Pub Date : 2024-08-02DOI: 10.1038/s44324-024-00022-5
Sana Raza, Sangam Rajak, Paul M. Yen, Rohit A. Sinha
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.
{"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}
Pub Date : 2024-08-02DOI: 10.1038/s44324-024-00020-7
John G. Jones
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.
{"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}
Pub Date : 2024-07-22DOI: 10.1038/s44324-024-00018-1
Urko M. Marigorta, Oscar Millet, Shelly C. Lu, José M. Mato
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.
{"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}
Pub Date : 2024-07-22DOI: 10.1038/s44324-024-00014-5
Lise Hunault, Daniel Hesselson
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.
{"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}
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.
核受体（NR）调控细胞过程，是治疗代谢功能障碍相关性脂肪肝（MASLD）和脂肪性肝炎（MASH）的关键靶点。它们能够相互作用并影响彼此的信号通路，这为 MASLD 和 MASH 的药物治疗引入了一个复杂但尚未充分探索的维度。本综述描述了这一领域中新出现的 NRs--雌激素相关受体α（ERRα）、糖皮质激素受体（GR）、雌激素受体α（ERα）、肝脏受体同源物-1（LRH-1）和维生素 D 受体（VDR）--以及它们与已有 NRs 的相互作用、受体（PPARα、PPARβ/δ、PPARγ）、类雌激素 X 受体（FXR）、肝 X 受体（LXR）、肝细胞核因子 4α (HNF4α) 和甲状腺激素受体 beta (THRβ)。我们讨论了它们对肝脏脂质代谢、炎症、纤维化和糖稳态的共同影响。我们探讨了通过直接和间接机制进行双重 NR 相互影响的最新发现，并讨论了使用选择性激动剂、反向激动剂、拮抗剂或特异性调节剂靶向受体通路以对抗 MASLD 和 MASH 的可能性。阐明 NR 相互作用为靶向治疗开辟了新途径，强调了在不断发展的肝病学领域开展进一步研究的迫切需要。
{"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}
Pub Date : 2024-07-01DOI: 10.1038/s44324-024-00016-3
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
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.
{"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}
Pub Date : 2024-07-01DOI: 10.1038/s44324-024-00012-7
Sharen Lee, Tong Liu, Cheuk To Chung, Johannes Reinhold, Vassilios S. Vassiliou, Gary Tse
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.
{"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}
Pub Date : 2024-07-01DOI: 10.1038/s44324-024-00010-9
In Ah Choi, Akio Umemoto, Masataka Mizuno, Kyung-Hyun Park-Min
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.
{"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}
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.
父亲在受孕前和受孕时的饮食习惯对后代未来的新陈代谢有很大影响。父亲的营养通过精子发出特定的表观遗传信号，影响发育中的胚胎，增加后代患代谢紊乱和心血管疾病的风险。在代际后果中，父亲的表观遗传信息会影响胚胎的 DNA 甲基化，改变程序基因的表达。确定受父代刺激而发生表观遗传改变的子代基因位点，对及时治疗子代代谢缺陷具有重要意义。我们在此利用小鼠模型证明，cyp19a1/aromatase（一种编码将睾酮转化为 17-β 雌二醇（两者都是胚胎发育和代谢的强效激素介质）的细胞色素的基因）是父系代际遗传的表观遗传转换器。通过影响 cyp19a1 的甲基化状态和替代剪接，父亲的饮食会协调后代的雄性激素代谢，以性别二态的方式影响后代，并促进雄性幼崽的雄性激素过低、生长迟缓和糖尿病。
{"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}
Pub Date : 2024-06-03DOI: 10.1038/s44324-024-00009-2
Pialuisa Quiriconi, Vanco Hristov, Mayu Aburaya, Una Greferath, Andrew I. Jobling, Erica L. Fletcher
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.
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