Pub Date : 2025-10-01Epub Date: 2025-08-05DOI: 10.1016/j.bbalip.2025.159679
Hanneke Leegwater, Zhengzheng Zhang, Xiaobing Zhang, Xuesong Wang, Thomas Hankemeier, Annelien J M Zweemer, Bob van de Water, Erik Danen, Menno Hoekstra, Amy C Harms, Alida Kindt, Sylvia E Le Dévédec
Rewiring of lipid metabolism is a hallmark of cancer, supporting tumor growth, survival, and therapy resistance. However, lipid metabolic heterogeneity in breast cancer remains poorly understood. In this study, we systematically profiled the lipidome of 52 breast cancer cell lines using liquid chromatography-mass spectrometry to uncover lipidomic signatures associated with tumor subtype, proliferation, and epithelial-to-mesenchymal (EMT) state. A total of 806 lipid species were identified and quantified across 21 lipid classes. The main lipidomic heterogeneity was associated with the EMT state, with lower sphingolipid, phosphatidylinositol and phosphatidylethanolamine levels and higher cholesterol ester levels in aggressive mesenchymal-like cell lines compared to epithelial-like cell lines. In addition, cell lines with higher proliferation rates had lower levels of sphingomyelins and polyunsaturated fatty acid (PUFA) side chains in phospholipids. Next, changes in the lipidome over time were analyzed for three fast-proliferating mesenchymal-like cell lines MDA-MB-231, Hs578T, and HCC38. Triglycerides decreased over time, leading to a reduction in lipid droplet levels, and especially PUFA-containing triglycerides and -phospholipids decreased during proliferation. These findings underscore the role of EMT in metabolic plasticity and highlight proliferation-associated lipid dependencies that may be exploited for therapeutic intervention. In conclusion, our study reveals that EMT-driven metabolic reprogramming is a key factor in lipid heterogeneity in breast cancer, providing new insights into tumor lipid metabolism and potential metabolic vulnerabilities.
{"title":"Distinct lipidomic profiles in breast cancer cell lines relate to proliferation and EMT phenotypes.","authors":"Hanneke Leegwater, Zhengzheng Zhang, Xiaobing Zhang, Xuesong Wang, Thomas Hankemeier, Annelien J M Zweemer, Bob van de Water, Erik Danen, Menno Hoekstra, Amy C Harms, Alida Kindt, Sylvia E Le Dévédec","doi":"10.1016/j.bbalip.2025.159679","DOIUrl":"10.1016/j.bbalip.2025.159679","url":null,"abstract":"<p><p>Rewiring of lipid metabolism is a hallmark of cancer, supporting tumor growth, survival, and therapy resistance. However, lipid metabolic heterogeneity in breast cancer remains poorly understood. In this study, we systematically profiled the lipidome of 52 breast cancer cell lines using liquid chromatography-mass spectrometry to uncover lipidomic signatures associated with tumor subtype, proliferation, and epithelial-to-mesenchymal (EMT) state. A total of 806 lipid species were identified and quantified across 21 lipid classes. The main lipidomic heterogeneity was associated with the EMT state, with lower sphingolipid, phosphatidylinositol and phosphatidylethanolamine levels and higher cholesterol ester levels in aggressive mesenchymal-like cell lines compared to epithelial-like cell lines. In addition, cell lines with higher proliferation rates had lower levels of sphingomyelins and polyunsaturated fatty acid (PUFA) side chains in phospholipids. Next, changes in the lipidome over time were analyzed for three fast-proliferating mesenchymal-like cell lines MDA-MB-231, Hs578T, and HCC38. Triglycerides decreased over time, leading to a reduction in lipid droplet levels, and especially PUFA-containing triglycerides and -phospholipids decreased during proliferation. These findings underscore the role of EMT in metabolic plasticity and highlight proliferation-associated lipid dependencies that may be exploited for therapeutic intervention. In conclusion, our study reveals that EMT-driven metabolic reprogramming is a key factor in lipid heterogeneity in breast cancer, providing new insights into tumor lipid metabolism and potential metabolic vulnerabilities.</p>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":" ","pages":"159679"},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-23DOI: 10.1016/j.bbalip.2025.159691
John Z. Chan , Michelle V. Tomczewski , Antonia N. Berdeklis , Robin E. Duncan
Barth Syndrome (BTHS) is an ultra-rare, X-linked mitochondrial disorder caused by a variety of different mutations in the cardiolipin remodeling gene TAFAZZIN that results in cardiac and skeletal myopathy, as well as immunological deficits. Epstein-Barr virus-mediated transformation of B-lymphocytes has been used to generate B-lymphoblastoid cells that retain many of the characteristics of the initial cell line, but can be propagated extensively in culture to generate biological materials enabling study of the basic, natural function of this enzyme in cells, as well as disease-relevant effects and interventions. Notably, these model lines from individual donors are of particular value for understanding a disease with variable penetrance such as BTHS, where variation in genetic background can alter symptom severity considerably, even among closely-related individuals with the same mutation. Here, we review the generation, benefits, and limitations of the B-lymphoblastoid cell model in BTHS research, and provide an overview of recent advances in understanding the role of TAFAZZIN in mitochondrial biology from this model. Implications of these findings for understanding the pathology of BTHS, and determining future directions, are also provided, along with a review of recent advances in our understanding of the mechanism of TAFAZZIN function in cardiolipin degradation, remodeling and stability.
{"title":"The B-lymphoblastoid model in Barth syndrome","authors":"John Z. Chan , Michelle V. Tomczewski , Antonia N. Berdeklis , Robin E. Duncan","doi":"10.1016/j.bbalip.2025.159691","DOIUrl":"10.1016/j.bbalip.2025.159691","url":null,"abstract":"<div><div>Barth Syndrome (BTHS) is an ultra-rare, X-linked mitochondrial disorder caused by a variety of different mutations in the cardiolipin remodeling gene <em>TAFAZZIN</em> that results in cardiac and skeletal myopathy, as well as immunological deficits. Epstein-Barr virus-mediated transformation of B-lymphocytes has been used to generate B-lymphoblastoid cells that retain many of the characteristics of the initial cell line, but can be propagated extensively in culture to generate biological materials enabling study of the basic, natural function of this enzyme in cells, as well as disease-relevant effects and interventions. Notably, these model lines from individual donors are of particular value for understanding a disease with variable penetrance such as BTHS, where variation in genetic background can alter symptom severity considerably, even among closely-related individuals with the same mutation. Here, we review the generation, benefits, and limitations of the B-lymphoblastoid cell model in BTHS research, and provide an overview of recent advances in understanding the role of TAFAZZIN in mitochondrial biology from this model. Implications of these findings for understanding the pathology of BTHS, and determining future directions, are also provided, along with a review of recent advances in our understanding of the mechanism of TAFAZZIN function in cardiolipin degradation, remodeling and stability.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 8","pages":"Article 159691"},"PeriodicalIF":3.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-13DOI: 10.1016/j.bbalip.2025.159690
Ankia Visser , Floris A. Feiner , Willemien Heerema-van Zwol , Marieke Smit , Nicolette C.A. Huijkman , Niels J. Kloosterhuis , Henry N. Ginsberg , Bart van de Sluis , Jan Albert Kuivenhoven
•
Investigating the intracellular biology of very low-density lipoproteins (VLDL) remains a challenge.
•
We therefore generated apoB100-FLAG mice, which display normal lipid levels and concentration of FLAG-tagged apoB100 in plasma. However, we were unable to detect either apoB or FLAG in primary hepatocytes using immunofluorescence.
•
Blocking proteasomal degradation alone or combined with inhibition of the secretory pathway only marginally improved apoB detection.
•
Our study suggests that the physiological concentration of apoB100 in isolated hepatocytes is too low and heterogeneous to allow for studies into the subcellular localisation of apoB.
{"title":"ApoB: The intracellular protein detection dilemma in lipoprotein biology","authors":"Ankia Visser , Floris A. Feiner , Willemien Heerema-van Zwol , Marieke Smit , Nicolette C.A. Huijkman , Niels J. Kloosterhuis , Henry N. Ginsberg , Bart van de Sluis , Jan Albert Kuivenhoven","doi":"10.1016/j.bbalip.2025.159690","DOIUrl":"10.1016/j.bbalip.2025.159690","url":null,"abstract":"<div><div><ul><li><span>•</span><span><div>Investigating the intracellular biology of very low-density lipoproteins (VLDL) remains a challenge.</div></span></li><li><span>•</span><span><div>We therefore generated apoB100-FLAG mice, which display normal lipid levels and concentration of FLAG-tagged apoB100 in plasma. However, we were unable to detect either apoB or FLAG in primary hepatocytes using immunofluorescence.</div></span></li><li><span>•</span><span><div>Blocking proteasomal degradation alone or combined with inhibition of the secretory pathway only marginally improved apoB detection.</div></span></li><li><span>•</span><span><div>Our study suggests that the physiological concentration of apoB100 in isolated hepatocytes is too low and heterogeneous to allow for studies into the subcellular localisation of apoB.</div></span></li></ul></div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 8","pages":"Article 159690"},"PeriodicalIF":3.3,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-08DOI: 10.1016/j.bbalip.2025.159688
Mishelle Morán-Lalangui , Marta Villoslada-González , Carmen Hevia-Lorenzo , Jesús Pérez-Gil , Begoña García-Álvarez
Pulmonary surfactant protein C (SP-C) may play a key role in alveolar homeostasis by modulating vesicle uptake in alveolar cells. This study explores how SP-C regulates internalization of model unilamellar lipid vesicles by type II alveolar epithelial cells (AECII) and alveolar macrophages (AMϕ), focusing on the effect of lipid composition, palmitoylation state, and interactions with external stimuli like lipopolysaccharides (LPS) or the other hydrophobic surfactant protein SP-B. Using fluorescence-based techniques, we demonstrated that SP-C enhances vesicle uptake in a lipid-dependent manner. While AECII internalize vesicles regardless of lipid composition, AMϕ show a preference for vesicles with specific lipid profiles. The palmitoylation of SP-C is essential for efficient vesicle uptake, highlighting the importance of membrane-protein interactions in this process. Furthermore, SP-C colocalizes with acidic organelles within both cell types, suggesting its involvement in intracellular trafficking and surfactant homeostasis. Notably, SP-C facilitates LPS uptake by AMϕ, potentially contributing to immune modulation in the alveolar spaces. The contribution of SP-C to metabolism and pulmonary immunity has important implications in lung diseases involving surfactant dysfunction or immune dysregulation.
{"title":"Pulmonary surfactant protein SP-C regulates lipid vesicle uptake by alveolar type II cells and macrophages: Role of lipids, palmitoylation, and environment","authors":"Mishelle Morán-Lalangui , Marta Villoslada-González , Carmen Hevia-Lorenzo , Jesús Pérez-Gil , Begoña García-Álvarez","doi":"10.1016/j.bbalip.2025.159688","DOIUrl":"10.1016/j.bbalip.2025.159688","url":null,"abstract":"<div><div>Pulmonary surfactant protein C (SP-C) may play a key role in alveolar homeostasis by modulating vesicle uptake in alveolar cells. This study explores how SP-C regulates internalization of model unilamellar lipid vesicles by type II alveolar epithelial cells (AECII) and alveolar macrophages (AMϕ), focusing on the effect of lipid composition, palmitoylation state, and interactions with external stimuli like lipopolysaccharides (LPS) or the other hydrophobic surfactant protein SP-B. Using fluorescence-based techniques, we demonstrated that SP-C enhances vesicle uptake in a lipid-dependent manner. While AECII internalize vesicles regardless of lipid composition, AMϕ show a preference for vesicles with specific lipid profiles. The palmitoylation of SP-C is essential for efficient vesicle uptake, highlighting the importance of membrane-protein interactions in this process. Furthermore, SP-C colocalizes with acidic organelles within both cell types, suggesting its involvement in intracellular trafficking and surfactant homeostasis. Notably, SP-C facilitates LPS uptake by AMϕ, potentially contributing to immune modulation in the alveolar spaces. The contribution of SP-C to metabolism and pulmonary immunity has important implications in lung diseases involving surfactant dysfunction or immune dysregulation.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 8","pages":"Article 159688"},"PeriodicalIF":3.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-08DOI: 10.1016/j.bbalip.2025.159686
Isidoros Axiotis , Asimina Kakale , Despina Lazaridou , Anastasia-Georgia Dedemadi , Angeliki Chroni , Marius Multescu , Anca Violeta Gafencu , Maria Tzardi , Dimitris Kardassis
Rheumatoid arthritis (RA) is associated with increased cardiovascular disease (CVD) risk, partly attributed to altered lipid metabolism. Apolipoprotein C-III (ApoC-III), a key regulator of triglyceride-rich lipoproteins in the plasma, has been implicated in both dyslipidemia and inflammation. In this study, we investigated the role of hypertriglyceridemia in RA using a transgenic mouse model overexpressing the human ApoC-III gene (ApoC-III Tg). Using a protocol of antigen-induced arthritis (AIA), we show that ApoC-III Tg mice exhibited significantly greater joint swelling, inflammatory infiltration and cartilage destruction compared to non-transgenic controls. These changes were accompanied by altered lipoprotein distribution in serum and High Density Lipoprotein (HDL) dysfunction including reduced antioxidant function. Furthermore, HDL isolated from arthritic ApoC-III Tg mice had pro-inflammatory properties on macrophages as demonstrated by the increased expression of iNOS and IL1β as well as increased mitochondrial respiration. Treatment of arthritic ApoC-III Tg mice with fenofibrate, a triglyceride-lowering drug, reduced triglyceride levels and increased ApoA-I content in HDL fractions. Importantly, fenofibrate significantly ameliorated arthritis severity, restored HDL antioxidant function and reduced macrophage activation. These findings highlight a mechanistic link between dyslipidemia, HDL dysfunction, and inflammatory exacerbation in RA and suggest that targeting ApoC-III-associated pathways may offer therapeutic benefit in patients with coexisting metabolic and inflammatory disorders.
{"title":"Hypertriglyceridemia impairs HDL functionality, promotes macrophage metabolic activation and exacerbates antigen-induced rheumatoid arthritis in mice which can be reversed by fenofibrate treatment","authors":"Isidoros Axiotis , Asimina Kakale , Despina Lazaridou , Anastasia-Georgia Dedemadi , Angeliki Chroni , Marius Multescu , Anca Violeta Gafencu , Maria Tzardi , Dimitris Kardassis","doi":"10.1016/j.bbalip.2025.159686","DOIUrl":"10.1016/j.bbalip.2025.159686","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is associated with increased cardiovascular disease (CVD) risk, partly attributed to altered lipid metabolism. Apolipoprotein C-III (ApoC-III), a key regulator of triglyceride-rich lipoproteins in the plasma, has been implicated in both dyslipidemia and inflammation. In this study, we investigated the role of hypertriglyceridemia in RA using a transgenic mouse model overexpressing the human ApoC-III gene (ApoC-III Tg). Using a protocol of antigen-induced arthritis (AIA), we show that ApoC-III Tg mice exhibited significantly greater joint swelling, inflammatory infiltration and cartilage destruction compared to non-transgenic controls. These changes were accompanied by altered lipoprotein distribution in serum and High Density Lipoprotein (HDL) dysfunction including reduced antioxidant function. Furthermore, HDL isolated from arthritic ApoC-III Tg mice had pro-inflammatory properties on macrophages as demonstrated by the increased expression of iNOS and IL1β as well as increased mitochondrial respiration. Treatment of arthritic ApoC-III Tg mice with fenofibrate, a triglyceride-lowering drug, reduced triglyceride levels and increased ApoA-I content in HDL fractions. Importantly, fenofibrate significantly ameliorated arthritis severity, restored HDL antioxidant function and reduced macrophage activation. These findings highlight a mechanistic link between dyslipidemia, HDL dysfunction, and inflammatory exacerbation in RA and suggest that targeting ApoC-III-associated pathways may offer therapeutic benefit in patients with coexisting metabolic and inflammatory disorders.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 8","pages":"Article 159686"},"PeriodicalIF":3.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-07DOI: 10.1016/j.bbalip.2025.159687
Philipp W. Weiß , Philip P. Kaltenborn , Christiane Frahm , Ulrike Schulze-Späte , Estelle Heyne , Marten Szibor , Sandor Nietzsche , Ralf A. Claus , Markus H. Gräler
Cardiolipins (CLs) are primarily expressed in the inner mitochondrial membrane where they play essential roles in membrane architecture and mitochondrial functions. CLs have a unique structure characterized by four acyl chains with different stoichiometries such as chain length and degree of saturation. CL composition changes with disease and age, but it is largely unknown how dynamic changes affect mitochondrial function. Here, we compared CL profiles in different mouse tissues across different age groups using liquid chromatography and triple quadrupole mass spectrometry. A key finding was that CLs in the brain differ significantly from those in peripheral organs, with a tendency towards longer-chain variants. We hypothesized that these differences may be influenced by the availability of fatty acids (FA), which in the brain could be affected by the blood-brain barrier. In support of this notion, we found that FA concentrations varied in the different compartments. In addition, we found that CL profiles changed during aging. In cultivated macrophages supplemented with different FAs, we tested how altered CL profiles may affect both, mitochondrial morphology and function such as cristae density, and mitochondrial membrane potential and respiration, respectively. Finally, we validated our in vitro results in vivo by altering the CL profile in mice by using palmitic acid and oleic acid enriched diets. Our study highlights a dynamic adaptation of CL profiles in response to FA availability and aging and emphasizes its functional importance for mitochondrial function. Furthermore, FA supplementation may be a promising therapeutic strategy to address disease- and age-related mitochondrial malfunctions.
{"title":"Age-related changes in cardiolipin profile and functional consequences of altered fatty acid supply","authors":"Philipp W. Weiß , Philip P. Kaltenborn , Christiane Frahm , Ulrike Schulze-Späte , Estelle Heyne , Marten Szibor , Sandor Nietzsche , Ralf A. Claus , Markus H. Gräler","doi":"10.1016/j.bbalip.2025.159687","DOIUrl":"10.1016/j.bbalip.2025.159687","url":null,"abstract":"<div><div>Cardiolipins (CLs) are primarily expressed in the inner mitochondrial membrane where they play essential roles in membrane architecture and mitochondrial functions. CLs have a unique structure characterized by four acyl chains with different stoichiometries such as chain length and degree of saturation. CL composition changes with disease and age, but it is largely unknown how dynamic changes affect mitochondrial function. Here, we compared CL profiles in different mouse tissues across different age groups using liquid chromatography and triple quadrupole mass spectrometry. A key finding was that CLs in the brain differ significantly from those in peripheral organs, with a tendency towards longer-chain variants. We hypothesized that these differences may be influenced by the availability of fatty acids (FA), which in the brain could be affected by the blood-brain barrier. In support of this notion, we found that FA concentrations varied in the different compartments. In addition, we found that CL profiles changed during aging. In cultivated macrophages supplemented with different FAs, we tested how altered CL profiles may affect both, mitochondrial morphology and function such as cristae density, and mitochondrial membrane potential and respiration, respectively. Finally, we validated our <em>in vitro</em> results <em>in vivo</em> by altering the CL profile in mice by using palmitic acid and oleic acid enriched diets. Our study highlights a dynamic adaptation of CL profiles in response to FA availability and aging and emphasizes its functional importance for mitochondrial function. Furthermore, FA supplementation may be a promising therapeutic strategy to address disease- and age-related mitochondrial malfunctions.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 8","pages":"Article 159687"},"PeriodicalIF":3.3,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-07DOI: 10.1016/j.bbalip.2025.159689
Alexandria L. Shaw , Isobel Barlow-Busch , John E. Burke
The class I phosphoinositide 3-kinase pathway (PI3K) is a master regulator of cellular growth, and plays essential roles in controlling immune cell function, metabolism, chemotaxis and proliferation. Activation of class I PI3Ks generates the signalling lipid PIP3 that activates multiple pro-growth signalling pathways. Class I PI3Ks can be activated by multiple plasma membrane stimuli, including G-protein coupled receptors, Ras superfamily GTPases, and receptor tyrosine kinases. The dysregulation of class I PI3Ks is critical in the progression of many human diseases, including cancers, immunodeficiencies, and developmental disorders. Highlighting this is frequent oncogenic mutations (2nd most frequently mutated gene in all human cancers) in PIK3CA encoding the p110α catalytic subunit of class IA PI3K. The class I PI3Ks are obligate heterodimers composed of a catalytic and regulatory subunit, split into two subclasses, class IA and class IB. Recent elucidation of the structures of class I PI3Ks bound to activating stimuli, with activating disease-linked mutations and bound to allosteric conformational selective inhibitors/activators, has revealed extensive insight into the molecular basis of class I PI3K regulation. This review will summarize our current molecular knowledge of class I PI3K regulation, as well as how this information is being used to generate both small molecules and biologics that can either inhibit or activate kinase activity as potential therapeutic agents and biochemical tools.
{"title":"Molecular basis for regulation of the class I phosphoinositide 3-kinases (PI3Ks), and their targeting in human disease","authors":"Alexandria L. Shaw , Isobel Barlow-Busch , John E. Burke","doi":"10.1016/j.bbalip.2025.159689","DOIUrl":"10.1016/j.bbalip.2025.159689","url":null,"abstract":"<div><div>The class I phosphoinositide 3-kinase pathway (PI3K) is a master regulator of cellular growth, and plays essential roles in controlling immune cell function, metabolism, chemotaxis and proliferation. Activation of class I PI3Ks generates the signalling lipid PIP<sub>3</sub> that activates multiple pro-growth signalling pathways. Class I PI3Ks can be activated by multiple plasma membrane stimuli, including G-protein coupled receptors, Ras superfamily GTPases, and receptor tyrosine kinases. The dysregulation of class I PI3Ks is critical in the progression of many human diseases, including cancers, immunodeficiencies, and developmental disorders. Highlighting this is frequent oncogenic mutations (2nd most frequently mutated gene in all human cancers) in <em>PIK3CA</em> encoding the p110α catalytic subunit of class IA PI3K. The class I PI3Ks are obligate heterodimers composed of a catalytic and regulatory subunit, split into two subclasses, class IA and class IB. Recent elucidation of the structures of class I PI3Ks bound to activating stimuli, with activating disease-linked mutations and bound to allosteric conformational selective inhibitors/activators, has revealed extensive insight into the molecular basis of class I PI3K regulation. This review will summarize our current molecular knowledge of class I PI3K regulation, as well as how this information is being used to generate both small molecules and biologics that can either inhibit or activate kinase activity as potential therapeutic agents and biochemical tools.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 8","pages":"Article 159689"},"PeriodicalIF":3.3,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-23DOI: 10.1016/j.bbalip.2025.159682
V V Sathibabu Uddandrao , Deepthi Krishna , Mallenahalli Neelakantappa Vasantha , G. Jayashree , Anitha Roy , V.R. Ravikkumar , S. Sengottuvelu , P. Chandrasekaran , C. Kathirvelan , Brahma Naidu Parim , Kaushik Das , Umesh Kumar
Metabolic (Dysfunction) Associated Steatotic Liver Disease (MASLD) is a complex metabolic condition, the progression of which toward steatohepatitis can be explained by the ‘two-hit’ hypothesis: the first hit involves lipid accumulation, and the second hit involves inflammation and oxidative stress. In this study, we aimed to evaluate the protective effects of a combination of hydroxycitric acid and capsaicin (CHC) against high-fat diet (HFD)-induced MASLD in rats, specifically by targeting the mechanisms associated with both hits. To establish the experimental model, rats were fed a HFD for 16 weeks, followed by treatment with CHC for 6 weeks starting on day one of the 16th week of HFD feeding. CHC treatment effectively mitigated the first hit by improving insulin sensitivity via IRS-1 upregulation and activating AMPK signaling, which in turn inhibited mTOR activity and suppressed key lipogenic markers including SREBP-1c, FAS, ACC, and PPAR-γ. Simultaneously, CHC countered the second hit by enhancing antioxidant defense through Nrf-2 and HO-1 upregulation, while attenuating hepatic inflammation via downregulation of NF-κB, TNF-α, IL-6, and NLRP3 at both mRNA and protein levels. In conclusion, CHC can effectively protect against MASLD in HFD-fed rats by defending against the “first and second hit” by mediating the IRS-1/AMPK-mTOR-SREBP-1c axis/NLRP3-NF-κB/Nrf-2-ARE signaling pathways.
{"title":"Combination of hydroxycitric acid and capsaicin regulates IRS-1/AMPK-mTOR-SREBP-1c Axis/NLRP3-NF-κB/Nrf-2-ARE signaling pathways to ameliorate the two-hit process in high-fat diet-induced hepatic steatosis","authors":"V V Sathibabu Uddandrao , Deepthi Krishna , Mallenahalli Neelakantappa Vasantha , G. Jayashree , Anitha Roy , V.R. Ravikkumar , S. Sengottuvelu , P. Chandrasekaran , C. Kathirvelan , Brahma Naidu Parim , Kaushik Das , Umesh Kumar","doi":"10.1016/j.bbalip.2025.159682","DOIUrl":"10.1016/j.bbalip.2025.159682","url":null,"abstract":"<div><div>Metabolic (Dysfunction) Associated Steatotic Liver Disease (MASLD) is a complex metabolic condition, the progression of which toward steatohepatitis can be explained by the ‘two-hit’ hypothesis: the first hit involves lipid accumulation, and the second hit involves inflammation and oxidative stress. In this study, we aimed to evaluate the protective effects of a combination of hydroxycitric acid and capsaicin (CHC) against high-fat diet (HFD)-induced MASLD in rats, specifically by targeting the mechanisms associated with both hits. To establish the experimental model, rats were fed a HFD for 16 weeks, followed by treatment with CHC for 6 weeks starting on day one of the 16th week of HFD feeding. CHC treatment effectively mitigated the first hit by improving insulin sensitivity via IRS-1 upregulation and activating AMPK signaling, which in turn inhibited mTOR activity and suppressed key lipogenic markers including SREBP-1c, FAS, ACC, and PPAR-γ. Simultaneously, CHC countered the second hit by enhancing antioxidant defense through Nrf-2 and HO-1 upregulation, while attenuating hepatic inflammation via downregulation of NF-κB, TNF-α, IL-6, and NLRP3 at both mRNA and protein levels. In conclusion, CHC can effectively protect against MASLD in HFD-fed rats by defending against the “first and second hit” by mediating the IRS-1/AMPK-mTOR-SREBP-1c axis/NLRP3-NF-κB/Nrf-2-ARE signaling pathways.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 8","pages":"Article 159682"},"PeriodicalIF":3.3,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-22DOI: 10.1016/j.bbalip.2025.159684
Nicole M. Fenton , Laura J. Sharpe , Andrew M. Jenner , Andrew J. Brown
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Pub Date : 2025-08-22DOI: 10.1016/j.bbalip.2025.159683
Youjia Du , Xucheng Lv , Yan Shen , Xiaoou Ren , Shoudong Ye
Endothelial cells form a single layer of endothelium that lines the inner surface of the blood vessels. Healthy endothelial cells play important roles in the maintenance of the circulation homeostasis, while endothelial cell apoptosis has been implicated in the pathology of cardiovascular diseases. Lipid droplets (LDs) are multifunctional organelles that can be formed in endothelial cells during various fatty acid-induced apoptosis. However, the role of LDs in endothelial cell apoptosis and the mechanism of action have received limited attention. Our previous study showed that docosahexaenoic acid (DHA) induces endothelial cell apoptosis through the activation of mitogen-activated kinases (MAPKs) and caspases, and suggested a critical role of p38 MAPK and unknown caspases other than caspase-8, -9, and -3 in the modulation of apoptosis. Therefore, the current study is to investigate the regulatory mechanism of lipid droplet biogenesis by p38 MAPK and caspase-1 in DHA-induced EA.hy926 endothelial cell apoptosis. Our results showed that p38 MAPK and caspase-1 formed a positive feedback loop in upregulating LD biogenesis. Inhibiting the formation of LDs through diacylglycerol acyltransferases suppression but not caspase-1 inhibition led to an alleviation of cell apoptosis. Inhibition of LD biogenesis also negatively impacted the activation of p38 MAPK and caspase-1. Our study suggested a role of the interaction between p38 MAPK and caspase-1 in the modulation of LD biogenesis and apoptosis in DHA-treated endothelial cells, and revealed a potential role of LD in the modulation of the signal transduction involving p38 MAPK and caspase-1.
{"title":"Modulation of lipid droplet biogenesis by p38 MAPK and caspase-1 in docosahexaenoic acid-induced EA.hy926 endothelial cell apoptosis","authors":"Youjia Du , Xucheng Lv , Yan Shen , Xiaoou Ren , Shoudong Ye","doi":"10.1016/j.bbalip.2025.159683","DOIUrl":"10.1016/j.bbalip.2025.159683","url":null,"abstract":"<div><div>Endothelial cells form a single layer of endothelium that lines the inner surface of the blood vessels. Healthy endothelial cells play important roles in the maintenance of the circulation homeostasis, while endothelial cell apoptosis has been implicated in the pathology of cardiovascular diseases. Lipid droplets (LDs) are multifunctional organelles that can be formed in endothelial cells during various fatty acid-induced apoptosis. However, the role of LDs in endothelial cell apoptosis and the mechanism of action have received limited attention. Our previous study showed that docosahexaenoic acid (DHA) induces endothelial cell apoptosis through the activation of mitogen-activated kinases (MAPKs) and caspases, and suggested a critical role of p38 MAPK and unknown caspases other than caspase-8, -9, and -3 in the modulation of apoptosis. Therefore, the current study is to investigate the regulatory mechanism of lipid droplet biogenesis by p38 MAPK and caspase-1 in DHA-induced EA.hy926 endothelial cell apoptosis. Our results showed that p38 MAPK and caspase-1 formed a positive feedback loop in upregulating LD biogenesis. Inhibiting the formation of LDs through diacylglycerol acyltransferases suppression but not caspase-1 inhibition led to an alleviation of cell apoptosis. Inhibition of LD biogenesis also negatively impacted the activation of p38 MAPK and caspase-1. Our study suggested a role of the interaction between p38 MAPK and caspase-1 in the modulation of LD biogenesis and apoptosis in DHA-treated endothelial cells, and revealed a potential role of LD in the modulation of the signal transduction involving p38 MAPK and caspase-1.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 8","pages":"Article 159683"},"PeriodicalIF":3.3,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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