[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-444829-105":59,"doc-detail-444829-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","lactate-dehydrogenase-inhibition-reverts-the-fatty-acid-induced-neurotoxic-phenotype-of-astrocytes","Lactate Dehydrogenase Inhibition Reverts the Fatty Acid-Induced Neurotoxic Phenotype of Astrocytes","","Astrocytes regulate lipid metabolism in the CNS by importing fatty acids and storing them in dynamic lipid droplets (LD). LD accumulation in astrocytes is linked to stress and proinflammatory signaling, contributing to neuronal dysfunction relevant to amyotrophic lateral sclerosis (ALS). In symptomatic ALS mice and patient-derived astrocytes, LD buildup closely aligns with NF-κB-driven responses and motor neuron toxicity. Pharmacological LDH inhibition reverses LD accumulation, while LDHA genetic ablation similarly reduces LD formation after fatty acid treatment, implicating lipid metabolic stress in harmful phenotypic transformation.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/lactate-dehydrogenase-inhibition-reverts-the-fatty-acid-induced-neurotoxic-phenotype-of-astrocytes/444829/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/lactate-dehydrogenase-inhibition-reverts-the-fatty-acid-induced-neurotoxic-phenotype-of-astrocytes/444829.png","ImageObject",300,407,{"name":92,"@type":93},"Alexandar","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What role do lipid droplets (LD) play in astrocytes during stress and ALS?","Question",{"text":113,"@type":114},"Astrocytes store imported fatty acids in dynamic LD. In ALS models and patient-derived astrocytes, LD accumulation is tightly coupled to proinflammatory signaling and correlates with motor neuron toxicity.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does NF-κB signaling relate to astrocyte LD accumulation and neurotoxicity?",{"text":118,"@type":114},"LD accumulation in nontransgenic astrocytes aligns with an NF-κB-driven proinflammatory response, linking metabolic stress to a detrimental astrocyte phenotype that impacts motor neurons.",{"name":120,"@type":111,"acceptedAnswer":121},"How do LDH inhibition and LDHA genetic ablation affect LD accumulation?",{"text":122,"@type":114},"Pharmacological inhibition of lactate dehydrogenase (LDH) reverses LD accumulation in mouse and human astrocytes carrying ALS-linked mutations. Genetic ablation of LDHA similarly reduces LD accumulation following fatty acid exposure.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},444829,1790763547,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},962090768658,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Glia  \nRESEARCH ARTICLE  OPEN ACCESS   \nLactate Dehydrogenase Inhibition Reverts the Fatty Acid-Induced Neurotoxic Phenotype of Astrocytes  \nDaniel Esteve1 | Mariana Bresque1 | Daniel Okhuevbie1 | Sandhya Ramachandran2 | Mariana Pehar2,3  | Marcelo R. Vargas1  \n1Department of Neurology, University of Wisconsin-Madison, Madison, Wisconsin, USA | 2Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA | 3Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, Wisconsin, USA  \nCorrespondence: Marcelo R. Vargas ([mvargas@wisc.edu](mvargas@wisc.edu))  \nReceived: 16 June 2025 | Revised: 26 November 2025 | Accepted: 24 December 2025  \nKeywords: astrocytes | inflammation | LDH | lipid droplets | NF-κB  \nABSTRACT  \nAstrocytes are central to lipid metabolism in the central nervous system. Due to their morphological and functional characteristics, astrocytes can uptake fatty acids (FAs) from the bloodstream and extracellular space and store them in lipid droplets (LD) . LD are dynamic organelles, whose accumulation in astrocytes has been shown to occur upon exposure to various stress stimuli. Different hypotheses proposed to explain motor neuron degeneration in amyotrophic lateral sclerosis (ALS) implicate mitochondrial dysfunction and oxidative stress. Mitochondrial dysfunction in astrocytes is associated with elevation of cytoplasmic lipids and lipid-binding proteins. We observed increased LD in the spinal cord of symptomatic ALS mice, as well as in human transdifferentiated astrocytes obtained from ALS patients. Using a co-culture model, we examined the effect ofFA overload and its impact on astrocyte–motor neuron interaction. LD accumulation was tightly coupled with an NF-κB-driven proinflammatory response in nontransgenic astrocytes, correlating with motor neuron toxicity. These results provide additional evidence to the notion that altered energy balance may contribute to neuronal death in ALS. Furthermore, pharmacological inhibition of lactate dehydrogenase (LDH) reversed LD accumulation in mouse and human astrocytes expressing ALS-linked mutations. Genetic ablation of LDHA similarly reduced LD accumulation in response to FA treatment. Collectively, our data underscore the role of lipid metabolism in astrocyte–neuron interactions in ALS models and suggest that LD accumulation, rather than serving solely as a protective mechanism, reflects a metabolic stress state linked to a detrimental phenotypic transformation in astrocytes.  \n1 | Introduction  \nAstrocytes play a major role in lipid metabolism in the central nervous system (CNS) . Due to their morphological and functional characteristics, astrocytes can uptake fatty acids (FAs) from the bloodstream and extracellular space and store them in lipid droplets (LD) . LD are dynamic organelles that store FAs astriacylglycerols (TAG) and sterol esters. The biogenesis of cytoplasmic LD is believed to occur in the endoplasmic reticulum (ER), starting with the esterification of an activated FA through the activity of acetyl-CoA acetyltransferases (ACAT1 and ACAT2) and diacylglycerol transferases (DGAT1 and DGAT1)  \n(Zadoorian et al. 2023) . The result is a core of neutral lipids surrounded by a phospholipid monolayer with some components from the ER bilayer. In this monolayer, LD-associated surface proteins control the dynamics of LD. Among them, proteins of the perilipin family, with subtypes that vary according to the cell type, are essential in the formation and degradation of LD (Itabe et al. 2017) .  \nWhile changes in the number of LD have been best characterized in adipocytes and hepatocytes as a side effect of metabolic disease (Farese Jr. and Walther 2009), LD have important functions beyond energy homeostasis. Recent studies have highlighted the  \nThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproductio","cbCaibonI4UcL5jn","https://ap.wps.com/l/cbCaibonI4UcL5jn","pdf",9622422,14,"English","# Introduction\n## Astrocytes and lipid metabolism\n## Lipid droplets beyond energy homeostasis\n## Lipotoxicity, neurodegeneration, and ALS context","[{\"question\":\"What role do lipid droplets (LD) play in astrocytes during stress and ALS?\",\"answer\":\"Astrocytes store imported fatty acids in dynamic LD. In ALS models and patient-derived astrocytes, LD accumulation is tightly coupled to proinflammatory signaling and correlates with motor neuron toxicity.\"},{\"question\":\"How does NF-κB signaling relate to astrocyte LD accumulation and neurotoxicity?\",\"answer\":\"LD accumulation in nontransgenic astrocytes aligns with an NF-κB-driven proinflammatory response, linking metabolic stress to a detrimental astrocyte phenotype that impacts motor neurons.\"},{\"question\":\"How do LDH inhibition and LDHA genetic ablation affect LD accumulation?\",\"answer\":\"Pharmacological inhibition of lactate dehydrogenase (LDH) reverses LD accumulation in mouse and human astrocytes carrying ALS-linked mutations. Genetic ablation of LDHA similarly reduces LD accumulation following fatty acid exposure.\"}]","Lactate Dehydrogenase Inhibition Reverts the Fatty Acid-Induced Neurotoxic Phenotype of Astrocytes | PDF",1790709401,35]