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

{"title":"Functional analysis and regulation mechanism of FGF19 on lipid metabolism in liver of large yellow croaker (Larimichthys crocea)","authors":"Jianlong Du ,&nbsp;Yuning Sun ,&nbsp;Jinze Zhang ,&nbsp;Wei Xu ,&nbsp;Kangsen Mai ,&nbsp;Qinghui Ai","doi":"10.1016/j.bbalip.2025.159700","DOIUrl":"10.1016/j.bbalip.2025.159700","url":null,"abstract":"<div><div>Fibroblast growth factor 19 (FGF19) is a key intestinally secreted factor in mammals, its physiological role in teleost remains largely unclear. This study aimed to investigate the function and underlying mechanisms of FGF19 in the regulation of lipid metabolism in large yellow croaker. Results revealed that FGF19 was predominantly expressed in the liver. Treatment with recombinant FGF19 protein significantly reduced triglyceride (TG) levels in hepatocytes in a dose-dependent manner. Both <em>in vitro</em> treatment and <em>in vivo</em> injection of FGF19 significantly downregulated lipogenic genes and upregulated lipolytic genes expression in hepatocytes and liver tissue. Further investigation demonstrated that FGFR1 inhibition attenuated the TG-lowering effects of FGF19 and reversed the suppression of lipogenic gene expression. Additionally, FGF19 treatment enhanced the phosphorylation of ERK, P38, AMPK, and AKT. Inhibition of P38, AMPK, or AKT significantly increased triglyceride levels which were reduced by FGF19. Inhibition of ERK, P38, and AKT impaired the FGF19-mediated regulation of lipolysis-related genes, whereas AMPK inhibition predominantly affected the regulation of lipogenic genes. Moreover, results showed that high linoleic acid (LA) intake induced endoplasmic reticulum stress and elevated expression of FGF19. The expression of XBP1s protein was significantly increased by LA treatment, while co-expression of XBP1s significantly induced the promoter activity of FGF19. In summary, these results suggest that FGF19 is primarily expressed in the liver and plays a crucial role in regulating lipid metabolism to prevent excessive lipid accumulation in large yellow croaker, while high LA intake can increase FGF19 expression through ER stress-induced XBP1s. This study will enhance the understanding of FGF19 in lipid metabolism, offering insights into the evolution of these processes in vertebrates.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1871 1","pages":"Article 159700"},"PeriodicalIF":3.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145480691","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":"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 ,&nbsp;Gaoying Wang ,&nbsp;Yingxian Shi ,&nbsp;Jianyi Gao ,&nbsp;Wen Hu ,&nbsp;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":"2026-01-01","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}

{"title":"ATGL-mediated lipolysis is essential for myocellular mitochondrial function, mitochondria-lipid droplet interaction and mitochondrial network connectivity","authors":"Anne Gemmink ,&nbsp;Tineke van de Weijer ,&nbsp;Gert Schaart ,&nbsp;Gernot F. Grabner ,&nbsp;Esther Kornips ,&nbsp;Kèvin Knoops ,&nbsp;Rudolf Zechner ,&nbsp;Martina Schweiger ,&nbsp;Matthijs K.C. Hesselink","doi":"10.1016/j.bbalip.2025.159703","DOIUrl":"10.1016/j.bbalip.2025.159703","url":null,"abstract":"<div><div>Defects in Adipose tissue TriGlyceride Lipase (ATGL)-mediated myocellular lipid droplet (LD) lipolysis results in mitochondrial dysfunction of unknown origin, which can be rescued by PPAR agonists. Here we examine if ATGL-mediated lipolysis is required to maintain mitochondrial network connectivity and function. Moreover, we explored if the functional implications of ATGL deficiency for mitochondrial network dynamics and function can be alleviated by promoting PPARα and/or PPARδ transcriptional activity. To this end, we cultured human primary myotubes from patients with neutral lipid storage disease with myopathy (NLSDM), a rare metabolic disorder caused by a mutation in the gene encoding for ATGL. These myotubes possess dysfunctional ATGL and compromised LD lipolysis. In addition, mitochondria-LD contact, mitochondrial network connectivity, and mitochondrial membrane potential were affected. Using a humanized ATGL inhibitor in myotubes (cultured form healthy donors) revealed similar results. Upon stimulating PPARδ transcriptional activity, mitochondrial respiration improved by more than 50 % in human primary myotubes from healthy lean individuals. This increase in respiration was dampened in myotubes with dysfunctional ATGL. Stimulation of PPARδ transcriptional activity had no effect on mitochondria-LD contacts, mitochondrial network connectivity, and mitochondrial membrane potential. Our results demonstrate that dysfunctional ATGL results in compromised mitochondrial-LD contacts and mitochondrial network connectivity, and that functional ATGL is required to improve mitochondrial respiratory capacity upon stimulation of PPARδ transcriptional activity.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1871 1","pages":"Article 159703"},"PeriodicalIF":3.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145501933","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":"Melatonin ameliorates ox-LDL-induced lipid accumulation and enhances ABCA1 expression in VSMCs via inhibition of the TRPV1-Ca2+-calpain signaling pathway","authors":"Yuehong Tang ,&nbsp;Yujiao Peng ,&nbsp;Yaling Zhang ,&nbsp;Wenjuan Tong ,&nbsp;Shaowei Sun","doi":"10.1016/j.bbalip.2025.159704","DOIUrl":"10.1016/j.bbalip.2025.159704","url":null,"abstract":"<div><div>Oxidized low-density lipoprotein (ox-LDL) has been shown to induce significant lipid accumulation and disrupt cholesterol homeostasis in vascular smooth muscle cells (VSMCs), which may contribute to the development of atherosclerosis (AS). In this study, we investigated the effects of ox-LDL on lipid accumulation, and the expression of key proteins involved in cholesterol transport, such as ATP-binding cassette transporter A family member 1 (ABCA1). Our results demonstrated that ox-LDL treatment led to a concentration-dependent increase in intracellular lipid content, as evidenced by Oil Red O and BODIPY staining. Additionally, ox-LDL elevated intracellular calcium (Ca²⁺) levels and activated the Ca²⁺-Calpain signaling pathway, which in turn suppressed the expression of ABCA1, a critical protein responsible for cholesterol efflux. We further explored the therapeutic potential of melatonin (MLT) in mitigating the harmful effects of ox-LDL. Treatment with MLT significantly improved cell viability and reduced lipid accumulation in VSMC. Moreover, MLT, along with specific inhibitors of the TRPV1-Ca²⁺-Calpain pathway (Capsazepine, EGTA, and Calpeptin), successfully lowered intracellular Ca²⁺ levels and calpain activity, while restoring ABCA1 expression at protein levels but not mRNA. These findings suggest that MLT exerts a protective effect by inhibiting the TRPV1-Ca²⁺-Calpain signaling pathway, thereby promoting cholesterol efflux and reducing lipid accumulation in VSMCs. To validate these findings in vivo, ApoE^−/− mice were fed a high-fat diet (HFD) for 12 weeks to induce atherosclerotic lesions, with MLT administered via intraperitoneal injection during the final 6 weeks. Histological analyses of the aortic root revealed that MLT treatment significantly reduced atherosclerotic plaque areas compared to untreated HFD-fed mice. Furthermore, Western blot analyses demonstrated that MLT increased ABCA1 expression and decreased TRPV1 expression in aortic tissues, aligning with our in vitro observations. In conclusion, our study highlights the role of the TRPV1-Ca²⁺-Calpain signaling pathway in ox-LDL-induced lipid dysregulation and identifies MLT as a potential therapeutic agent for reversing these effects, offering new insights into the molecular mechanisms underlying lipid accumulation in VSMCs.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1871 1","pages":"Article 159704"},"PeriodicalIF":3.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487656","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":"Decoding class II PI3K signaling: From membrane identity to human disease","authors":"Roberta Rubino ,&nbsp;Gabriele Squillero ,&nbsp;Lorenzo Prever ,&nbsp;Emanuele Fantastico,&nbsp;Maria Chiara De Santis,&nbsp;Arezou Kahnamouei,&nbsp;Federico Gulluni,&nbsp;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)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.</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":"2026-01-01","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}

{"title":"Induction of lipid autophagy by chitosan-coated selenium nanoparticles mitigates NAFLD in vitro and in vivo","authors":"Yanqiu Zhu ,&nbsp;Yihan Wang ,&nbsp;Chenglong Xia ,&nbsp;Yi Yan ,&nbsp;Rui Du ,&nbsp;Tingting Yang ,&nbsp;Lin Jing ,&nbsp;Yanbing Lou ,&nbsp;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":"2026-01-01","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}

{"title":"Sphinganine-induced lysosomal membrane permeabilization: Interplay with subcellular oxidative levels","authors":"Guodong Cheng ,&nbsp;Changxi Qi ,&nbsp;Huiling Xu ,&nbsp;Xiaozhou Wang ,&nbsp;Muzi Li ,&nbsp;Huahua Chen ,&nbsp;Pimiao Zheng ,&nbsp;Yongxia Liu ,&nbsp;Jianzhu Liu ,&nbsp;Xiaona Zhao","doi":"10.1016/j.bbalip.2025.159705","DOIUrl":"10.1016/j.bbalip.2025.159705","url":null,"abstract":"<div><div>Sphinganine (SA), a fundamental sphingolipid whose cytotoxicity remains incompletely characterized, has received less attention compared to other sphingoid bases. Here, we demonstrate that SA predominantly triggers cell death via lysosomal membrane permeabilization (LMP) resulting from pH dysregulation and osmotic imbalance, rather than through direct ROS-mediated mechanisms, although mitochondrial ROS contribute to oxidative stress. SA-induced mitochondrial fragmentation significantly increased hydrogen peroxide levels in both the mitochondrial matrix and intermembrane space (IMS). Strikingly, lysosomes exhibited spatial colocalization with elevated hydrogen peroxide microdomains under SA exposure, suggesting a redox-dependent mechanism governing organelle repositioning. The cysteine protease inhibitor E64D attenuated SA-induced apoptosis through suppressing cathepsin B/L release, confirming lysosomal membrane permeabilization as an executor of apoptotic signaling. These findings unveil SA's dual-targeting organelle toxicity mechanism. Our study not only elucidates key aspects of sphingolipid-mediated cytotoxicity but also provides therapeutic rationale for counteracting fumonisin B1 (FB1)-induced pathologies and related sphingolipid disorders, potentially through lysosomal stabilization or targeted ROS modulation.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1871 1","pages":"Article 159705"},"PeriodicalIF":3.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487152","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":"Physiological role of plasmalogen homeostasis in the liver - A link to cholesterol metabolism","authors":"Masanori Honsho ,&nbsp;Fabian Dorninger ,&nbsp;Johannes Berger ,&nbsp;Roshni R. Singaraja ,&nbsp;Laia Trigueros-Motos ,&nbsp;Yuichi Abe ,&nbsp;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":"2026-01-01","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}

{"title":"Generation and characterization of a mouse model for bile salt export pump deficiency with the p.E297G mutation","authors":"Antonia Felzen ,&nbsp;Willemien F.J. Hof ,&nbsp;Hilde de Vries ,&nbsp;Milaine V. Hovingh ,&nbsp;Rick Havinga ,&nbsp;Niels L. Mulder ,&nbsp;Martijn Koehorst ,&nbsp;Niels Kloosterhuis ,&nbsp;Marieke Smit ,&nbsp;Nicolette Huijkman ,&nbsp;Bart van de Sluis ,&nbsp;Jan Freark de Boer ,&nbsp;Folkert Kuipers ,&nbsp;Henkjan J. Verkade","doi":"10.1016/j.bbalip.2025.159697","DOIUrl":"10.1016/j.bbalip.2025.159697","url":null,"abstract":"<div><h3>Background &amp; 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^E297G) mouse model to evaluate interventions to improve residual BSEP function.</div></div><div><h3>Methods</h3><div>We generated BSEP^E297G mice by CRISPR-Cas9 technology. BSEP^E297G 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^E297G and BSEP⁻^/⁻ mice.</div></div><div><h3>Results</h3><div>Western blot analysis showed immature BSEP protein in BSEP^E297G livers. Median plasma AST was three-fold higher in BSEP^E297G mice (Males: 198 vs. 60 U/L; Females: 188 vs. 50 U/L; each <em>p</em> &lt; 0.001) while plasma bile acid levels were higher in female BSEP^E297G mice compared to WT (Females: 36 vs. 6 μM, <em>p</em> &lt; 0.001; Males: 11 vs. 3 μM, <em>p</em> = 0.07). Histological analysis revealed features of cholestatic liver pathology in BSEP^E297G mice. TUDCA infusion strongly increased biliary bile acid secretion in WT but not in BSEP^E297G and BSEP⁻^/⁻ mice. 4-PB treatment did not enhance bile acid transport capacity in BSEP^E297G mice.</div></div><div><h3>Conclusions</h3><div>BSEP^E297G 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":"2026-01-01","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}

{"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 ,&nbsp;Marta Villoslada-González ,&nbsp;Carmen Hevia-Lorenzo ,&nbsp;Jesús Pérez-Gil ,&nbsp;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":"2025-12-01","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}