Metabolism: clinical and experimental最新文献

{"title":"NRH, a potent NAD+ enhancer, improves glucose homeostasis and lipid metabolism in diet-induced obese mice through an active adenosine kinase pathway","authors":"Xinliu Zeng ,&nbsp;Yongjie Wang ,&nbsp;Karina Farias ,&nbsp;Andrew Rappa ,&nbsp;Christine Darko ,&nbsp;Anthony Sauve ,&nbsp;Qingxia Huang ,&nbsp;Laura C. Alonso ,&nbsp;Yue Yang","doi":"10.1016/j.metabol.2024.156110","DOIUrl":"10.1016/j.metabol.2024.156110","url":null,"abstract":"<div><h3>Aims</h3><div>NAD⁺ deficiency underlies obesity-induced metabolic disturbances. This study evaluated dihydronicotinamide riboside (NRH), a potent NAD⁺ enhancer, in lean and obese mice and explored whether NRH operates through a unique mechanism involving adenosine kinase (ADK), an enzyme critical for NRH-driven NAD⁺ synthesis.</div></div><div><h3>Methods</h3><div>Pharmacokinetic and pharmacodynamic analyses were performed following a single 250 mg/kg intraperitoneal injection of NRH in healthy mice. In long-term studies, lean and high-fat diet-induced obese mice were treated with 250 mg/kg NRH thrice weekly for 7 weeks. Blood NAD⁺ levels, body composition, energy expenditure, and glucose and lipid metabolism were monitored. To test ADK's role, the ADK inhibitor ABT702 was co-administered with NRH in obese mice.</div></div><div><h3>Results</h3><div>NRH entered tissues unassisted and was rapidly metabolized for NAD⁺ biosynthesis, while ADK inhibition blocked its phosphorylation, leading to NRH accumulation in all examined tissues and possible release back into circulation. The 7-week NRH administration was well-tolerated in both lean and obese mice. In obese mice, NRH improved glucose homeostasis by boosting insulin secretion, enhancing muscle insulin signaling, and reducing hepatic gluconeogenesis. It also lowered fat mass, decreased serum lipids, and improved white adipose function. These benefits were linked to elevated tissue NAD⁺ levels, enhanced Sirtuin activities, and increased mitochondrial antioxidant defenses. ADK inhibition abolished these effects, confirming that NRH's direct entry into tissues and subsequent phosphorylation is essential for its full benefits.</div></div><div><h3>Conclusion</h3><div>This study establishes NRH as a promising therapeutic agent for obesity-induced metabolic dysfunction, correcting glucose intolerance and hyperlipidemia through ADK-dependent NAD⁺ enhancement.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156110"},"PeriodicalIF":10.8,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877551","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":"NORAD exacerbates metabolic dysfunction-associated steatotic liver disease development via the miR-511-3p/Rock2 axis and inhibits ubiquitin-mediated degradation of ROCK2","authors":"Xu Zhang ,&nbsp;Tianxing Chen ,&nbsp;Zhenhan Li ,&nbsp;Lingfeng Wan ,&nbsp;Zhihang Zhou ,&nbsp;Ying Xu ,&nbsp;Dong Yan ,&nbsp;Wei Zhao ,&nbsp;Hao Chen","doi":"10.1016/j.metabol.2024.156111","DOIUrl":"10.1016/j.metabol.2024.156111","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Abnormal regulation of lncRNA is strongly linked to metabolic dysfunction-associated steatotic liver disease (MASLD). However, the precise molecular mechanisms remain unclear. This study explores the roles of noncoding RNA activated by DNA damage (NORAD)/miR-511-3p/Rho-associated protein kinase 2 (<em>Rock2</em>) axis and the NORAD/ROCK2 interaction in the development of MASLD.</div></div><div><h3>Methods</h3><div><em>In vitro</em> and <em>in vivo</em> models of MASLD were created using high-fat diet-fed mice and free fatty acid (FFA)-treated hepatocytes. To examine the relationships between NORAD, miR-511-3p, and ROCK2, we employed bioinformatics, luciferase assays, RNA immunoprecipitation, and biotinylated NORAD pull-down assays. MASLD progression was assessed based on food intake, energy expenditure, insulin resistance, hepatic steatosis, inflammation, white fat growth, and liver fibrosis.</div></div><div><h3>Results</h3><div>NORAD and ROCK2 were upregulated, while miR-511-3p was downregulated in MASLD liver tissues and FFA-treated hepatocytes. Mechanistically, NORAD competitively interacted with miR-511-3p to modulate <em>Rock2</em> mRNA expression, and directly stabilized ROCK2 protein by abrogating its ubiquitination degradation. Functionally, liver-specific knockdown of NORAD or overexpression of miR-511-3p significantly slowed MASLD progression. Overexpression of NORAD or ROCK2 partially reversed miR-511-3p-induced inhibition of MASLD. Additionally, ROCK2 knockdown attenuated NORAD-induced worsening of MASLD. Moreover, overexpressing NORAD or ROCK2 or interfering miR-511-3p influenced resmetirom treatment to suppress MASLD development. Finally, metabolic changes in liver driven by the NORAD/miR-511-3p/<em>Rock2</em> axis and NORAD/ROCK2 interaction also influenced white adipose growth, pancreatic β-cell dedifferentiation, and liver fibrosis.</div></div><div><h3>Conclusions</h3><div>The NORAD/miR-511-3p/<em>Rock2</em> axis and the NORAD/ROCK2 interaction play critical roles in MASLD progression, identifying potential therapeutic targets for its treatment.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156111"},"PeriodicalIF":10.8,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877612","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":"Shared genetic architecture of type 2 diabetes with muscle mass and function and frailty reveals comorbidity etiology and pleiotropic druggable targets","authors":"Chun Dou ,&nbsp;Dong Liu ,&nbsp;Lijie Kong,&nbsp;Mingling Chen,&nbsp;Chaojie Ye,&nbsp;Zheng Zhu,&nbsp;Jie Zheng,&nbsp;Min Xu,&nbsp;Yu Xu,&nbsp;Mian Li,&nbsp;Zhiyun Zhao,&nbsp;Jieli Lu,&nbsp;Yuhong Chen,&nbsp;Guang Ning,&nbsp;Weiqing Wang,&nbsp;Yufang Bi,&nbsp;Tiange Wang","doi":"10.1016/j.metabol.2024.156112","DOIUrl":"10.1016/j.metabol.2024.156112","url":null,"abstract":"<div><h3>Background</h3><div>Delineating the shared genetic architecture of type 2 diabetes with muscle mass and function and frailty is essential for unraveling the common etiology and developing holistic therapeutic strategies for these co-existing conditions.</div></div><div><h3>Methods</h3><div>In this genome-wide pleiotropic association study, we performed multi-level pairwise trait pleiotropic analyses using genome-wide association study summary statistics from up to 461,026 European ancestry individuals to dissect the shared genetic factors and causal relationships of type 2 diabetes and seven glycemic traits with four muscle mass- and function-related phenotypes and the frailty index.</div></div><div><h3>Results</h3><div>We first identified 27 pairs with significant genetic correlations through the linkage disequilibrium score regression and high-definition likelihood analysis. Then we determined 79 pleiotropic loci and 109 pleiotropic genes across linkage pairs via the pleiotropic analysis under the composite null hypothesis (PLACO), the colocalization, and the Multi-marker Analysis of GenoMic Annotation (MAGMA) analyses. We subsequently performed transcriptome-wide association study (TWAS) analyses using joint-tissue imputation, refined by gene-based integrative fine-mapping through a conditional TWAS approach, and identified 44 unique causal shared genes across 13 tissues in linkage pairs, including eight druggable genes (<em>ABO</em>, <em>AOC1</em>, <em>FTO</em>, <em>GCKR</em>, <em>MTOR</em>, <em>POLK</em>, <em>PPARG</em>, and <em>APEH</em>), with <em>MTOR</em> and <em>PPARG</em> categorized as clinically actionable. Two-sample Mendelian randomization analysis supported bidirectional causality between diabetes and frailty index and unidirectional causal effects of muscle phenotypes on glycemic profiles.</div></div><div><h3>Conclusions</h3><div>Our findings highlight the common genetic underpinnings between type 2 diabetes and muscle loss and frailty and inform drug targets with pleiotropic effects on both of these aging-related challenges.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156112"},"PeriodicalIF":10.8,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877555","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":"PRR14 mediates mechanotransduction and regulates myofiber identity via MEF2C in skeletal muscle","authors":"Mei Yang ,&nbsp;Jiajie Wang ,&nbsp;Zhongyue Liu ,&nbsp;Zhihong Li","doi":"10.1016/j.metabol.2024.156109","DOIUrl":"10.1016/j.metabol.2024.156109","url":null,"abstract":"<div><div>Skeletal muscle is a crucial tissue for physical activity and energy metabolism. Muscle atrophy, characterized by the loss of muscle mass and strength, contributes to adverse outcomes among individuals. This study elucidated the involvement of the nuclear lamina component PRR14 in transmitting mechanical signals and mediating the impact of exercise on skeletal muscle. The expression of PRR14 demonstrated a positive correlation with exercise, while a decline in adult skeletal muscle is evident in disuse muscle conditions. Genetically, multiple single nucleotide polymorphisms (SNPs) within PRR14's genomic locus were linked with muscle mass and function. Specific knockout (KO) of skeletal muscle Prr14 in mice lead to muscle atrophy, validating the genetic association. By employing biochemical analysis and high-throughput sequencing techniques, including transcriptome profile and epigenome investigations such as Cleavage Under Targets and Tagmentation sequencing (CUT&amp;Tag-seq) and Transposase-Accessible Chromatin sequencing (ATAC-seq), we discovered that PRR14's deficiency altered chromatin structure, regulated MEF2C's activity, and disrupted myofiber identity maintenance, ultimately causing muscle atrophy. Our finding highlights the crucial role of PRR14 in mechanotransduction and epigenetic regulation, offering new therapeutic avenues for skeletal muscle pathologies related to these mechanisms.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156109"},"PeriodicalIF":10.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872511","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":"HDAC6 mediates NLRP3 inflammasome activation in the pathogenesis of diabetic retinopathy","authors":"Jun-Sik Kim ,&nbsp;Jae Hyun Jun ,&nbsp;Jeongmi Lee ,&nbsp;Sunyoung Park ,&nbsp;Eunae Kim ,&nbsp;Su Jung Hwang ,&nbsp;Heesu Moon ,&nbsp;Seung Hyun Baek ,&nbsp;Hark Kyun Kim ,&nbsp;Jinsu Park ,&nbsp;Yoonsuk Cho ,&nbsp;Jihoon Han ,&nbsp;Chanhee Kim ,&nbsp;Jongho Kim ,&nbsp;Hyun-Mo Yang ,&nbsp;Changsik Lee ,&nbsp;Yeonseok Chung ,&nbsp;Hyo-Jong Lee ,&nbsp;Dong-Gyu Jo","doi":"10.1016/j.metabol.2024.156108","DOIUrl":"10.1016/j.metabol.2024.156108","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic retinopathy (DR), a major blindness cause in developed countries, is intricately linked to diabetes management and its duration. Here, we demonstrate that HDAC6 mediates NLRP3 inflammasome activation under diabetic conditions, leading to retinal inflammation and degeneration.</div></div><div><h3>Methods</h3><div>This study demonstrated the therapeutic effects of HDAC6 genetic ablation, pharmacological inhibition, and HDAC6-deficient bone marrow transplantation in a diabetes model induced by streptozotocin and a high-fat diet. The therapeutic potential was evaluated from a metabolic perspective, including ocular pathologies such as retinal lesions, neovascularization, and vascular leakage.</div></div><div><h3>Results</h3><div>We discovered that inhibition or genetic ablation of HDAC6 markedly alleviates DR symptoms by dampening NLRP3 inflammasome activation and mitigating retinal damage. Moreover, bone marrow transplantation from HDAC6-deficient mice into wild-type counterparts reversed DR symptoms, underscoring the significance of HDAC6 in systemic immune regulation. The study introduces a novel HDAC6 inhibitor, noted for superior bioavailability and blood-retinal barrier permeability, further highlights the therapeutic promise of targeting HDAC6 in DR.</div></div><div><h3>Conclusions</h3><div>Our findings not only underscore the crucial role of HDAC6 in the immune regulatory mechanisms underlying DR pathogenesis through NLRP3 inflammasome activation but also position HDAC6 inhibition as a promising strategy for addressing diabetic complications beyond DR.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156108"},"PeriodicalIF":10.8,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847011","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":"Intermittent fasting and neurodegenerative diseases: Molecular mechanisms and therapeutic potential","authors":"Renjun Lv ,&nbsp;Bin Liu ,&nbsp;Ziying Jiang ,&nbsp;Runfa Zhou ,&nbsp;Xiaoxing Liu ,&nbsp;Tangsheng Lu ,&nbsp;Yanping Bao ,&nbsp;Chunxia Huang ,&nbsp;Guichang Zou ,&nbsp;Zongyong Zhang ,&nbsp;Lin Lu ,&nbsp;Qingqing Yin","doi":"10.1016/j.metabol.2024.156104","DOIUrl":"10.1016/j.metabol.2024.156104","url":null,"abstract":"<div><div>Neurodegenerative disorders are straining public health worldwide. During neurodegenerative disease progression, aberrant neuronal network activity, bioenergetic impairment, adaptive neural plasticity impairment, dysregulation of neuronal Ca²⁺ homeostasis, oxidative stress, and immune inflammation manifest as characteristic pathological changes in the cellular milieu of the brain. There is no drug for the treatment of neurodegenerative disorders, and therefore, strategies/treatments for the prevention or treatment of neurodegenerative disorders are urgently needed. Intermittent fasting (IF) is characterized as an eating pattern that alternates between periods of fasting and eating, requiring fasting durations that vary depending on the specific protocol implemented. During IF, depletion of liver glycogen stores leads to the production of ketone bodies from fatty acids derived from adipocytes, thereby inducing an altered metabolic state accompanied by cellular and molecular adaptive responses within neural networks in the brain. At the cellular level, adaptive responses can promote the generation of synapses and neurons. At the molecular level, IF triggers the activation of associated transcription factors, thereby eliciting the expression of protective proteins. Consequently, this regulatory process governs central and peripheral metabolism, oxidative stress, inflammation, mitochondrial function, autophagy, and the gut microbiota, all of which contribute to the amelioration of neurodegenerative disorders. Emerging evidence suggests that weight regulation significantly contributes to the neuroprotective effects of IF. By alleviating obesity-related factors such as blood-brain barrier dysfunction, neuroinflammation, and β-amyloid accumulation, IF enhances metabolic flexibility and insulin sensitivity, further supporting its potential in mitigating neurodegenerative disorders. The present review summarizes animal and human studies investigating the role and underlying mechanisms of IF in physiology and pathology, with an emphasis on its therapeutic potential. Furthermore, we provide an overview of the cellular and molecular mechanisms involved in regulating brain energy metabolism through IF, highlighting its potential applications in neurodegenerative disorders. Ultimately, our findings offer novel insights into the preventive and therapeutic applications of IF for neurodegenerative disorders.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156104"},"PeriodicalIF":10.8,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824181","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":"Targeted metabolomics identified novel metabolites, predominantly phosphatidylcholines and docosahexaenoic acid-containing lipids, predictive of incident chronic kidney disease in middle-to-elderly-aged Chinese adults","authors":"Ling Liu ,&nbsp;Hao Cai ,&nbsp;Handong Yang ,&nbsp;Sihan Wang ,&nbsp;Yingmei Li ,&nbsp;Yacan Huang ,&nbsp;Mingjing Gao ,&nbsp;Xiaogang Zhang ,&nbsp;Xiaomin Zhang ,&nbsp;Hao Wang ,&nbsp;Gaokun Qiu","doi":"10.1016/j.metabol.2024.156085","DOIUrl":"10.1016/j.metabol.2024.156085","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Evidence is limited regarding the association of circulating metabolites with decline of kidney function, letting alone their value in prediction of development of chronic kidney disease (CKD).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;This study included 3802 participants aged 64.1 ± 7.4 years from the Dongfeng-Tongji cohort, among whom 3327 were CKD-free at baseline (estimated glomerular filtration rate [eGFR] &gt; 60 ml/min per 1.73 m&lt;sup&gt;2&lt;/sup&gt;). We measured baseline levels of 211 metabolites with liquid chromatography coupled with mass spectrometry, including 25 amino acids, 12 acyl-carnitines, 161 lipids, and 13 other metabolites.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The mean (SD) absolute annual change in eGFR was −0.14 ± 4.11 ml/min per 1.73 m&lt;sup&gt;2&lt;/sup&gt; per year, and a total of 472 participants who were free of CKD at baseline developed incident CKD during follow-up of 4.6 ± 0.2 years (14.2 %). We identified a total of 22 metabolites associated with annual eGFR change and survived Bonferroni correction for multiple testing, including seven metabolites associated with eGFR increase (six being docosahexaenoic acid [DHA]-containing lipids) and 15 associated with eGFR decline (nine being phosphatidylcholines [PCs]). Among them, eight metabolites obtained non-zero coefficients in least absolute shrinkage and selection operator (LASSO) regression on incident CKD, indicating predictive potential, including one amino acid (arginine), one acyl-carnitine (C2), one lysophosphatidylcholine (LPC 22:6), two PCs (32:1 and 34:3), one triacylglycerol (TAG 56:8 [22:6]) and two other metabolites (inosine, niacinamide), and the composite score of these eight metabolites showed an odds ratio (OR) of 8.79 (95 % confidence interval [CI]: 7.49, 10.32; &lt;em&gt;P&lt;/em&gt; &lt; 0.001) per SD increase in association with incident CKD. The addition of the metabolite score increased the c-statistic of the reference model of traditional risk factors (including baseline eGFR) by 0.065 (95 % CI: 0.046 to 0.084; &lt;em&gt;P&lt;/em&gt; = 3.39 × 10&lt;sup&gt;−11&lt;/sup&gt;) to 0.765 (0.742 to 0.788) in 1000 repetitions of 10-fold cross-validation, while the application of two advanced machine learning algorithms, random forest (RF), and extreme gradient boosting (XGBoost) models produced similar c-statistics, to 0.753 (0.729 to 0.777) and 0.778 (0.733 to 0.824) with increases of 0.074 (0.055 to 0.093; &lt;em&gt;P&lt;/em&gt; = 4.11 × 10&lt;sup&gt;−14&lt;/sup&gt;) and 0.073 (0.032 to 0.114; &lt;em&gt;P&lt;/em&gt; = 4.00 × 10&lt;sup&gt;−4&lt;/sup&gt;), respectively.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;In this study, we identified 22 metabolites associated with longitudinal eGFR change, nine of which were PCs and six were DHA-containing lipids. We screened out a panel of eight metabolites which improved prediction for the development of CKD by 9 % beyond traditional risk factors including baseline eGFR. Our findings highlighted involvement of lipid metabolism in kidney function impairment, and provided novel predictors for ","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156085"},"PeriodicalIF":10.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751246","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":"Bilirubin bioconversion to urobilin in the gut-liver-kidney axis: A biomarker for insulin resistance in the Cardiovascular-Kidney-Metabolic (CKM) Syndrome","authors":"Zachary A. Kipp ,&nbsp;Olufunto O. Badmus ,&nbsp;David E. Stec ,&nbsp;Brantley Hall ,&nbsp;Terry D. Hinds Jr","doi":"10.1016/j.metabol.2024.156081","DOIUrl":"10.1016/j.metabol.2024.156081","url":null,"abstract":"<div><div>The rising rates of obesity worldwide have increased the incidence of cardiovascular disease (CVD), making it the number one cause of death. Higher plasma bilirubin levels have been shown to prevent metabolic dysfunction and CVD. However, reducing levels leads to deleterious outcomes, possibly due to reduced bilirubin half-life that escalates the production of its catabolized product, urobilinogen, produced by gut bacteria and naturally oxidized to urobilin. Recent findings suggest that the involvement of the microbiome catabolism of bilirubin to urobilin and its absorption via the hepatic portal vein contributes to CVD, suggesting a liver-gut axis involvement. We discuss the studies that demonstrate that urobilin is frequently raised in the urine of persons with CVD and its probable role in acquiring the disease. Urobilin is excreted from the kidneys into the urine and may serve as a biomarker for Cardiovascular-Kidney-Metabolic (CKM) Syndrome. We deliberate on the newly discovered bilirubin reductase (BilR) bacterial enzyme that produces urobilin. We discuss the bacterial species expressing BilR, how they impact CVD, and whether suppressing urobilin production and increasing bilirubin may provide new therapeutic strategies for CKM. Possible therapeutic mechanisms for achieving this goal are discussed.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156081"},"PeriodicalIF":10.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695533","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":"Reducing the global prevalence of cardiometabolic risk factors: a bet worth winning","authors":"Federica Fogacci ,&nbsp;Kausik K. Ray ,&nbsp;Stephen J. Nicholls ,&nbsp;Arrigo F.G. Cicero","doi":"10.1016/j.metabol.2024.156084","DOIUrl":"10.1016/j.metabol.2024.156084","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156084"},"PeriodicalIF":10.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142703187","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":"An updated overview on hepatocellular carcinoma in patients with Metabolic dysfunction-Associated Steatotic Liver Disease: Trends, pathophysiology and risk-based surveillance","authors":"Angelo Armandi,&nbsp;Chiara Rosso,&nbsp;Gian Paolo Caviglia ,&nbsp;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}