptor antagonist, was used to investigate GLP-1 paracrine effects in &lt;em&gt;Fam3a&lt;/em&gt;&lt;sup&gt;α−/−&lt;/sup&gt; mice and in their primary islets.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Compared with wild-type mice, pancreatic and plasma active GLP-1 levels were increased in &lt;em&gt;Fam3a&lt;/em&gt;&lt;sup&gt;−/−&lt;/sup&gt; mice. Analysis of human islet scRNA-seq datasets showed a significant negative correction between &lt;em&gt;FAM3A&lt;/em&gt; and &lt;em&gt;PCSK1&lt;/em&gt; in α-cells. &lt;em&gt;Fam3a&lt;/em&gt; knockdown upregulated PC1/3 expression and GLP-1 production in αTC1.9 cells, while &lt;em&gt;Fam3a&lt;/em&gt; overexpression displayed inverse effects. Transcriptomic analysis identified &lt;em&gt;Nr4a2&lt;/em&gt; as a key downstream mediator of Fam3a, and Nr4a2 expression in αTC1.9 cells was downregulated and upregulated by &lt;em&gt;Fam3a&lt;/em&gt; knockdown and overexpression, respectively. &lt;em&gt;Nr4a2&lt;/em&gt; silencing increased PC1/3 expression, albeit Nr4a2 did not directly bind to &lt;em&gt;Pcsk1&lt;/em&gt; promoter. Instead, Nr4a2 formed a complex with Foxa2 to facilitate Fam3a-mediated Foxa2 nuclear translocation. Foxa2 negatively regulated PC1/3 expression and GLP-1 production. Besides, Foxa2 inhibited the transcriptional activity of &lt;em&gt;Pcsk1&lt;/em&gt; promoter at specific binding sites 10 and 6, and this inhibition was intensified by Nr4a2 in αTC1.9 cells. Compared with Flox/cre littermates, improved glucose tolerance, increased active GLP-1 level","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156042"},"PeriodicalIF":10.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372341","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":"Inhibition of ACSS2 triggers glycolysis inhibition and nuclear translocation to activate SIRT1/ATG5/ATG2B deacetylation axis, promoting autophagy and reducing malignancy and chemoresistance in ovarian cancer","authors":"Jiang Yang ,&nbsp;Haoyu Wang ,&nbsp;Bingshu Li ,&nbsp;Jingchun Liu ,&nbsp;Xiaoyi Zhang ,&nbsp;Ying Wang ,&nbsp;Jiaxin Peng ,&nbsp;Likun Gao ,&nbsp;Xinqi Wang ,&nbsp;Siyuan Hu ,&nbsp;Wenyi Zhang ,&nbsp;Li Hong","doi":"10.1016/j.metabol.2024.156041","DOIUrl":"10.1016/j.metabol.2024.156041","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Metabolic reprogramming is a hallmark of cancer, characterized by a high dependence on glycolysis and an enhanced utilization of acetate as an alternative carbon source. ACSS2 is a critical regulator of acetate metabolism, playing a significant role in the development and progression of various malignancies. ACSS2 facilitates the conversion of acetate to acetyl-CoA, which participates in multiple metabolic pathways and functions as an epigenetic regulator of protein acetylation, thereby modulating key cellular processes such as autophagy. However, the roles and intrinsic connections of ACSS2, glycolysis, protein acetylation, and autophagy in ovarian cancer (OC) remain to be elucidated.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Basic procedures&lt;/h3&gt;&lt;div&gt;Utilizing clinical specimens and online databases, we analysed the expression of ACSS2 in OC and its relationship with clinical prognosis. By knocking down ACSS2, we evaluated its effects on the malignant phenotype, acetate metabolism, glycolysis, and autophagy. The metabolic alterations in OC cells were comprehensively analysed using Seahorse assays, transmission electron microscopy, membrane potential measurements, and stable-isotope labeling techniques. CUT&amp;TAG and co-immunoprecipitation techniques were employed to explore the deacetylation of autophagy-related proteins mediated by ACSS2 via SIRT1. Additionally, through molecular docking, transcriptome sequencing, and metabolomics analyses, we validated the pharmacological effects of paeonol on ACSS2 and the glycolytic process in OC cells. Finally, both in vitro and in vivo experiments were performed to investigate the impact of paeonol on autophagy and its anti-OC effects mediated through the ACSS2/SIRT1 deacetylation axis.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Main findings&lt;/h3&gt;&lt;div&gt;ACSS2 is significantly upregulated in OC and is associated with poor prognosis. Knockdown of ACSS2 inhibits OC cells proliferation, migration, invasion, angiogenesis, and platinum resistance, while reducing tumour burden in vivo. Mechanistically, inhibiting ACSS2 reduces acetate metabolism and suppresses glycolysis by targeting HXK2. This glycolytic reduction promotes the translocation of ACSS2 from the cytoplasm to the nucleus, leading to increased expression of the deacetylase SIRT1. SIRT1 mediates the deacetylation of autophagy-related proteins, such as ATG5 and ATG2B, thereby significantly activating autophagy in OC cells and exerting antitumor effects. Paeonol inhibits acetate metabolism and glycolysis in OC cells by targeting ACSS2. Paeonol activates autophagy through the ACSS2/SIRT1/ATG5/ATG2B deacetylation axis, demonstrating inhibition of OC in vitro and in vivo.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Principal conclusions&lt;/h3&gt;&lt;div&gt;Pae can serve as an effective, low-toxicity, multi-targeted drug targeting ACSS2 and glycolysis. It activates autophagy through the ACSS2/SIRT1/ATG5/ATG2B deacetylation signalling cascade, thereby exerting anti-OC effects. Our study provides new insights","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156041"},"PeriodicalIF":10.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372342","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":"Central NUCB2/nesfatin-1 signaling ameliorates liver steatosis through suppression of endoplasmic reticulum stress in the hypothalamus","authors":"Yirui He ,&nbsp;Cheng Zhang ,&nbsp;Shaobo Wu ,&nbsp;Ke Li ,&nbsp;Siliang Zhang ,&nbsp;Mingyuan Tian ,&nbsp;Chen Chen ,&nbsp;Dongfang Liu ,&nbsp;Gangyi Yang ,&nbsp;Ling Li ,&nbsp;Mengliu Yang","doi":"10.1016/j.metabol.2024.156046","DOIUrl":"10.1016/j.metabol.2024.156046","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Nucleobindin-2 (NUCB2)/nesfatin-1, a signal with recognized anorexigenic and insulin-sensitizing properties in peripheral tissues, is expressed within the hypothalamus. However, the potential involvement of central nesfatin-1 signaling in the pathophysiology of hepatic steatosis remains unknown. This study aimed to determine whether and how central NUCB2/nesfatin-1 plays a role in liver steatosis.</div></div><div><h3>Methods</h3><div>We generated <em>Nucb2</em> knockout (<em>Nucb2</em>^{<em>−/−</em>}) rats and administered continuous intracerebroventricular (ICV) nesfatin-1 infusion, while observing its effect on liver steatosis. The molecular mechanism of action of nesfatin-1 was elucidated <em>via</em> proteomics, phosphoproteomics and molecular biology methods.</div></div><div><h3>Results</h3><div>Herein, we present compelling evidence indicating diminished NUCB2 expression in the hypothalamus of obese rodents. We demonstrated that chronic ICV infusion of nesfatin-1 mitigated both diet-induced obesity and liver steatosis in high-fat diet (HFD)-fed <em>Nucb2</em>^{<em>−/−</em>} rats by regulating hypothalamic endoplasmic reticulum (ER) stress and Akt phosphorylation. Furthermore, we revealed that the increase in hypothalamic insulin resistance (IR) and ER stress induced by tunicamycin infusion or Ero1α overexpression exacerbated hepatic steatosis and offset the favorable influence of central nesfatin-1 on hepatic steatosis. The metabolic action of central nesfatin-1 is contingent upon vagal nerve transmission to the liver. Mechanistically, nesfatin-1 impedes ER stress and interacts with Ero1α to repress its Ser106 phosphorylation. This leads to the enhancement of Akt activity in the hypothalamus, culminating in the inhibition of hepatic lipogenesis.</div></div><div><h3>Conclusions</h3><div>These findings underscore the importance of hypothalamic NUCB2/nesfatin-1 as a key mediator in the top-down neural mechanism that combats diet-induced liver steatosis.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156046"},"PeriodicalIF":10.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400753","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,&nbsp;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":"162 ","pages":"Article 156055"},"PeriodicalIF":10.8,"publicationDate":"2025-01-01","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":"Life's essential 8 and cardiovascular diseases progression among adults in the United Kingdom","authors":"Huangda Guo ,&nbsp;Siyue Wang ,&nbsp;Hexiang Peng ,&nbsp;Weiwei Wang ,&nbsp;Tianjiao Hou ,&nbsp;Yixin Li ,&nbsp;Hanyu Zhang ,&nbsp;Jin Jiang ,&nbsp;Bohao Ma ,&nbsp;Yilei Qin ,&nbsp;Mengying Wang ,&nbsp;Liming Li ,&nbsp;Jie Huang ,&nbsp;Tao Wu","doi":"10.1016/j.metabol.2024.156031","DOIUrl":"10.1016/j.metabol.2024.156031","url":null,"abstract":"<div><h3>Background</h3><div>Recently, the American Heart Association introduced Life's Essential 8 (LE8) as a new cardiovascular health (CVH) metric, and studies have reported associations between LE8 and CVH outcomes. However, there is limited understanding of LE8's impact on the risk of transitions between different stages of CVH. The current study investigated whether adhering to LE8 during a healthy stage could mitigate the progression from hypertension (HT) to cardiovascular diseases (CVDs), and consequent death.</div></div><div><h3>Methods</h3><div>The study included 107,682 participants in the UK Biobank who were initially free of HT and CVDs. CVH were evaluated using LE8 metrics (diet, physical activity, nicotine exposure, sleep duration, body mass index, non-high-density lipoprotein cholesterol, blood glucose, and blood pressure). Multistate models were used to analyse the impacts of LE8 on the progression of CVDs.</div></div><div><h3>Results</h3><div>During a median follow-up of 12.2 years, 5727 participants developed HT, 7243 developed CVDs, and 1183 died afterwards. LE8 was negatively associated with the dynamic disease progression. A per-10 points increase of CVH scores was significantly associated with the reduced risk [Hazard ratios (95 % confidence intervals)] at 0.71 (0.69, 0.72), 0.83 (0.81, 0.85), 0.79 (0.77, 0.82), and 0.91 (0.86, 0.96) in the transition from healthy to HT, CVDs, death, and from CVDs to death, respectively. Mediation analyses indicated that HT significantly mediated LE8-reduced risks of CVDs and mortality.</div></div><div><h3>Conclusions</h3><div>This study offered evidence that LE8 may influence the stages of CVD progression. The findings underscore the significance of adhering to LE8 in health management and CVDs management.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156031"},"PeriodicalIF":10.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180684","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":"Disruption of branched-chain amino acid homeostasis promotes the progression of DKD via enhancing inflammation and fibrosis-associated epithelial-mesenchymal transition","authors":"Xiaoqing Deng ,&nbsp;Chao Tang ,&nbsp;Ting Fang ,&nbsp;Ting Li ,&nbsp;Xiaoyu Li ,&nbsp;Yajin Liu ,&nbsp;Xuejiao Zhang ,&nbsp;Bei Sun ,&nbsp;Haipeng Sun ,&nbsp;Liming Chen","doi":"10.1016/j.metabol.2024.156037","DOIUrl":"10.1016/j.metabol.2024.156037","url":null,"abstract":"<div><h3>Background and aims</h3><div>The disrupted homeostasis of branched-chain amino acids (BCAAs, including leucine, isoleucine, and valine) has been strongly correlated with diabetes with a potential causal role. However, the relationship between BCAAs and diabetic kidney disease (DKD) remains to be established. Here, we show that the elevated BCAAs from BCAAs homeostatic disruption promote DKD progression unexpectedly as an independent risk factor.</div></div><div><h3>Methods and results</h3><div>Similar to other tissues, the suppressed BCAAs catabolic gene expression and elevated BCAAs abundance were detected in the kidneys of type 2 diabetic mice and individuals with DKD. Genetic and nutritional studies demonstrated that the elevated BCAAs from systemic disruption of BCAAs homeostasis promoted the progression of DKD. Of note, the elevated BCAAs promoted DKD progression without exacerbating diabetes in the animal models of type 2 DKD. Mechanistic studies demonstrated that the elevated BCAAs promoted fibrosis-associated epithelial-mesenchymal transition (EMT) by enhancing the activation of proinflammatory macrophages through mTOR signaling. Furthermore, pharmacological enhancement of systemic BCAAs catabolism using small molecule inhibitor attenuated type 2 DKD. Finally, the elevated BCAAs also promoted DKD progression in type 1 diabetic mice without exacerbating diabetes.</div></div><div><h3>Conclusion</h3><div>BCAA homeostatic disruption serves as an independent risk factor for DKD and restoring BCAA homeostasis pharmacologically or dietarily represents a promising therapeutic strategy to ameliorate the progression of DKD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156037"},"PeriodicalIF":10.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350220","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":"Subphenotypes of body composition and their association with cardiometabolic risk – Magnetic resonance imaging in a population-based sample","authors":"Elena Grune ,&nbsp;Johanna Nattenmüller ,&nbsp;Lena S. Kiefer ,&nbsp;Jürgen Machann ,&nbsp;Annette Peters ,&nbsp;Fabian Bamberg ,&nbsp;Christopher L. Schlett ,&nbsp;Susanne Rospleszcz","doi":"10.1016/j.metabol.2024.156130","DOIUrl":"10.1016/j.metabol.2024.156130","url":null,"abstract":"<div><h3>Background</h3><div>For characterizing health states, fat distribution is more informative than overall body size. We used population-based whole-body magnetic resonance imaging (MRI) to identify distinct body composition subphenotypes and characterize associations with cardiovascular disease (CVD) risk.</div></div><div><h3>Methods</h3><div>Bone marrow, visceral, subcutaneous, cardiac, renal, hepatic, skeletal muscle and pancreatic adipose tissue were measured by MRI in <em>n</em> = 299 individuals from the population-based KORA cohort. Body composition subphenotypes were identified by data-driven k-means clustering. CVD risk was calculated by established scores.</div></div><div><h3>Results</h3><div>We identified five body composition subphenotypes, which differed substantially in CVD risk factor distribution and CVD risk. Compared to reference subphenotype I with favorable risk profile, two high-risk phenotypes, III&amp;V, had a 3.8-fold increased CVD risk. High-risk subphenotype III had increased bone marrow and skeletal muscle fat (26.3 % vs 11.4 % in subphenotype I), indicating ageing effects, whereas subphenotype V showed overall high fat contents, and particularly elevated pancreatic fat (25.0 % vs 3.7 % in subphenotype I), indicating metabolic impairment. Subphenotype II had a 2.7-fold increased CVD risk, and an unfavorable fat distribution, probably smoking-related, while BMI was only slightly elevated. Subphenotype IV had a 2.8-fold increased CVD risk with comparably young individuals, who showed high blood pressure and hepatic fat (17.7 % vs 3.0 % in subphenotype I).</div></div><div><h3>Conclusions</h3><div>Whole-body MRI can identify distinct body composition subphenotypes associated with different degrees of cardiometabolic risk. Body composition profiling may enable a more comprehensive risk assessment than individual fat compartments, with potential benefits for individualized prevention.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156130"},"PeriodicalIF":10.8,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914456","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":"PPARα-ERRα crosstalk mitigates metabolic dysfunction-associated steatotic liver disease progression","authors":"Milton Boaheng Antwi ,&nbsp;Sander Lefere ,&nbsp;Dorien Clarisse ,&nbsp;Lisa Koorneef ,&nbsp;Anneleen Heldens ,&nbsp;Louis Onghena ,&nbsp;Kylian Decroix ,&nbsp;Daria Fijalkowska ,&nbsp;Jonathan Thommis ,&nbsp;Madeleine Hellemans ,&nbsp;Anne Hoorens ,&nbsp;Anja Geerts ,&nbsp;Lindsey Devisscher ,&nbsp;Karolien De Bosscher","doi":"10.1016/j.metabol.2024.156128","DOIUrl":"10.1016/j.metabol.2024.156128","url":null,"abstract":"<div><h3>Background and aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent liver disease worldwide, continues to rise. More effective therapeutic strategies are urgently needed. We investigated how targeting two key nuclear receptors involved in hepatic energy metabolism, peroxisome proliferator-activated receptor alpha (PPARα) and estrogen-related receptor alpha (ERRα), ameliorates MASLD.</div></div><div><h3>Methods</h3><div>The PPARα agonist pemafibrate and/or ERRα inverse agonist C29 were administered in a short- and long-term Western diet plus fructose model, and a diabetic-background streptozotocin-Western diet model (STZ-WD). Liver and adipose tissue morphology, histological samples, serum metabolites, RNA and protein levels were analysed and scanning electron microscopy was performed. In addition, we performed cell-based assays and immunohistochemistry and immunofluorescence stainings with light and super-resolution confocal microscopy of healthy, MASLD and MASH human livers.</div></div><div><h3>Results</h3><div>The ligand combinations' efficacy was highlighted by reduced liver steatosis across all mouse models, alongside improvements in body weight, inflammation, and fibrosis in both long-term models. Additionally, tumour formation was prevented in the STZ-WD mice model. Cell-based assays demonstrated that ERRα inhibits PPARα's activity, explaining why ERRα blockage improves inflammatory and lipid metabolism gene profiles and enhances lipid-lowering effects. Complementary RNA sequencing and shotgun proteomics, combined with enrichment analysis, jointly identified downregulated serum amyloid A1/A2 as essential components underlying the combination treatment's effectiveness. MASLD/MASH patient livers showed reduced PPARα and increased ERRα levels supporting disrupted NR crosstalk in the hepatocyte nucleus.</div></div><div><h3>Conclusion</h3><div>Our study supports that dual nuclear receptor targeting, which simultaneously increases PPARα and diminishes ERRα activity, may represent a viable novel strategy against MASLD.</div></div><div><h3>Impact and implications</h3><div>Our research introduces a novel therapeutic strategy against MASLD by simultaneously increasing PPARα activity while diminishing ERRα activity. With PPARα agonists already tested in phase III clinical trials, ERRα ligands/modulators need further (clinical) development to make our findings applicable to both MASLD patients and physicians.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156128"},"PeriodicalIF":10.8,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915469","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}