npj Metabolic Health and Disease最新文献

{"title":"Autophagy and hepatic lipid metabolism: mechanistic insight and therapeutic potential for MASLD","authors":"Sana Raza, Sangam Rajak, Paul M. Yen, Rohit A. Sinha","doi":"10.1038/s44324-024-00022-5","DOIUrl":"10.1038/s44324-024-00022-5","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) originates from a homeostatic imbalance in hepatic lipid metabolism. Increased fat deposition in the liver of people suffering from MASLD predisposes them to develop further metabolic derangements, including diabetes mellitus, metabolic dysfunction-associated steatohepatitis (MASH), and other end-stage liver diseases. Unfortunately, only limited pharmacological therapies exist for MASLD to date. Autophagy, a cellular catabolic process, has emerged as a primary mechanism of lipid metabolism in mammalian hepatocytes. Furthermore, preclinical studies with autophagy modulators have shown promising results in resolving MASLD and mitigating its progress into deleterious liver pathologies. In this review, we discuss our current understanding of autophagy-mediated hepatic lipid metabolism, its therapeutic modulation for MASLD treatment, and current limitations and scope for clinical translation.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11296953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891510","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":"Some paradoxes and unresolved aspects of hepatic de novo lipogenesis","authors":"John G. Jones","doi":"10.1038/s44324-024-00020-7","DOIUrl":"10.1038/s44324-024-00020-7","url":null,"abstract":"Hepatic de novo lipogenesis (DNL) is a critical pathway in both liver intermediary metabolism and whole-body nutrient management. In the setting of excessive caloric intake, increased DNL fluxes are implicated in the pathogenesis of metabolic-associated steatotic liver disease (MASLD). As a result, there is intense interest both in the measurement of DNL activity and in gaining a better understanding on how this drives MASLD development. While much progress has been made towards these objectives, a number of intriguing uncertainties and paradoxes remain. This short perspective will focus on some of these aspects, namely a), how DNL contributes to triglyceride overload, b), the timing of DNL pathway activation with nutrient availability, c) the sources of acetyl-CoA for DNL and d), the sources of NADPH reducing equivalents for DNL. The implications of these uncertainties on pharmacological targeting of hepatic DNL activity will also be discussed.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-5"},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00020-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141968579","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":"Dysfunctional VLDL metabolism in MASLD","authors":"Urko M. Marigorta, Oscar Millet, Shelly C. Lu, José M. Mato","doi":"10.1038/s44324-024-00018-1","DOIUrl":"10.1038/s44324-024-00018-1","url":null,"abstract":"Lipidomics has unveiled the intricate human lipidome, emphasizing the extensive diversity within lipid classes in mammalian tissues critical for cellular functions. This diversity poses a challenge in maintaining a delicate balance between adaptability to recurring physiological changes and overall stability. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), linked to factors such as obesity and diabetes, stems from a compromise in the structural and functional stability of the liver within the complexities of lipid metabolism. This compromise inaccurately senses an increase in energy status, such as during fasting-feeding cycles or an upsurge in lipogenesis. Serum lipidomic studies have delineated three distinct metabolic phenotypes, or “metabotypes” in MASLD. MASLD-A is characterized by lower very low-density lipoprotein (VLDL) secretion and triglyceride (TG) levels, associated with a reduced risk of cardiovascular disease (CVD). In contrast, MASLD-C exhibits increased VLDL secretion and TG levels, correlating with elevated CVD risk. An intermediate subtype, with a blend of features, is designated as the MASLD-B metabotype. In this perspective, we examine into recent findings that show the multifaceted regulation of VLDL secretion by S-adenosylmethionine, the primary cellular methyl donor. Furthermore, we explore the differential CVD and hepatic cancer risk across MASLD metabotypes and discuss the context and potential paths forward to gear the findings from genetic studies towards a better understanding of the observed heterogeneity in MASLD.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11263124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141763941","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":"Finishing the odyssey to a stem cell cure for type 1 diabetes","authors":"Lise Hunault, Daniel Hesselson","doi":"10.1038/s44324-024-00014-5","DOIUrl":"10.1038/s44324-024-00014-5","url":null,"abstract":"For over two decades pluripotent stem cells have promised a renewable source of β cells to treat patients with type 1 diabetes. Major efforts to optimize the differentiation, survival, and function of transplanted stem cell-derived tissue have recently delivered clinically meaningful metabolic benefits using a perforated encapsulation device that promotes integration with recipient vasculature under the protection of systemic immunosuppression. Despite this success, the journey is not over as a universal cure will require a larger β cell mass. Here, we summarize recent interdisciplinary advances that could maximize the functional β cell mass within transplanted devices and provide an immune privileged niche that could eliminate the need for systemic immunosuppression.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00014-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141816298","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":"Unlocking therapeutic potential: exploring cross-talk among emerging nuclear receptors to combat metabolic dysfunction in steatotic liver disease","authors":"Milton Boaheng Antwi, Ariann Jennings, Sander Lefere, Dorien Clarisse, Anja Geerts, Lindsey Devisscher, Karolien De Bosscher","doi":"10.1038/s44324-024-00013-6","DOIUrl":"10.1038/s44324-024-00013-6","url":null,"abstract":"Nuclear receptors (NRs) regulate cellular processes and serve as key targets in treating metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). Their ability to interact and influence each other’s signaling pathways introduces a complex yet underexplored dimension in the pharmacotherapy of MASLD and MASH. This review delineates the emerging NRs in this field—estrogen-related receptor alpha (ERRα), glucocorticoid receptor (GR), estrogen receptor alpha (ERα), liver receptor homolog-1 (LRH-1), and vitamin D receptor (VDR)—and their interplay with established NRs, including peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, PPARγ), farnesoid X receptor (FXR), liver X receptors (LXR), hepatocyte nuclear factor 4α (HNF4α), and thyroid hormone receptor beta (THRβ). We discuss their collective impact on hepatic lipid metabolism, inflammation, fibrosis, and glucose homeostasis. We explore recent findings on dual NR crosstalk, via direct and indirect mechanisms, and discuss the potential of targeting receptor pathways using selective agonists, inverse agonists, antagonists, or specific modulators to combat MASLD and MASH. Elucidating NR interactions opens up new avenues for targeted therapies, emphasizing the critical need for further research in the evolving field of hepatology.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00013-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141500494","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":"Serum and CSF metabolomics analysis shows Mediterranean Ketogenic Diet mitigates risk factors of Alzheimer’s disease","authors":"Annalise Schweickart, Richa Batra, Bryan J. Neth, Cameron Martino, Liat Shenhav, Anru R. Zhang, Pixu Shi, Naama Karu, Kevin Huynh, Peter J. Meikle, Leyla Schimmel, Amanda Hazel Dilmore, Kaj Blennow, Henrik Zetterberg, Colette Blach, Pieter C. Dorrestein, Rob Knight, Alzheimer’s Gut Microbiome Project Consortium, Suzanne Craft, Rima Kaddurah-Daouk, Jan Krumsiek","doi":"10.1038/s44324-024-00016-3","DOIUrl":"10.1038/s44324-024-00016-3","url":null,"abstract":"Alzheimer’s disease (AD) is influenced by a variety of modifiable risk factors, including a person’s dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KD’s metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean Ketogenic Diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6-week washout period. We employed nuclear magnetic resonance (NMR)-based metabolomics to profile serum and CSF and metagenomics profiling on fecal samples. While the AHAD induced no notable metabolic changes, MMKD led to significant alterations in both serum and CSF. These changes included improved modifiable risk factors, like increased HDL-C and reduced BMI, reversed serum metabolic disturbances linked to AD such as a microbiome-mediated increase in valine levels, and a reduction in systemic inflammation. Additionally, the MMKD was linked to increased amino acid levels in the CSF, a breakdown of branched-chain amino acids (BCAAs), and decreased valine levels. Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. Our findings highlight that MMKD can improve AD-related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood-CSF barrier.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00016-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489061","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":"PowerAI-Diabetes: Review of glycemic and lipid variability to predict cardiovascular events in Chinese diabetic population","authors":"Sharen Lee, Tong Liu, Cheuk To Chung, Johannes Reinhold, Vassilios S. Vassiliou, Gary Tse","doi":"10.1038/s44324-024-00012-7","DOIUrl":"10.1038/s44324-024-00012-7","url":null,"abstract":"The aim of this study is to review the predictive value of visit-to-visit variability in glycaemic or lipid tests for forecasting major adverse cardiovascular events (MACE) in diabetes mellitus. Data from existing studies suggests that such variability is an independent predictor of adverse outcomes in this patient cohort. This understanding is then applied to the development of PowerAI-Diabetes, a Chinese-specific artificial intelligence-enhanced predictive model for predicting the risks of major adverse cardiovascular events and diabetic complications. The model integrates an amalgam of variables including demographics, laboratory and medication information to assess the risk of MACE. Future efforts should focus on the incorporation of treatment effects and non-traditional cardiovascular risk factors, such as social determinants of health variables, to improve the performance of predictive models.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00012-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489070","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":"Bone metabolism – an underappreciated player","authors":"In Ah Choi, Akio Umemoto, Masataka Mizuno, Kyung-Hyun Park-Min","doi":"10.1038/s44324-024-00010-9","DOIUrl":"10.1038/s44324-024-00010-9","url":null,"abstract":"Bone is constantly being remodeled, and this process is orchestrated by a dynamic crosstalk of bone cells, including osteoclasts, osteoblasts, and osteocytes. Recent evidence suggests that cellular metabolism plays a crucial role in the differentiation and function of bone cells and facilitates the adaptation of bone cells to changes in the bone microenvironment. Moreover, bone affects whole-body energy metabolism. However, it is not yet completely understood how different cells in bone coordinate metabolic processes under physiological conditions, and how altered metabolic processes in bone cells contribute to pathological conditions where the balance among bone cells is disrupted. Therefore, gaining a better understanding of the distinct metabolic requirements of bone cells can provide crucial insights into the dysfunction of bone cells in pathological conditions and can be used to identify new therapeutic approaches to treat bone diseases. Here, we discuss recent advances in understanding metabolic reprogramming in bone cells.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00010-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489069","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":"Pre-conceptional paternal diet impacts on offspring testosterone homoeostasis via epigenetic modulation of cyp19a1/aromatase activity","authors":"Arianna Pastore, Nadia Badolati, Francesco Manfrevola, Serena Sagliocchi, Valentina Laurenzi, Giorgia Musto, Veronica Porreca, Melania Murolo, Teresa Chioccarelli, Roberto Ciampaglia, Valentina Vellecco, Mariarosaria Bucci, Monica Dentice, Gilda Cobellis, Mariano Stornaiuolo","doi":"10.1038/s44324-024-00011-8","DOIUrl":"10.1038/s44324-024-00011-8","url":null,"abstract":"Paternal eating habits, before and at conception, have a strong impact on offspring future metabolism. By sending specific epigenetic signals through spermatozoa, paternal nutrition influences developing embryos and increases offspring risk of developing dysmetabolism and cardiovascular diseases. Among the intergenerational consequences, paternal epigenetic messages affect embryo DNA methylation altering programmed gene expression. The identification of offspring genetic loci that are epigenetically altered by paternal stimuli is of pivotal interest for timely post-natal treatment of offspring metabolic defects. We here use a murine model to show that, cyp19a1/aromatase, a gene coding for the cytochrome converting testosterone into 17-β estradiol (both potent hormonal mediators of embryo development and metabolism), is an epigenetic transducer of paternal intergenerational inheritance. By affecting cyp19a1 methylation status and alternative splicing, paternal diet coordinates androgens’ metabolism in the progeny affecting it in a sexually dimorphic way and promoting hypoandrogenism, growth retardation and diabetes in male pups.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-14"},"PeriodicalIF":0.0,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00011-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141334115","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":"The role of microglia in the development of diabetic retinopathy","authors":"Pialuisa Quiriconi, Vanco Hristov, Mayu Aburaya, Una Greferath, Andrew I. Jobling, Erica L. Fletcher","doi":"10.1038/s44324-024-00009-2","DOIUrl":"10.1038/s44324-024-00009-2","url":null,"abstract":"Diabetic retinopathy is a vision-threatening disease and remains the most feared complication for those living with diabetes. Historically, the disease has been considered primarily vascular in nature, based on clinically detectable vascular pathology. Nonetheless, it is now recognized that the retina undergoes a variety of cellular changes from the early onset of diabetes. In fact, one of the earliest changes to occur is a loss in vasoregulation, yet our understanding of the underlying mechanisms is lacking. Microglia, the resident immune cells of the central nervous system, perform a range of physiological, non-inflammatory functions to maintain retinal homeostasis which includes surveying the microenvironment to constantly monitor tissue health, neuronal surveillance to maintain synaptic integrity and vasoregulation, a recently discovered role that these cells additionally perform. The role of microglia in the development of diabetic retinopathy is well-established, centered around their contribution to inflammation which remains an integral component in disease pathogenesis, particularly in later stages of disease. However, recent findings reveal that early in the development of diabetes the vasoregulatory function of microglia is dysfunctional, leading to early vascular compromise. This review summarizes recent work to highlight how microglia are affected by diabetes and the implications of these changes in the development of diabetic retinopathy from pre-clinical to advanced stages of disease.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00009-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246193","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}