Biochimica et biophysica acta. Molecular and cell biology of lipids最新文献

{"title":"Molecular mechanisms of cytochrome P450-derived epoxy-fatty acids neuroprotection","authors":"Cynthia Navarro-Mabarak,&nbsp;Julio Morán","doi":"10.1016/j.bbalip.2025.159663","DOIUrl":"10.1016/j.bbalip.2025.159663","url":null,"abstract":"<div><div>The epoxyeicosatrienoic acids (EETs) are metabolites that result from the oxidation of the arachidonic acid by cytochrome P450 (CYP) epoxygenases. EETs are known to exert anti-inflammatory, antioxidant, vasodilatory, pro-angiogenic and anti-apoptotic actions. In the nervous system, EETs have been found to be neuroprotective in different models of neuronal damage. However, the molecular mechanisms responsible for these effects are not yet fully understood. This article seeks to review what is known about the signaling pathways involved in the EETs mediated neuroprotection. The mechanisms responsible for these effects are complex and involve several biological pathways that often crosstalk, including an inhibition of NFκB pathway, the activation of PPARα/γ nuclear receptors, and the activation of the PI3K/Akt pathway, among others. We also review what is known about the production and the biological significance of the epoxyeicosatrienoic acid ethanolamides (EET-EAs) and the epoxyeicosatrienoic acid glycerols (EET-EGs), metabolites that result from the epoxidation of the anandamide (AEA) and 2-arachidonylglycerol (2-AG) by CYP epoxygenases, which show endocannabinoid features.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 7","pages":"Article 159663"},"PeriodicalIF":3.9,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616111","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}

{"title":"Fatty acid binding protein 1 (FABP1) depletion promotes an oxidative metabolic shift in Caco-2 colorectal cancer cells","authors":"Delfina Lucía Borús ,&nbsp;Giorgia Zadra ,&nbsp;Daniel Minsky ,&nbsp;María Lucía Costa ,&nbsp;Betina Córsico ,&nbsp;Judith Storch ,&nbsp;Natalia Scaglia","doi":"10.1016/j.bbalip.2025.159661","DOIUrl":"10.1016/j.bbalip.2025.159661","url":null,"abstract":"<div><div>Lipid metabolism reprogramming is a well-established hallmark of many cancer types, including colorectal cancer (CRC). Nevertheless, a clear understanding on how fatty acid (FA) metabolism is fine-tuned during CRC development and progression is still missing. Given that CRC is the second leading cause of cancer-related death, addressing these critical aspects may provide the rationale for new therapeutic approaches and early biomarker identification. Fatty acid binding protein 1 (FABP1) is a small protein that binds FA and other lipophilic compounds, acting as a lipid transporter in the intestine. Little is currently known about the function of FABP1 in CRC. Here we show that the <em>knockdown</em> of FABP1 in CRC cells impairs <em>de novo</em> FA and cholesterol synthesis, specifically, <em>via</em> altering the transcriptional regulation of lipid metabolism genes. FABP1 depletion suppresses the expression of FA and cholesterol synthesis-associated genes while promoting that of FA oxidation genes and mitochondrial oxidative pathways. The latter is associated with increased oxygen consumption rate and activation of the energy sensor 5’ AMP-activated kinase (AMPK). Taken together, our results show that FABP1 orchestrates the balance between FA synthesis and oxidation, most likely to prevent the cytotoxic effects of circulating unbound free fatty acids. Thus, targeting FABP1 function may represent a potential therapeutic strategy in advanced CRC.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 7","pages":"Article 159661"},"PeriodicalIF":3.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607183","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}

{"title":"LIMP-2 deficiency-associated glycolipid abnormalities in mice","authors":"Paulo Gaspar ,&nbsp;André R.A. Marques ,&nbsp;Maria J. Ferraz ,&nbsp;Markus Damme ,&nbsp;Gertjan Kramer ,&nbsp;Mina Mirzaian ,&nbsp;Marion Gijbels ,&nbsp;Roelof Ottenhoff ,&nbsp;Cindy van Roomen ,&nbsp;Herman S. Overkleeft ,&nbsp;Michael Schwake ,&nbsp;Saskia Heybrock ,&nbsp;Maria Carmo Macário ,&nbsp;Paul Saftig ,&nbsp;Johannes M. Aerts","doi":"10.1016/j.bbalip.2025.159657","DOIUrl":"10.1016/j.bbalip.2025.159657","url":null,"abstract":"<div><div>Glucocerebrosidase (GCase) catalyzes the lysosomal degradation of glucosylceramide (GlcCer). GCase deficiency results in Gaucher disease (GD), a lysosomal storage disorder with characteristic hepatosplenomegaly. Transport of GCase to lysosomes is mediated by the lysosomal integral membrane protein type 2 (LIMP-2). Deficiency of LIMP-2 leads to reduced cellular GCase levels and manifests as Action Myoclonic Renal Failure Syndrome (AMRF). We investigated the cause for the markedly different symptomatology of GD and AMRF. In tissues of <em>Limp2 −/−</em> mice no prominent abnormalities in lysosomal enzymes were noted except for variable deficiency of GCase, as measured with enzymatic activity assay and detection of active GCase molecules with an activity-based probe. Noteworthy, in LIMP-2-deficient mice, residual GCase is remarkably high in leukocytes. GCase deficiency in tissues does not correlate with increases in GlcCer, but rather with increases in glucosylsphingosine (GlcSph) and glucosylated cholesterol (GlcChol), both glucosylated metabolites derived from GlcCer. Isolated lysosomes from hepatocytes of <em>Limp2 −/−</em> mice revealed no prominent abnormalities in lysosomal matrix proteins except GCase. The <em>Limp2 −/−</em> tritosomes showed clear increases in GlcSph and GlcChol but not in GlcCer. In conclusion, our data imply a critical role of LIMP-2 in glycosphingolipid homeostasis. Despite low GCase levels striking GlcCer accumulation is avoided in tissues of LIMP-2 deficient mice.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 7","pages":"Article 159657"},"PeriodicalIF":3.9,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607184","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}

{"title":"Partial inhibition of adipose CIDEC improves insulin sensitivity and increases energy expenditure in high-fat diet-fed mice via activating ATGL-PPARα pathway","authors":"Qinghua Fu ,&nbsp;Peng Wang ,&nbsp;Weilin Li ,&nbsp;Zhenhua Cai ,&nbsp;Shiji Zhao ,&nbsp;Weidong Ling ,&nbsp;Mingxun Li ,&nbsp;Xiaochuan Tang ,&nbsp;Ziyi Song","doi":"10.1016/j.bbalip.2025.159659","DOIUrl":"10.1016/j.bbalip.2025.159659","url":null,"abstract":"<div><div>Obesity poses a significant risk for metabolic disorders, such as insulin resistance and metabolic-associated fatty liver disease (MAFLD), yet effective treatments remain limited. Cell Death-Inducing DNA Fragmentation Factor-α-Like Effector C (CIDEC), a lipid droplet membrane protein, facilitates lipid droplet fusion and is crucial for adipose tissue expansion, making it a key target for obesity and related metabolic diseases. However, previous research revealed that complete genetic deletion of <em>Cidec</em> in adipose tissues, while reducing fat accumulation, induced severe insulin resistance in high-fat diet (HFD)-fed mice, potentially due to ectopic fat storage in the liver. Given that complete knockout is an extreme approach, partial inhibition holds greater clinical relevance. Therefore, this study aimed to investigate the effects of partial inhibition of CIDEC in adipose tissues on fat accumulation and insulin sensitivity in mice. Using the Cre-LoxP system, we generated adipose <em>Cidec</em> haploinsufficient mice. Under a standard diet, these mice exhibited normal body weight, fat accumulation, and insulin sensitivity. Notably, under HFD conditions, mice with partial <em>Cidec</em> deficiency showed reduced fat accumulation in adipose tissues while hepatic fat accumulation remained unchanged, accompanied by improved insulin sensitivity and increased energy expenditure. Mechanistically, we found partial <em>Cidec</em> deficiency activated thermogenic program in adipocytes <em>in vivo</em> and <em>in vitro</em> through the ATGL-PPARα pathway. In conclusion, adipose CIDEC partial inhibition attenuates HFD-induced obesity and insulin resistance by enhancing ATGL-PPARα-mediated energy expenditure, establishing this approach as a promising therapeutic strategy for obesity and related metabolic diseases.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159659"},"PeriodicalIF":3.9,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144595994","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}

{"title":"Agonist- and stress-driven compartmentalized phosphoinositide signaling in cells","authors":"Mo Chen ,&nbsp;Jay Xiaojun Tan ,&nbsp;Yue Sun ,&nbsp;Narendra Thapa ,&nbsp;Vincent L. Cryns ,&nbsp;Richard A. Anderson","doi":"10.1016/j.bbalip.2025.159662","DOIUrl":"10.1016/j.bbalip.2025.159662","url":null,"abstract":"<div><div>Phosphoinositides (PIPs) are essential lipid messengers that regulate cellular responses to external stimuli and stress through spatially organized signaling pathways. In recent years, compartment-specific mechanisms by which PIP signaling integrates diverse cellular processes have been extensively expanded. This review discusses the distinct roles of PIP signaling across cellular compartments, including the plasma membrane, endosomes, lysosomes, protein scaffolds, and the nucleus. PIPs coordinate key processes such as receptor trafficking, cytoskeletal remodeling, autophagy, and signal transduction. Dynamic lysosomal PIP switches regulate critical functions like nutrient sensing, mTORC1 activity, and membrane repair, emphasizing their adaptability in maintaining cellular homeostasis. Furthermore, emerging evidence highlights nuclear PIP signaling in transcriptional regulation, DNA repair, and oncogenic pathways. Dysregulation of PIP signaling pathways is implicated in diseases such as cancer, neurodegeneration, and lysosomal storage disorders, underscoring their therapeutic potential in various pathological conditions.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159662"},"PeriodicalIF":3.9,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574771","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}

{"title":"The inositol 5-phosphatases OCRL and INPP5B: Cellular functions and roles in disease","authors":"Aloka de Sa ,&nbsp;Gaoyu Li ,&nbsp;Connor Byrne ,&nbsp;Martin Lowe","doi":"10.1016/j.bbalip.2025.159660","DOIUrl":"10.1016/j.bbalip.2025.159660","url":null,"abstract":"<div><div>OCRL and INPP5B are evolutionary conserved inositol 5-phosphatases that preferentially hydrolyse PI(4,5)P₂, a key regulator of numerous cellular processes. Mutation of OCRL causes Lowe syndrome and Dent-2 disease that manifest in the eye, brain and kidney, whereas mutations in INPP5B have not been reported to cause disease. Here, we provide a current view of the biology of both proteins, describing their subcellular locations, interaction partners and cellular processes they mediate or that are sensitive to their loss of function. There are many similarities in these properties between OCRL and INPP5B, albeit with some important differences. We also discuss the mechanisms underlying Lowe syndrome and Dent-2 disease, and the possible influence of INPP5B in dictating final phenotypic outcome. The knowledge gained studying OCRL and INPP5B has improved understanding of how cells function and will inform the design of new treatments for Lowe syndrome and Dent-2 disease and possibly other conditions.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159660"},"PeriodicalIF":3.9,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144570418","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}

{"title":"Impact of minor cannabinoids on key pharmacological targets of estrogen receptor-positive breast cancer","authors":"Cristina Ferreira Almeida,&nbsp;Georgina Correia-da-Silva,&nbsp;Ana Paula Ribeiro,&nbsp;Natércia Teixeira,&nbsp;Cristina Amaral","doi":"10.1016/j.bbalip.2025.159658","DOIUrl":"10.1016/j.bbalip.2025.159658","url":null,"abstract":"<div><div>Endocrine therapy for estrogen receptor-positive (ER⁺) breast cancer has significantly improved over the last decades. However, it presents some limitations that make the search for novel therapeutic options mandatory. Several studies have been conducted to understand the anti-tumor potential of cannabinoids in breast cancer. Yet, most of them are focused on the major phytocannabinoids Δ⁹-tetrahydrocannabinol (<strong>THC</strong>) and cannabidiol (<strong>CBD</strong>). However, <em>Cannabis</em> has other minor phytocannabinoids whose anti-cancer properties are still to be elucidated. Here, we investigated the mechanisms of action of four minor cannabinoids, cannabigerol (<strong>CBG</strong>), cannabidivarin (<strong>CBDV</strong>), cannabinol (<strong>CBN</strong>), and cannabichromene (<strong>CBC</strong>), in 2D and 3D ER⁺ breast cancer models. These cannabinoids dysregulate MCF-7aro cell cycle progression, induce apoptosis by different mechanisms, and inhibit the growth of MCF-7aro spheroids. <strong>CBG</strong> exerts its effects through a down-regulation of both ER and AR protein levels, while <strong>CBDV</strong> reduces aromatase protein levels. <strong>CBN</strong> and <strong>CBC</strong> simultaneously affect the three targets, ER, aromatase, and AR. In fact, <strong>CBN</strong> and <strong>CBC</strong> present an AR-dependent cell death, down-regulate aromatase levels, and act as ER negative regulators impairing cancer cell growth. <strong>CBN</strong> caused the most pronounced effects. Overall, this study highlights the anti-cancer properties and the therapeutic potential of these minor cannabinoids in ER⁺ breast cancer.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159658"},"PeriodicalIF":3.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564323","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}

{"title":"Specificity mechanism of Group VIA calcium-independent phospholipase A2 toward truncated-oxidized phospholipids and its application for specific inhibitor design","authors":"Daiki Hayashi ,&nbsp;Charikleia S. Batsika ,&nbsp;Asimina Bourboula ,&nbsp;Masakazu Shinohara ,&nbsp;Kengo Kanamaru ,&nbsp;George Kokotos ,&nbsp;Edward A. Dennis","doi":"10.1016/j.bbalip.2025.159655","DOIUrl":"10.1016/j.bbalip.2025.159655","url":null,"abstract":"<div><div>Phospholipase A₂ (PLA₂) constitutes a superfamily of enzymes that hydrolyze the <em>sn</em>-2 fatty acyl chain of glycerophospholipids. Polyunsaturated fatty acids (PUFAs) are preferentially attached at the <em>sn</em>-2 position of glycerophospholipids and are easily truncated by oxidation. The truncated-oxidized phospholipids (tr-oxPLs) trigger various cellular responses, and PLA₂s may play a critical role in the metabolism of the tr-oxPLs by removing the oxidized <em>sn</em>-2 chain. In the present study, we demonstrated using an in vitro lipidomics assay that Group VIA calcium-independent PLA₂ (GVIA iPLA₂) showed high activity toward phosphatidylcholine with a 9-oxononanoyl chain, but not with an azelaoyl chain on the <em>sn</em>-2 position. We conducted molecular dynamics simulations which revealed that the hydrophilicity of the <em>sn</em>-2 acyl chain critically affects the binding of the substrate in the active site. Based on the unique specificity of GVIA iPLA₂ toward tr-oxPLs, we synthesized an oxidatively modified inhibitor (GK766) for GVIA iPLA₂, aiming for improvement of its selectivity and/or potency. As we expected, the modified inhibitor improved its selectivity of GVIA iPLA₂ compared to the unmodified inhibitor (GK187), although the inhibitory effect became somewhat weaker. More importantly, we demonstrated that GK766 induces cell death by ferroptosis more effectively than GK187 using an erythroleukemia cell line. In the present study, we have further defined the unique substrate specificity of GVIA iPLA₂ toward tr-oxPLs and its molecular mechanism. Furthermore, we have developed a novel specificity-based inhibitor that induces ferroptosis demonstrating that using substrate selectivity helps in developing more effective therapeutics.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159655"},"PeriodicalIF":3.9,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537953","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}

{"title":"Substrates, intermediates, and products of avian ketocarotenoid metabolism","authors":"Matthew B. Toomey ,&nbsp;Rebecca E. Koch ,&nbsp;Yu Liu ,&nbsp;Johannes von Lintig ,&nbsp;Joseph C. Corbo ,&nbsp;Geoffrey E. Hill ,&nbsp;Yufeng Zhang","doi":"10.1016/j.bbalip.2025.159654","DOIUrl":"10.1016/j.bbalip.2025.159654","url":null,"abstract":"<div><div>Carotenoid-based coloration is an essential feature of avian diversity and has important roles in communication and mate choice. The red feathers of birds from phylogenetically diverse orders and families are pigmented with C4-ketocarotenoids produced via the successive action of Cytochrome P450 2J19 (CYP2J19) and 3-hydroxybutyrate dehydrogenase 1-like (BDH1L) on yellow dietary precursors. Yet, the biochemistry of these enzymes remains incompletely understood. Here we present a series of experiments characterizing the substrates, intermediates, and products of CYP2J19 and BDH1L expressed in heterologous cell culture. We confirm that CYP2J19 preferentially hydroxylates the 4 and 4′ positions of β-ring substrates, but can also hydroxylate the 3 and 3 positions of C4-ketocarotenoids. We confirm that BDH1L catalyzes the conversion of zeaxanthin to canary xanthophyll B (ε,ε’-carotene-3,3′-dione) a major pigment in plumage of many yellow bird species. These results suggest that the actions of CYP2J19 and/or BDH1L can explain the presence of many metabolically transformed carotenoids in avian tissues.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159654"},"PeriodicalIF":3.9,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526338","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}

{"title":"Carotenoid molecular actions in plants and animals","authors":"Hideki Hashimoto ,&nbsp;John W. Erdman Jr.","doi":"10.1016/j.bbalip.2025.159656","DOIUrl":"10.1016/j.bbalip.2025.159656","url":null,"abstract":"","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159656"},"PeriodicalIF":3.9,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526264","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}