Phospholipids play crucial roles in autophagy; however, the underlying mechanisms remain elusive. We previously found that the phosphatidylserine (PtdSer) transporter Osh5 is critical for autophagosome formation. Therefore, in this study, we aimed to investigate the impact of the knockout of cho1, which encodes PtdSer synthase, on autophagy. Green fluorescent protein-autophagy-related gene 8 (GFP-Atg8) processing assay revealed a significant defect in the macroautophagic activity of the cho1∆ mutant, regardless of the presence or absence of ethanolamine (Etn). Notably, autophagosomes were absent in the cytosol, and macroautophagic bodies were not observed in the vacuoles of the starved cho1∆ mutant, underscoring the essential role of PtdSer synthesized using Cho1 in autophagosome biogenesis. In contrast, numerous microautophagic vesicles containing lipid droplets were observed in the vacuoles of cho1∆ mutants starved in the presence of Etn, suggesting the crucial role of phosphatidylethanolamine (PtdEtn) synthesized via the Kennedy pathway in microautophagic lipophagy when PtdSer synthesis using Cho1 is disrupted. Given recent evidence pointing to the involvement of the ubiquitination system in various autophagy-related processes, we also examined the role of ubiquitin-conjugating enzyme E2 gene ubc4. In addition, deletion of ubc4 gene led to a pronounced reduction in microautophagic lipophagy in starved cho1∆ cells, but not in wild-type cells. Together, these observations highlight an essential role for Ubc4-mediated ubiquitination in driving vacuolar microautophagic lipophagy specifically under Cho1-deficient conditions.
{"title":"Regulation of macroautophagy and microautophagic lipophagy by phosphatidylserine synthase Cho1 and external ethanolamine","authors":"Nanaru Mineoka , Rikako Konishi , Yuri Nakashima , Moe Muramoto , Kayoko Fukuda , Sayuri Kuriyama , Tatsunori Masatani , Akikazu Fujita","doi":"10.1016/j.bbalip.2025.159702","DOIUrl":"10.1016/j.bbalip.2025.159702","url":null,"abstract":"<div><div>Phospholipids play crucial roles in autophagy; however, the underlying mechanisms remain elusive. We previously found that the phosphatidylserine (PtdSer) transporter Osh5 is critical for autophagosome formation. Therefore, in this study, we aimed to investigate the impact of the knockout of <em>cho1</em>, which encodes PtdSer synthase, on autophagy. Green fluorescent protein-autophagy-related gene 8 (GFP-Atg8) processing assay revealed a significant defect in the macroautophagic activity of the <em>cho1</em>∆ mutant, regardless of the presence or absence of ethanolamine (Etn). Notably, autophagosomes were absent in the cytosol, and macroautophagic bodies were not observed in the vacuoles of the starved <em>cho1</em>∆ mutant, underscoring the essential role of PtdSer synthesized using Cho1 in autophagosome biogenesis. In contrast, numerous microautophagic vesicles containing lipid droplets were observed in the vacuoles of <em>cho1</em>∆ mutants starved in the presence of Etn, suggesting the crucial role of phosphatidylethanolamine (PtdEtn) synthesized via the Kennedy pathway in microautophagic lipophagy when PtdSer synthesis using Cho1 is disrupted. Given recent evidence pointing to the involvement of the ubiquitination system in various autophagy-related processes, we also examined the role of ubiquitin-conjugating enzyme E2 gene <em>ubc4</em>. In addition, deletion of <em>ubc4</em> gene led to a pronounced reduction in microautophagic lipophagy in starved <em>cho1</em>∆ cells, but not in wild-type cells. Together, these observations highlight an essential role for Ubc4-mediated ubiquitination in driving vacuolar microautophagic lipophagy specifically under Cho1-deficient conditions.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1871 2","pages":"Article 159702"},"PeriodicalIF":3.3,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145426360","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 : 2025-10-26DOI: 10.1016/j.bbalip.2025.159701
Yanqiu Zhu , Yihan Wang , Chenglong Xia , Yi Yan , Rui Du , Tingting Yang , Lin Jing , Yanbing Lou , Hongrui Guo
Excessive lipid accumulation within the liver is a main factor inducing non-alcoholic fatty liver diseases (NAFLD). Chitosan coated selenium nanoparticles (CS-SeNPs), a new kind of selenium supplement. In vitro study, CS-SeNPs remarkably decreased FFA-induced lipid accumulation. CS-SeNPs could reverse the inhibition effects of FFA on the autophagy process. Inhibition of autophagy increased lipid accumulation and TC and TG levels, and decreased the expression levels of fat metabolism-related genes. In vivo analysis, CS-SeNPs administration apparently improved the pathological changes in NAFLD, including body weight, liver function, serum lipids, and liver histopathological changes. Additionally, autophagy levels in the liver were also increased, oxidative stress and inflammation were reduced after CS-SeNPs treatment. In summary, CS-SeNPs showed protective effects on NAFLD both in vivo and in vitro, likely through a mechanism involving promotion of lipid degradation and reduction of fat accumulation in hepatocytes by inducing lipid autophagy.
{"title":"Induction of lipid autophagy by chitosan-coated selenium nanoparticles mitigates NAFLD in vitro and in vivo","authors":"Yanqiu Zhu , Yihan Wang , Chenglong Xia , Yi Yan , Rui Du , Tingting Yang , Lin Jing , Yanbing Lou , Hongrui Guo","doi":"10.1016/j.bbalip.2025.159701","DOIUrl":"10.1016/j.bbalip.2025.159701","url":null,"abstract":"<div><div>Excessive lipid accumulation within the liver is a main factor inducing non-alcoholic fatty liver diseases (NAFLD). Chitosan coated selenium nanoparticles (CS-SeNPs), a new kind of selenium supplement. <em>In vitro</em> study, CS-SeNPs remarkably decreased FFA-induced lipid accumulation. CS-SeNPs could reverse the inhibition effects of FFA on the autophagy process. Inhibition of autophagy increased lipid accumulation and TC and TG levels, and decreased the expression levels of fat metabolism-related genes. <em>In vivo</em> analysis, CS-SeNPs administration apparently improved the pathological changes in NAFLD, including body weight, liver function, serum lipids, and liver histopathological changes. Additionally, autophagy levels in the liver were also increased, oxidative stress and inflammation were reduced after CS-SeNPs treatment. In summary, CS-SeNPs showed protective effects on NAFLD both <em>in vivo</em> and <em>in vitro</em>, likely through a mechanism involving promotion of lipid degradation and reduction of fat accumulation in hepatocytes by inducing lipid autophagy.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1871 1","pages":"Article 159701"},"PeriodicalIF":3.3,"publicationDate":"2025-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145385253","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}
Phosphoinositides are regulators of key cell biological processes such as plasma membrane function, vesicular transport, cytoskeletal and nuclear organization. In turn, their levels are tightly controlled by the function of lipid kinases and phosphatases that modify specific hydroxyl groups on the inositol ring. Phosphatidylinositol 5 phosphate 4-kinase (PIP4K) is one such lipid kinase. Although initially discovered as an enzyme that phosphorylates the 4th hydroxyl on the inositol ring of phosphatidylinositol 5 phosphate (PI5P) with exquisite specificity, it has recently emerged that PIP4K may also work on other substrates. Interestingly, recent studies have also proposed functions for this enzyme that do not require its catalytic activity. Although most elements of phosphoinositide signalling are conserved across all eukaryota, a limited number of phosphoinositide kinases and phosphatases including PIP4K seem to be a unique feature of the genomes of organisms that exist in a multicellular state but not unicellular eukaryotes. Genetic studies in model organisms implicate PIP4K function in key processes such as hormone regulated metabolic control as well as cell division and growth. Consequently, PIP4K function has important biomedical implications in the context of cancer, metabolic syndrome and autoimmune disorders. In this review, we analyze emerging findings on PIP4K function and reflect on the biochemical raison d'être of how this protein regulates cell physiology in metazoans.
{"title":"The multifaceted phosphatidylinositol 5 phosphate 4-kinase proteins: molecular properties and biological functions","authors":"Harini Krishnan, Aishwarya Venugopal, Preethi Alex, Padinjat Raghu","doi":"10.1016/j.bbalip.2025.159698","DOIUrl":"10.1016/j.bbalip.2025.159698","url":null,"abstract":"<div><div>Phosphoinositides are regulators of key cell biological processes such as plasma membrane function, vesicular transport, cytoskeletal and nuclear organization. In turn, their levels are tightly controlled by the function of lipid kinases and phosphatases that modify specific hydroxyl groups on the inositol ring. Phosphatidylinositol 5 phosphate 4-kinase (PIP4K) is one such lipid kinase. Although initially discovered as an enzyme that phosphorylates the 4th hydroxyl on the inositol ring of phosphatidylinositol 5 phosphate (PI5P) with exquisite specificity, it has recently emerged that PIP4K may also work on other substrates. Interestingly, recent studies have also proposed functions for this enzyme that do not require its catalytic activity. Although most elements of phosphoinositide signalling are conserved across all eukaryota, a limited number of phosphoinositide kinases and phosphatases including PIP4K seem to be a unique feature of the genomes of organisms that exist in a multicellular state but not unicellular eukaryotes. Genetic studies in model organisms implicate PIP4K function in key processes such as hormone regulated metabolic control as well as cell division and growth. Consequently, PIP4K function has important biomedical implications in the context of cancer, metabolic syndrome and autoimmune disorders. In this review, we analyze emerging findings on PIP4K function and reflect on the biochemical <em>raison d'être</em> of how this protein regulates cell physiology in metazoans.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1871 1","pages":"Article 159698"},"PeriodicalIF":3.3,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353513","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 : 2025-10-20DOI: 10.1016/j.bbalip.2025.159699
Svetlana S. Gorina, Natalia V. Lantsova, Tatiana M. Iljina, Yana Y. Toporkova, Alexander N. Grechkin
The CYP71 clan comprises the majority of Arabidopsis thaliana P450s. The functional role of the great majority of CYP71 clan enzymes remains unknown hitherto. Some Arabidopsis CYP71B subfamily proteins, such as AtCYP71B23, exhibit primary structural similarities to CYP74 enzymes and prostacyclin synthase (CYP8A1). Particularly, AtCYP71B23 and some related CYP71B proteins, along with the CYP74s and CYP8A1, exhibit a critical substitution of the D/E residue, which is conserved in monooxygenases, in the centre of the I-helix groove motif, with an asparagine (N) residue. This substitution may result in a nonclassical behaviour of these P450s. These observations prompted us to prepare the recombinant AtCYP71B23 and examine its behaviour towards the fatty acid hydroperoxides. AtCYP71B23 was active towards the linoleic acid 9(S)-hydroperoxides of linoleic (9-HPOD) and α-linolenic (9-HPOT) acids, as well as the 13(S)-hydroperoxide of linoleic acid (13-HPOD). α-Linolenic acid 13(S)-hydroperoxide was an inefficient substrate. Major products were the divinyl ethers (1′Z)-colneleic (9-HPOD), (1′Z)-colnelenic (9-HPOT), and (11Z)-etheroleic (13-HPOD) acids. Thus, AtCYP71B23 is an unprecedented CYP71 clan enzyme of fatty acid hydroperoxide metabolism and behaves primarily as a divinyl ether synthase.
{"title":"Arabidopsis AtCYP71B23: Detection of non-CYP74 enzyme of oxylipin biosynthesis","authors":"Svetlana S. Gorina, Natalia V. Lantsova, Tatiana M. Iljina, Yana Y. Toporkova, Alexander N. Grechkin","doi":"10.1016/j.bbalip.2025.159699","DOIUrl":"10.1016/j.bbalip.2025.159699","url":null,"abstract":"<div><div>The CYP71 clan comprises the majority of <em>Arabidopsis thaliana</em> P450s. The functional role of the great majority of CYP71 clan enzymes remains unknown hitherto. Some Arabidopsis CYP71B subfamily proteins, such as AtCYP71B23, exhibit primary structural similarities to CYP74 enzymes and prostacyclin synthase (CYP8A1). Particularly, AtCYP71B23 and some related CYP71B proteins, along with the CYP74s and CYP8A1, exhibit a critical substitution of the D/E residue, which is conserved in monooxygenases, in the centre of the I-helix groove motif, with an asparagine (N) residue. This substitution may result in a nonclassical behaviour of these P450s. These observations prompted us to prepare the recombinant AtCYP71B23 and examine its behaviour towards the fatty acid hydroperoxides. AtCYP71B23 was active towards the linoleic acid 9(<em>S</em>)-hydroperoxides of linoleic (9-HPOD) and α-linolenic (9-HPOT) acids, as well as the 13(<em>S</em>)-hydroperoxide of linoleic acid (13-HPOD). α-Linolenic acid 13(<em>S</em>)-hydroperoxide was an inefficient substrate. Major products were the divinyl ethers (1′<em>Z</em>)-colneleic (9-HPOD), (1′<em>Z</em>)-colnelenic (9-HPOT), and (11<em>Z</em>)-etheroleic (13-HPOD) acids. Thus, AtCYP71B23 is an unprecedented CYP71 clan enzyme of fatty acid hydroperoxide metabolism and behaves primarily as a divinyl ether synthase.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1871 1","pages":"Article 159699"},"PeriodicalIF":3.3,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145343123","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 : 2025-10-17DOI: 10.1016/j.bbalip.2025.159697
Antonia Felzen , Willemien F.J. Hof , Hilde de Vries , Milaine V. Hovingh , Rick Havinga , Niels L. Mulder , Martijn Koehorst , Niels Kloosterhuis , Marieke Smit , Nicolette Huijkman , Bart van de Sluis , Jan Freark de Boer , Folkert Kuipers , Henkjan J. Verkade
Background & aims
Bile Salt Export Pump (BSEP) deficiency is a rare genetic cholestatic liver disease, often necessitating liver transplantation. The p.E297G missense mutation is associated with residual BSEP function in vitro and delayed need for transplantation in patients. We aimed to generate a p.E297G BSEP knock-in (BSEPE297G) mouse model to evaluate interventions to improve residual BSEP function.
Methods
We generated BSEPE297G mice by CRISPR-Cas9 technology. BSEPE297G mice and wild type (WT) littermates were characterized for BSEP expression and liver pathology at 14 weeks of age. Maximal BSEP transport capacity without and after 4-phenylbutyrate (4-PB) treatment were determined in vivo by quantification of biliary bile acid secretion during intravenous infusion of increasing dosages of tauroursodeoxycholic acid (TUDCA) in WT, BSEPE297G and BSEP−/− mice.
Results
Western blot analysis showed immature BSEP protein in BSEPE297G livers. Median plasma AST was three-fold higher in BSEPE297G mice (Males: 198 vs. 60 U/L; Females: 188 vs. 50 U/L; each p < 0.001) while plasma bile acid levels were higher in female BSEPE297G mice compared to WT (Females: 36 vs. 6 μM, p < 0.001; Males: 11 vs. 3 μM, p = 0.07). Histological analysis revealed features of cholestatic liver pathology in BSEPE297G mice. TUDCA infusion strongly increased biliary bile acid secretion in WT but not in BSEPE297G and BSEP−/− mice. 4-PB treatment did not enhance bile acid transport capacity in BSEPE297G mice.
Conclusions
BSEPE297G mice display a BSEP deficiency phenotype with a strongly reduced hepatobiliary bile acid transport capacity. The expression of immature BSEP protein suggests the potential to assess correctors of the BSEP functionality in vivo.
背景与目的：胆汁盐输出泵缺乏症是一种罕见的遗传性胆汁淤积性肝病，经常需要肝移植。p.E297G错义突变与体外BSEP功能残留和患者移植需求延迟有关。我们旨在建立p.E297G BSEP敲入（BSEPE297G）小鼠模型，以评估干预措施对改善剩余BSEP功能的作用。方法：采用CRISPR-Cas9技术制备BSEPE297G小鼠。BSEPE297G小鼠和野生型（WT）仔鼠在14 周龄时进行BSEP表达和肝脏病理特征的检测。通过对WT、BSEPE297G和BSEP-/-小鼠静脉输注增加剂量的牛磺酸去氧胆酸（TUDCA）时的胆汁酸分泌量的定量测定，测定未经4-苯基丁酸（4-PB）处理和处理后BSEP的最大转运能力。结果：Western blot分析显示BSEPE297G肝脏中存在未成熟的BSEP蛋白。BSEPE297G小鼠的中位血浆AST比WT高3倍(雄性：198 vs. 60 U/L；雌性：188 vs. 50 U/L；每只 E297G小鼠与WT相比（雌性：36 vs. 6 μM， p E297G小鼠）。TUDCA输注能显著增加WT小鼠的胆汁酸分泌，但对BSEPE297G和BSEP-/-小鼠无明显影响。4-PB处理没有增强BSEPE297G小鼠胆汁酸转运能力。结论：BSEPE297G小鼠表现出BSEP缺陷表型，肝胆胆汁酸运输能力明显降低。未成熟BSEP蛋白的表达提示了在体内评估BSEP功能校正因子的潜力。
{"title":"Generation and characterization of a mouse model for bile salt export pump deficiency with the p.E297G mutation","authors":"Antonia Felzen , Willemien F.J. Hof , Hilde de Vries , Milaine V. Hovingh , Rick Havinga , Niels L. Mulder , Martijn Koehorst , Niels Kloosterhuis , Marieke Smit , Nicolette Huijkman , Bart van de Sluis , Jan Freark de Boer , Folkert Kuipers , Henkjan J. Verkade","doi":"10.1016/j.bbalip.2025.159697","DOIUrl":"10.1016/j.bbalip.2025.159697","url":null,"abstract":"<div><h3>Background & aims</h3><div>Bile Salt Export Pump (BSEP) deficiency is a rare genetic cholestatic liver disease, often necessitating liver transplantation. The p.E297G missense mutation is associated with residual BSEP function <em>in vitro</em> and delayed need for transplantation in patients. We aimed to generate a p.E297G BSEP knock-in (BSEP<sup>E297G</sup>) mouse model to evaluate interventions to improve residual BSEP function.</div></div><div><h3>Methods</h3><div>We generated BSEP<sup>E297G</sup> mice by CRISPR-Cas9 technology. BSEP<sup>E297G</sup> mice and wild type (WT) littermates were characterized for BSEP expression and liver pathology at 14 weeks of age. Maximal BSEP transport capacity without and after 4-phenylbutyrate (4-PB) treatment were determined <em>in vivo</em> by quantification of biliary bile acid secretion during intravenous infusion of increasing dosages of tauroursodeoxycholic acid (TUDCA) in WT, BSEP<sup>E297G</sup> and BSEP<sup>−</sup><sup>/</sup><sup>−</sup> mice.</div></div><div><h3>Results</h3><div>Western blot analysis showed immature BSEP protein in BSEP<sup>E297G</sup> livers. Median plasma AST was three-fold higher in BSEP<sup>E297G</sup> mice (Males: 198 vs. 60 U/L; Females: 188 vs. 50 U/L; each <em>p</em> < 0.001) while plasma bile acid levels were higher in female BSEP<sup>E297G</sup> mice compared to WT (Females: 36 vs. 6 μM, <em>p</em> < 0.001; Males: 11 vs. 3 μM, <em>p</em> = 0.07). Histological analysis revealed features of cholestatic liver pathology in BSEP<sup>E297G</sup> mice. TUDCA infusion strongly increased biliary bile acid secretion in WT but not in BSEP<sup>E297G</sup> and BSEP<sup>−</sup><sup>/</sup><sup>−</sup> mice. 4-PB treatment did not enhance bile acid transport capacity in BSEP<sup>E297G</sup> mice.</div></div><div><h3>Conclusions</h3><div>BSEP<sup>E297G</sup> mice display a BSEP deficiency phenotype with a strongly reduced hepatobiliary bile acid transport capacity. The expression of immature BSEP protein suggests the potential to assess correctors of the BSEP functionality <em>in vivo</em>.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1871 1","pages":"Article 159697"},"PeriodicalIF":3.3,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328367","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 : 2025-10-11DOI: 10.1016/j.bbalip.2025.159693
Roberta Rubino , Gabriele Squillero , Lorenzo Prever , Emanuele Fantastico, Maria Chiara De Santis, Arezou Kahnamouei, Federico Gulluni, Emilio Hirsch
This review provides an integrated overview of the current understanding of class II PI3Ks, with particular attention to their structural and enzymatic properties, lipid substrate specificity, and emerging roles in membrane trafficking, cellular signaling, and disease. Class II phosphoinositide 3-kinases (PI3Ks) are lipid kinases that regulate membrane identity and intracellular signaling by generating phosphatidylinositol 3-phosphate [PI(3)P] and phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P2] at distinct subcellular compartments. Advances over the past decade have clarified the structural organization, regulatory principles, and lipid output of all the three mammalian isoforms (PI3K-C2α, PI3K-C2β, and PI3K-C2γ). These studies have revealed that class II PI3K function is highly context-dependent, governed by compartment-specific cues and the spatial restriction of lipid products. Dysregulation of class II PI3Ks has been implicated in diverse pathological conditions, including cancer, metabolic disorders, epilepsy, congenital myopathies, vascular dysfunction, and premature aging. These findings establish a framework for understanding how localized phosphoinositide synthesis contributes to cellular homeostasis and disease, and underscore the therapeutic potential of selectively targeting class II PI3K isoforms.
{"title":"Decoding class II PI3K signaling: From membrane identity to human disease","authors":"Roberta Rubino , Gabriele Squillero , Lorenzo Prever , Emanuele Fantastico, Maria Chiara De Santis, Arezou Kahnamouei, Federico Gulluni, Emilio Hirsch","doi":"10.1016/j.bbalip.2025.159693","DOIUrl":"10.1016/j.bbalip.2025.159693","url":null,"abstract":"<div><div>This review provides an integrated overview of the current understanding of class II PI3Ks, with particular attention to their structural and enzymatic properties, lipid substrate specificity, and emerging roles in membrane trafficking, cellular signaling, and disease. Class II phosphoinositide 3-kinases (PI3Ks) are lipid kinases that regulate membrane identity and intracellular signaling by generating phosphatidylinositol 3-phosphate [PI(3)P] and phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P<sub>2</sub>] at distinct subcellular compartments. Advances over the past decade have clarified the structural organization, regulatory principles, and lipid output of all the three mammalian isoforms (PI3K-C2α, PI3K-C2β, and PI3K-C2γ). These studies have revealed that class II PI3K function is highly context-dependent, governed by compartment-specific cues and the spatial restriction of lipid products. Dysregulation of class II PI3Ks has been implicated in diverse pathological conditions, including cancer, metabolic disorders, epilepsy, congenital myopathies, vascular dysfunction, and premature aging. These findings establish a framework for understanding how localized phosphoinositide synthesis contributes to cellular homeostasis and disease, and underscore the therapeutic potential of selectively targeting class II PI3K isoforms.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1871 1","pages":"Article 159693"},"PeriodicalIF":3.3,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285556","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 : 2025-10-09DOI: 10.1016/j.bbalip.2025.159696
Hequn Li , Zhen Wang , Hongjuan Yuan , Tianyu Wang , Ying Gao , Bushra Iqbal , Huaiyuan Zhang
Palmitoyl-protein thioesterase 1 (PPT1), a key depalmitoylating enzyme, modulates substrate protein function and lipid metabolism through enzymatic thioester bond hydrolysis of the palmitoyl-thioester bond. While PPT1 may regulate lipid metabolism through dynamic palmitoylation, its fundamental regulatory pathways require further elucidation. In this study, PPT1 was homologously overexpressed in Mucor circinelloides to investigate the mechanism of PPT1-mediated lipid metabolism. The results showed that the cell dry weight (CDW) did not differ significantly between the strains. However, the total fatty acids (TFA) content, expressed as a percentage of CDW, was significantly higher in the recombinant strain (34.7 % of CDW) than in the control strain (25.9 % of CDW), representing a 34.0 % increase. Concurrently, the proportion of C16:0 in TFA increased significantly by 32.1 %. To determine the effects of PPT1 overexpression on lipid accumulation in M. circinelloides, the lipid composition was analyzed by using thin-layer chromatography coupled with gas chromatography. The results revealed that the content of free fatty acids (FFA) exhibited a significant increase of 128.2 %, with the percentages of C16:0 and C18:0 in FFA increasing by 64.7 % and 24.8 %, respectively. The analysis of the mRNA level of key genes involved in lipid synthesis indicated that PPT1 overexpression enhances the flux of acyl-CoA towards FFA. This study reveals the mechanism by which PPT1 regulates lipid synthesis in oleaginous fungi through depalmitoylation, providing novel insights for engineering lipid metabolism.
{"title":"Palmitoyl-protein thioesterase 1 mediated depalmitoylation regulates lipid accumulation in the oleaginous fungus Mucor circinelloides","authors":"Hequn Li , Zhen Wang , Hongjuan Yuan , Tianyu Wang , Ying Gao , Bushra Iqbal , Huaiyuan Zhang","doi":"10.1016/j.bbalip.2025.159696","DOIUrl":"10.1016/j.bbalip.2025.159696","url":null,"abstract":"<div><div>Palmitoyl-protein thioesterase 1 (PPT1), a key depalmitoylating enzyme, modulates substrate protein function and lipid metabolism through enzymatic thioester bond hydrolysis of the palmitoyl-thioester bond. While PPT1 may regulate lipid metabolism through dynamic palmitoylation, its fundamental regulatory pathways require further elucidation. In this study, PPT1 was homologously overexpressed in <em>Mucor circinelloides</em> to investigate the mechanism of PPT1-mediated lipid metabolism. The results showed that the cell dry weight (CDW) did not differ significantly between the strains. However, the total fatty acids (TFA) content, expressed as a percentage of CDW, was significantly higher in the recombinant strain (34.7 % of CDW) than in the control strain (25.9 % of CDW), representing a 34.0 % increase. Concurrently, the proportion of C16:0 in TFA increased significantly by 32.1 %. To determine the effects of PPT1 overexpression on lipid accumulation in <em>M. circinelloides</em>, the lipid composition was analyzed by using thin-layer chromatography coupled with gas chromatography. The results revealed that the content of free fatty acids (FFA) exhibited a significant increase of 128.2 %, with the percentages of C16:0 and C18:0 in FFA increasing by 64.7 % and 24.8 %, respectively. The analysis of the mRNA level of key genes involved in lipid synthesis indicated that PPT1 overexpression enhances the flux of acyl-CoA towards FFA. This study reveals the mechanism by which PPT1 regulates lipid synthesis in oleaginous fungi through depalmitoylation, providing novel insights for engineering lipid metabolism.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1871 1","pages":"Article 159696"},"PeriodicalIF":3.3,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257274","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 : 2025-10-07DOI: 10.1016/j.bbalip.2025.159695
Masanori Honsho , Fabian Dorninger , Johannes Berger , Roshni R. Singaraja , Laia Trigueros-Motos , Yuichi Abe , Yukio Fujiki
In mammals, plasmalogens are enriched in the brain, kidney, and heart, while the lowest amounts of plasmalogens are found in the liver. The physiological significance of the low level of plasmalogens in the liver remains unknown. Here, we used alkylglycerol, a precursor that is readily converted to plasmalogen upon exogenous administration, to study the effects of elevated liver plasmalogens on fatty acyl-CoA reductase (FAR1), a rate-limiting enzyme in plasmalogen biosynthesis. Indeed, oral administration of alkylglycerol in wild-type mice augmented plasmalogen levels in the liver and resulted in reduced FAR1 protein levels. Vice versa, we determined increased FAR1 levels in mice with diminished plasmalogen levels due to a genetic defect in plasmalogen biosynthesis. Together, these findings suggest a role of FAR1-mediated regulation of plasmalogen biosynthesis in liver physiology. Further experiments indicated that elevation of plasmalogens in the liver of wild-type mice reduces the protein level of squalene epoxidase, and further suppresses a liver X receptor-mediated transcription of genes encoding ATP-binding cassette transporters such as Abca1, Abcg5, and Abcg8. In the livers of plasmalogen-deficient mice, the expression of Abca1 appears to be reduced due to the suppressed function of the nuclear receptor protein hepatocyte nuclear factor 4. These aberrant expression of transporters causes reduced levels of high-density lipoprotein cholesterol in plasma derived from wild-type mice administered alkylglycerol and plasmalogen synthesis-deficient mice. Taken together, the present results suggest that the homeostasis of plasmalogens, mediated by the regulation of FAR1 protein levels in the liver, plays a physiologically important role in the synthesis of high-density lipoprotein.
{"title":"Physiological role of plasmalogen homeostasis in the liver - A link to cholesterol metabolism","authors":"Masanori Honsho , Fabian Dorninger , Johannes Berger , Roshni R. Singaraja , Laia Trigueros-Motos , Yuichi Abe , Yukio Fujiki","doi":"10.1016/j.bbalip.2025.159695","DOIUrl":"10.1016/j.bbalip.2025.159695","url":null,"abstract":"<div><div>In mammals, plasmalogens are enriched in the brain, kidney, and heart, while the lowest amounts of plasmalogens are found in the liver. The physiological significance of the low level of plasmalogens in the liver remains unknown. Here, we used alkylglycerol, a precursor that is readily converted to plasmalogen upon exogenous administration, to study the effects of elevated liver plasmalogens on fatty acyl-CoA reductase (FAR1), a rate-limiting enzyme in plasmalogen biosynthesis. Indeed, oral administration of alkylglycerol in wild-type mice augmented plasmalogen levels in the liver and resulted in reduced FAR1 protein levels. Vice versa, we determined increased FAR1 levels in mice with diminished plasmalogen levels due to a genetic defect in plasmalogen biosynthesis. Together, these findings suggest a role of FAR1-mediated regulation of plasmalogen biosynthesis in liver physiology. Further experiments indicated that elevation of plasmalogens in the liver of wild-type mice reduces the protein level of squalene epoxidase, and further suppresses a liver X receptor-mediated transcription of genes encoding ATP-binding cassette transporters such as <em>Abca1</em>, <em>Abcg5</em>, and <em>Abcg8</em>. In the livers of plasmalogen-deficient mice, the expression of <em>Abca1</em> appears to be reduced due to the suppressed function of the nuclear receptor protein hepatocyte nuclear factor 4. These aberrant expression of transporters causes reduced levels of high-density lipoprotein cholesterol in plasma derived from wild-type mice administered alkylglycerol and plasmalogen synthesis-deficient mice. Taken together, the present results suggest that the homeostasis of plasmalogens, mediated by the regulation of FAR1 protein levels in the liver, plays a physiologically important role in the synthesis of high-density lipoprotein.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1871 1","pages":"Article 159695"},"PeriodicalIF":3.3,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249417","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 : 2025-10-06DOI: 10.1016/j.bbalip.2025.159694
P. Poursharifi , C. Schmitt , I. Chenier , Y.H. Leung , A.K. Oppong , Y. Bai , L.-L. Klein , L. Vilanou , A. Al-Mass , R. Lussier , M. Abu-Farha , J. Abubaker , F. Al-Mulla , É. Dumais , N. Flamand , N. Provost , C. Bernard , P. Delerive , M.-L. Peyot , S.R.M. Madiraju , M. Prentki
α/β-hydrolase domain-containing-6 (ABHD6) hydrolyzes various lipids, including monoacylglycerols (MAGs). Pharmacological inhibition of ABHD6 with WWL70 is anti-inflammatory in animal models. However, because of the multiple substrates of ABHD6 and the off-target effects of WWL70, the precise role of ABHD6 in inflammation remains to be clarified. Here, we investigated the role of ABHD6 in lipopolysaccharide (LPS)-mediated inflammatory response, employing a more specific ABHD6 inhibitor, KT203, and ABHD6-KO mice. ABHD6-KO mice showed lower susceptibility to LPS-mediated systemic endotoxemia. Inhibition by KT203 or deletion of ABHD6 in LPS-stressed macrophages reduced the pro-inflammatory and elevated the anti-inflammatory markers. In RAW 264.7 macrophages, KT203 reduced LPS-induced morphological changes, migration and cytokine release. In vivo, KT203 treatment of LPS-exposed wild-type mice markedly curtailed circulating TNF-α levels. Analysis of cellular and secreted bioactive lipids in the LPS-treated RAW 264.7 macrophages revealed that KT203 markedly elevated the levels of various lipid species, in particular secreted docosahexaenoic acid (DHA)-derived MAG (1/2-docosahexaenoylglycerol (DHG)) and DHA-containing N-acylethanolamines and oxylipins. We further observed that 1-DHG, 2-arachidonoylglycerol, docosahexaenoylethanolamide and 17-hydroxydocosahexaenoic acid showed anti-inflammatory effects and PPARα agonism in LPS-treated RAW 264.7 macrophages. The data suggest that ABHD6 suppression results in the accumulation of various bioactive lipids, in particular DHA-containing MAG, N-acylethanolamines and oxylipins, which activate PPARα signaling pathway to curtail the inflammatory response of macrophages to LPS. Overall, the findings provide evidence for a mechanism involving MAG and possibly other lipid species/PPARα signaling, for the anti-inflammatory effects of ABHD6 suppression during endotoxemia. Thus, the inhibition of ABHD6 is a promising approach to mitigate inflammation.
{"title":"ABHD6 suppression attenuates pro-inflammatory responses in mice and promotes anti-inflammatory polarization of macrophages during endotoxin stress","authors":"P. Poursharifi , C. Schmitt , I. Chenier , Y.H. Leung , A.K. Oppong , Y. Bai , L.-L. Klein , L. Vilanou , A. Al-Mass , R. Lussier , M. Abu-Farha , J. Abubaker , F. Al-Mulla , É. Dumais , N. Flamand , N. Provost , C. Bernard , P. Delerive , M.-L. Peyot , S.R.M. Madiraju , M. Prentki","doi":"10.1016/j.bbalip.2025.159694","DOIUrl":"10.1016/j.bbalip.2025.159694","url":null,"abstract":"<div><div>α/β-hydrolase domain-containing-6 (ABHD6) hydrolyzes various lipids, including monoacylglycerols (MAGs). Pharmacological inhibition of ABHD6 with WWL70 is anti-inflammatory in animal models. However, because of the multiple substrates of ABHD6 and the off-target effects of WWL70, the precise role of ABHD6 in inflammation remains to be clarified. Here, we investigated the role of ABHD6 in lipopolysaccharide (LPS)-mediated inflammatory response, employing a more specific ABHD6 inhibitor, KT203, and ABHD6-KO mice. ABHD6-KO mice showed lower susceptibility to LPS-mediated systemic endotoxemia. Inhibition by KT203 or deletion of ABHD6 in LPS-stressed macrophages reduced the pro-inflammatory and elevated the anti-inflammatory markers. In RAW 264.7 macrophages, KT203 reduced LPS-induced morphological changes, migration and cytokine release. <em>In vivo,</em> KT203 treatment of LPS-exposed wild-type mice markedly curtailed circulating TNF-α levels. Analysis of cellular and secreted bioactive lipids in the LPS-treated RAW 264.7 macrophages revealed that KT203 markedly elevated the levels of various lipid species, in particular secreted docosahexaenoic acid (DHA)-derived MAG (1/2-docosahexaenoylglycerol (DHG)) and DHA-containing <em>N</em>-acylethanolamines and oxylipins. We further observed that 1-DHG, 2-arachidonoylglycerol, docosahexaenoylethanolamide and 17-hydroxydocosahexaenoic acid showed anti-inflammatory effects and PPARα agonism in LPS-treated RAW 264.7 macrophages. The data suggest that ABHD6 suppression results in the accumulation of various bioactive lipids, in particular DHA-containing MAG, <em>N</em>-acylethanolamines and oxylipins, which activate PPARα signaling pathway to curtail the inflammatory response of macrophages to LPS. Overall, the findings provide evidence for a mechanism involving MAG and possibly other lipid species/PPARα signaling, for the anti-inflammatory effects of ABHD6 suppression during endotoxemia. Thus, the inhibition of ABHD6 is a promising approach to mitigate inflammation.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1871 1","pages":"Article 159694"},"PeriodicalIF":3.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249497","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 : 2025-10-03DOI: 10.1016/j.bbalip.2025.159692
Ruirui Dong , Gaoying Wang , Yingxian Shi , Jianyi Gao , Wen Hu , Ting Zhang
Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse fetal outcomes, while current biomarkers such as total bile acid remain suboptimal. This study aimed to identify novel biomarkers and clarify metabolic pathways underlying ICP through integrated metabolomic and proteomic analyses. Placental profiles were obtained from ICP model rats and healthy controls, with differential metabolites and proteins validated in human placental and serum samples. Multiomics integration revealed prominent dysregulation of lipid metabolism, particularly fatty acid degradation and biosynthesis, highlighting lipids as central players in ICP. Palmitic acid and acyl-CoA synthetase long chain family member 1 (ACSL1) were central to these pathways, markedly elevated in ICP, and showed high diagnostic value (area under the curve 0.794 and 0.825), with combined detection reaching 0.894. Both markers also stratified patients by disease severity, suggesting their potential use for disease monitoring and risk classification. Moreover, ferroptosis was implicated in ICP pathophysiology, supported by validations in both patient placental tissues and taurocholic acid (TCA)-treated trophoblast cells, showing reduced glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) together with increased six-transmembrane epithelial antigen of prostate 3 (STEAP3), transferrin receptor protein 1 (CD71), and acyl-CoA synthetase long-chain family member 4 (ACSL4). In summary, palmitic acid and ACSL1 represent promising biomarkers for ICP diagnosis and classification, while ferroptosis contributes to ICP-related placental dysfunction. These findings provide comprehensive evidence linking altered lipid metabolism and ferroptosis to ICP, offering new insights for clinical diagnosis and potential therapeutic strategies.
{"title":"Integrated proteomic and metabolomic analysis reveals lipid metabolic dysregulation and ferroptosis as potential drivers of placental dysfunction in intrahepatic cholestasis of pregnancy","authors":"Ruirui Dong , Gaoying Wang , Yingxian Shi , Jianyi Gao , Wen Hu , Ting Zhang","doi":"10.1016/j.bbalip.2025.159692","DOIUrl":"10.1016/j.bbalip.2025.159692","url":null,"abstract":"<div><div>Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse fetal outcomes, while current biomarkers such as total bile acid remain suboptimal. This study aimed to identify novel biomarkers and clarify metabolic pathways underlying ICP through integrated metabolomic and proteomic analyses. Placental profiles were obtained from ICP model rats and healthy controls, with differential metabolites and proteins validated in human placental and serum samples. Multiomics integration revealed prominent dysregulation of lipid metabolism, particularly fatty acid degradation and biosynthesis, highlighting lipids as central players in ICP. Palmitic acid and acyl-CoA synthetase long chain family member 1 (ACSL1) were central to these pathways, markedly elevated in ICP, and showed high diagnostic value (area under the curve 0.794 and 0.825), with combined detection reaching 0.894. Both markers also stratified patients by disease severity, suggesting their potential use for disease monitoring and risk classification. Moreover, ferroptosis was implicated in ICP pathophysiology, supported by validations in both patient placental tissues and taurocholic acid (TCA)-treated trophoblast cells, showing reduced glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) together with increased six-transmembrane epithelial antigen of prostate 3 (STEAP3), transferrin receptor protein 1 (CD71), and acyl-CoA synthetase long-chain family member 4 (ACSL4). In summary, palmitic acid and ACSL1 represent promising biomarkers for ICP diagnosis and classification, while ferroptosis contributes to ICP-related placental dysfunction. These findings provide comprehensive evidence linking altered lipid metabolism and ferroptosis to ICP, offering new insights for clinical diagnosis and potential therapeutic strategies.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1871 1","pages":"Article 159692"},"PeriodicalIF":3.3,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145227671","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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