Metabolism and target organ damage最新文献

{"title":"Pharmacologic management of metabolic and alcohol-associated liver disease.","authors":"Mangesh Pagadala, Sajid Jalil, Nicholas Dunn, Ashwani K Singal","doi":"10.20517/mtod.2026.29","DOIUrl":"10.20517/mtod.2026.29","url":null,"abstract":"<p><p>Metabolic and alcohol-associated liver disease (MetALD) is an emerging phenotype within the steatotic liver disease spectrum, characterized by cardiometabolic risk factors coexisting with alcohol exposure, resulting in synergistic liver injury and fibrosis progression. Therapeutic development remains limited because most steatotic liver disease trials exclude patients with ongoing alcohol use. In contrast, alcohol-associated liver disease (ALD) trials have focused primarily on severe alcohol-associated hepatitis. Current management of patients with MetALD relies on an integrated approach that simultaneously controls alcohol use and cardiometabolic risk. In clinical practice, for patients with MetALD and ongoing alcohol use, therapies aimed at controlling alcohol use remain most critical, given the faster, more progressive disease course related to alcohol as compared to metabolic liver injury. Given the dynamic nature of alcohol intake and metabolic risk factors, longitudinal monitoring of disease stage with noninvasive fibrosis tests is essential. Liver-directed therapies with efficacy in metabolic dysfunction-associated steatotic liver disease (MASLD), including incretin-based agents, fibroblast growth factor 21 analogs, peroxisome proliferator-activated receptor agonists, and thyroid hormone receptor beta agonists, may benefit selected MetALD patients. Several agents may modulate both metabolic pathways and alcohol consumption through central reward mechanisms. Specific pharmacotherapies targeting alcohol use (acamprosate, naltrexone) combined with structured psychosocial interventions are effective in controlling alcohol use. Given the lack of dedicated clinical trials in MetALD patients, we synthesized data from clinical trials in MASLD and ALD. We propose adapting these data to inform the design of future clinical trials in patients with MetALD.</p>","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"6 2","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148708824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-term L-arabinose administration alleviates MASLD by remodeling gut microbiota and activating hepatic ATF5-dependent mitochondrial unfolded protein response","authors":"Heng Zhang, Ruhan Chen, Weiwei Zhang, Jie Ning, Yao Wang, Yunxiao Li, Meng Zhao, Lin Dong, Xiaolei Wang","doi":"10.20517/mtod.2025.179","DOIUrl":"https://doi.org/10.20517/mtod.2025.179","url":null,"abstract":"Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) involves gut microbial dysbiosis and mitochondrial stress, yet the molecular link between these processes remains unclear. This study explored whether short-term L-arabinose (LA) supplementation mitigates MASLD by modulating the gut-liver axis and mitochondrial adaptive signaling. Methods: A murine early-stage fatty liver model was established and treated orally with LA for four weeks. Gut microbial changes were assessed by 16S ribosomal RNA gene (16S rRNA) sequencing and functional prediction, while hepatic mechanisms were examined through activating transcription factor 5 (ATF5) gain- and loss-of-function experiments both in vivo and in vitro. Results: Short-term LA administration significantly reshaped gut microbiota, enriching short-chain fatty acid-producing taxa and improving hepatic lipid metabolism. Mechanistically, LA enhanced hepatic expression of ATF5, leading to the upregulation of mitochondrial chaperone heat shock protein 60 (HSP60) and protease Lon protease 1 (LONP1), thereby initiating the mitochondrial unfolded protein response (UPRmt). Activation of UPRmt restored mitochondrial integrity, reduced oxidative stress, and attenuated hepatic lipid deposition. Silencing ATF5 abolished these protective effects, confirming its central regulatory role. Conclusion: Short-term LA treatment alleviates MASLD by reprogramming gut microbiota and activating hepatic ATF5-mediated UPRmt signaling. These findings reveal a novel gut–mitochondrial regulatory pathway that links microbial metabolism to hepatic mitochondrial proteostasis, providing new mechanistic insight and therapeutic potential for metabolic liver disease.","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"5 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://f.oaes.cc/xmlpdf/published/article/dbd5cae9682e848bba3fd241c4d6aa6e/mtod50179.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147918846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Yohimbine attenuates oxidative stress through circGNB1/CDA1 axis in diabetic nephropathy","authors":"Xiaoxu Ge, Juan Du, Wenyi Li, Peng Zhou, Jianfang Gao, Wenfang Peng, Shan Huang","doi":"10.20517/mtod.2025.134","DOIUrl":"https://doi.org/10.20517/mtod.2025.134","url":null,"abstract":"Aim: To investigate the role of yohimbine (YH) in diabetic nephropathy (DN) progression and identify its underlying molecular mechanisms. Methods: Human renal proximal tubular epithelial cells (HK-2) were cultured with high glucose (HG) and treated with varying doses of YH. Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. Inflammatory markers and oxidative stress were measured. Male diabetic C57BLKS/J-LepR (db/db) mice received YH (2.5, 5, or 10 mg/kg) daily for eight weeks. Circular RNA (circRNA) microarray analysis was performed on HG-induced HK-2 cells. RNA pull-down assays combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to identify circGNB1-interacting proteins. Cellular localization and protein expression were determined through fractionation, RNA fluorescence in situ hybridization (RNA-FISH), and western blotting. Results: YH significantly enhanced viability of HG-induced HK-2 cells while reducing inflammatory factors and oxidative stress markers. These protective effects were confirmed in db/db mice, where YH reduced blood glucose, urinary albumin-to-creatinine ratio, and blood urea nitrogen levels. CircRNA microarray identified circGNB1 as the most significantly upregulated gene in YH-treated HG-induced cells. RNA pull-down assays identified cell division autoantigen 1 (CDA1) as a circGNB1-interacting protein. CircGNB1 positively regulated CDA1 expression at the protein level in HK-2 cells. CDA1 knockdown significantly decreased cell viability and counteracted the protective effects of YH treatment. Conclusion: Our study identifies a novel YH/circGNB1/CDA1 axis in DN progression. YH attenuates oxidative stress through upregulation of circGNB1, which interacts with and regulates CDA1 protein expression, thereby mitigating HG-induced renal cell damage. These findings provide new insights for developing therapeutic strategies for DN.","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"5 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://f.oaes.cc/xmlpdf/published/article/4e199e37756494b9a164af769fd2a794/mtod50134.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147906148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Will a \"multivitamin\" a day keep the \"MASLD doctor\" away?","authors":"Fernando Bril","doi":"10.20517/mtod.2025.24","DOIUrl":"10.20517/mtod.2025.24","url":null,"abstract":"<p><p>This commentary discusses the results of a study that assessed the relationship between homocysteine metabolism and histological severity of metabolic dysfunction-associated steatotic liver disease (MASLD), and applied a mathematical model to examine how replacement with different cofactors (pyridoxine, cobalamin, betaine, and folate) may affect homocysteine levels in patients with MASLD. It highlights the clinical implications of the study and examines the pathophysiological support behind the detected associations. It also discusses its limitations, emphasizing the need for further longitudinal and interventional studies to confirm whether modulating homocysteine levels could be a viable therapeutic strategy for MASLD.</p>","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"5 3","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12574233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bilirubin ameliorates metabolic dysregulation by targeting the HSP90β/SREBPs signaling axis to improve insulin resistance and mitigate ectopic lipid deposition","authors":"Jing Zhu, Haitao Xiao, Qiong Wu, Xue-Xue Shao, Yufan Meng, Jie Ding, Jia-Xin He, Li-Na Lai, Ning Xue, Zu‐Guo Zheng","doi":"10.20517/mtod.2025.47","DOIUrl":"https://doi.org/10.20517/mtod.2025.47","url":null,"abstract":"Aim: Sterol regulatory element-binding proteins (SREBPs) are key transcription factors driving de novo lipid synthesis (DNL) and associated metabolic disorders. This study aims to investigate whether bilirubin, a potential SREBP inhibitor, alleviates lipid accumulation and insulin resistance by targeting the HSP90β/SREBP pathway. Methods: In vitro, HL-7702 cells were treated with bilirubin to assess lipid-lowering effects and SREBP-related gene expression. In vivo, high-fat diet (HFD)-induced obese mice received bilirubin intervention for 6 weeks. Lipid profiles, insulin sensitivity, hepatic SREBP protein levels, and downstream gene expression were analyzed. Mechanistic studies focused on HSP90β activity modulation by bilirubin. Results: Bilirubin significantly reduced lipid accumulation in HL-7702 cells and downregulated SREBPs and their target genes. In HFD-fed mice, bilirubin attenuated obesity, hepatic steatosis, and insulin resistance, accompanied by suppressed SREBP protein levels and expression of target genes. Mechanistically, bilirubin inhibited SREBP activation by targeting HSP90β. Conclusion: Bilirubin ameliorates metabolic syndrome via the HSP90β/SREBP axis, providing a novel therapeutic strategy for lipid metabolism disorders and insulin resistance. These findings highlight bilirubin’s potential as a pharmacological agent against metabolic diseases.","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://f.oaes.cc/xmlpdf/published/article/ad64b0910b23835c8fe6f302a5ae0016/mtod5047.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147918521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monitoring and treatment of alcohol use disorder: an integrated multidisciplinary model.","authors":"Ashwani K Singal","doi":"10.20517/mtod.2024.103","DOIUrl":"10.20517/mtod.2024.103","url":null,"abstract":"<p><p>Alcohol-associated liver disease (ALD) is one of the most prevalent liver diseases and a leading indication for liver transplantation (LT). Alcohol use disorder (AUD), commonly present in patients with ALD, may also be associated with psychiatric comorbidities such as depression and anxiety. Early identification of ALD and timely treatment of AUD can help prevent the progression to advanced stages of ALD, including cirrhosis and alcoholic hepatitis. However, screening for alcohol use and managing AUD in ALD patients are often not performed due to various barriers at the patient, clinician, and administrative levels. This review highlights an integrated multidisciplinary care model, emphasizing the roles of hepatologists, psychiatrists, addiction counselors, and social workers in providing comprehensive management of both liver disease and AUD. It outlines laboratory assessments, pharmacological and behavioral therapies, and recommended follow-up evaluations by specialists. The goal of this article is to promote team-based comprehensive care for patients with ALD.</p>","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"5 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12916135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146230197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin increases type I collagen synthesis in hepatic stellate cells via α5β1 integrin.","authors":"Milan Dodig, Min Li, Srinivasan Dasarathy, Sivarajan Kumarasamy, Takhar Kasumov, Sonia M Najjar, Arthur J McCullough","doi":"10.20517/mtod.2024.59","DOIUrl":"10.20517/mtod.2024.59","url":null,"abstract":"<p><strong>Aim: </strong>A direct effect of insulin on the synthesis of extracellular matrix proteins has been described in extrahepatic organs. The current study investigates the role of insulin in type I collagen production in hepatic stellate cells (HSCs).</p><p><strong>Methods: </strong>Primary HSC cultures from wild-type mice and from L-SACC1 transgenic mice that exhibit hyperinsulinemia and resultant insulin resistance due to a defect in hepatic insulin clearance were used.</p><p><strong>Results: </strong>Insulin significantly increased type I collagen synthesis in HSC primary cultures in the presence of high but not low glucose concentrations. Although HSCs contain a functional, insulin-activated PI3 kinase signaling pathway, insulin increases type I collagen synthesis by mechanisms independent of PI3 kinase. Insulin stimulated α5β1 integrin levels and phosphorylation of focal adhesion kinase, a major signaling mediator in the integrin pathway. In addition, α5β1 integrin siRNA interference abolished insulin-mediated type I collagen synthesis by HSCs. L-SACC1 mice showed increased hepatic collagen deposition as compared to wild-type mice. HSCs isolated from L-SACC1 mice synthesize more type I collagen and α5β1 integrin than HSCs isolated from wild-type controls.</p><p><strong>Conclusion: </strong>Insulin exerts a direct profibrotic impact on HSCs by an α5β1 integrin-mediated mechanism, independently of the PI3 kinase signaling pathway. Thus, chronic hyperinsulinemia may potentiate liver collagen deposition in insulin resistance states. This likely increases the risk of significant fibrosis burden in chronic liver disease associated with insulin resistance.</p>","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"4 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12345635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144850066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-specific regulation of insulin action and hepatic fibrosis by CEACAM1.","authors":"Basel G Aldroubi, John A Najjar, Tya S Youssef, Carl E Rizk, Basil A M Abuamreh, Karl Aramouni, Hilda E Ghadieh, Sonia M Najjar","doi":"10.20517/mtod.2024.48","DOIUrl":"10.20517/mtod.2024.48","url":null,"abstract":"<p><p>The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has reached an epidemic rise worldwide. The disease is a constellation of a broad range of metabolic and histopathologic abnormalities. It begins with hepatic steatosis and progresses to metabolic dysfunction-associated steatohepatitis (MASH), including hepatic fibrosis, apoptosis, and cell injury. Despite ample research effort, the pathogenesis of the disease has not been fully delineated. Whereas insulin resistance is implicated in the early stages of the disease, its role in hepatic fibrosis remains controversial. We have focused our studies on the role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in hepatocytes and endothelial cells in the metabolic and histopathological dysregulation in MASH. Patients with MASH exhibit lower hepatic CEACAM1 with a progressive decline in hepatocytes and endothelial cells as the fibrosis stage advances. In mice, conditional deletion of CEACAM1 in hepatocytes impairs insulin clearance to cause hyperinsulinemia-driven insulin resistance with steatohepatitis and hepatic fibrosis even when mice are fed a regular chow diet. In contrast, its conditional deletion in endothelial cells causes inflammation-driven hepatic fibrosis without adversely affecting metabolism (mice remain insulin-sensitive and do not develop hepatic steatosis). Thus, this review provides <i>in vivo</i> evidence that supports or discards the role of insulin resistance in liver injury and hepatic fibrosis.</p>","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"4 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevention and treatment of type 1 diabetes: in search of the ideal combination therapy targeting multiple immunometabolic pathways","authors":"M. Pinheiro, Felipe Moura Maia Pinheiro, M. Garo, D. Pastore, F. Pacifici, Camillo Ricordi, D. Della-Morte, Marco Infante","doi":"10.20517/mtod.2024.12","DOIUrl":"https://doi.org/10.20517/mtod.2024.12","url":null,"abstract":"Type 1 diabetes (T1D) represents an autoimmune disease caused by the gradual immune-mediated destruction of the insulin-producing beta cells within the pancreatic islets of Langerhans, resulting in the lifelong need for exogenous insulin therapy. According to recent estimates, T1D currently affects about 8.4 million individuals worldwide. Since a definitive biological cure for this disease is not available yet, there is a great need for novel therapeutic strategies aimed at safely and effectively altering the natural history of the disease during its sequential stages. Ideal therapeutic goals in T1D include the prevention of autoimmune beta-cell destruction, the preservation of residual beta-cell mass and endogenous insulin secretion, the replacement and/or regeneration of beta cells, as well as automated insulin delivery through advanced closed-loop artificial pancreas systems. With this regard, an important research area focused on the identification of a definitive biological cure for T1D is represented by the investigation of immunotherapeutic and beta-cell-protective agents used as disease-modifying therapies to forestall or eliminate insulin dependence. In this commentary, we discuss the reasons why the use of combination therapies targeting the multiple immunometabolic dysfunctions associated with T1D (other than beta-cell autoimmunity) is likely to be more effective in preserving beta cell function in individuals at different stages of T1D, as compared to the use of single therapeutic agents.","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"112 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140967928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetes mellitus and heart disease","authors":"Preethi Chandrasekaran, Ralf Weiskirchen","doi":"10.20517/mtod.2024.15","DOIUrl":"https://doi.org/10.20517/mtod.2024.15","url":null,"abstract":"","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"35 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140727444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}