Journal of Lipid Research最新文献

{"title":"Cardiac lipid droplets differ under pathological and physiological conditions.","authors":"Ni-Huiping Son, Sunny Son, Michael Verano, Zhen-Xiu Liu, Waqas Younis, Makenzie Komack, Kelly V Ruggles, Jana Gjini, Song-Tao Tang, Ainara Gonzalez Cabodevilla, Feng-Xia Liang, Hai-Zhen Wang, Dimitrios Nasias, José O Alemán, Ira J Goldberg","doi":"10.1016/j.jlr.2025.100920","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100920","url":null,"abstract":"<p><p>Excessive accumulation of lipids within cardiomyocytes can sometimes initiate cardiomyopathy, while in other situations excess lipids do not cause harm. To understand how pathologic and non-pathologic lipid accumulation differ, we isolated lipid droplets (LDs) from two genetically altered mouse lines and from wild-type (WT) mice after an overnight fast. The LDs from MHC-peroxisomal proliferator-activated receptor γ1(MHC-Pparg1) transgenic mice were 3-fold larger than those from either fasted WT or non-cardiomyopathy MHC-diacylglycerol acyl transferase 1 (MHC-Dgat1) transgenic mice. Proteomic analysis of the LD associated membrane proteins (LDAMPs) showed that MHC-Pparg1 LDs had less perilipin (Plin). Proteins associated with lipolysis and LD formation (CIDEs and MTP), lipid synthesis, and Pparg signaling pathways were increased in MHC-Pparg1 LDAMPs. Unlike in MHC-Pparg1, MHC-Dgat1 LDAMPs exhibited increased mitochondrial peroxidative proteins with reduced adipose triglyceride lipase (Pnpla2), and Pparg coactivator 1 alpha (Pgc1A). Cardiomyocytes from MHC-Pparg1 hearts had transmission electron microscopy (TEM) images of ongoing lipolysis and greater amounts of lipolytic proteins. In contrast, images from MHC-Dgat1 cardiomyocytes showed more lipophagy. Consistent with the proteomic study and EM images, cardiac immunofluorescence staining showed that Plin 5 protein, thought to block LD lipolysis, was markedly reduced with MHC-Pparg1 overexpression, while hormone sensitive lipase was increased. The autophagosome marker protein LC3B was increased in MHC-Dgat1 but not in MHC-Pparg1 hearts. Potentially toxic lipids like diacylglycerols and ceramides were increased in hearts but not LDs from MHC-Pparg1 mice. Our data indicates that cardiomyocyte LDs vary in size, composition, and metabolism. Cardiotoxicity was associated with greater LD lipolysis, which we postulate leads to intracellular release of toxic lipids.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100920"},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective Agonism of Liver and Gut FXR Prevents Cholestasis and Intestinal Atrophy in Parenterally Fed Neonatal Pigs.","authors":"Yanjun Jiang, Zhengfeng Fang, Gregory Guthrie, Barbara Stoll, Shaji Chacko, Sen Lin, Bolette Hartmann, Jens J Holst, Harry Dawson, Jose J Pastor, Ignacio R Ipharraguerre, Douglas G Burrin","doi":"10.1016/j.jlr.2025.100919","DOIUrl":"10.1016/j.jlr.2025.100919","url":null,"abstract":"<p><p>We aimed to investigate the relative efficacy of feeding different bile acids in preventing PNALD in neonatal pigs. Newborn pigs given total parenteral nutrition (TPN) combined with minimal enteral feeding of chenodeoxycholic acid (CDCA), or increasing doses of obeticholic acid (OCA) for 19 days. Enteral OCA (5 and 15 mg/kg), but not CDCA (30 mg/kg) reduced blood cholestasis markers compared to TPN controls and increased bile acids in the gallbladder and intestine. Major bile acids in the liver and distal intestine were CDCA, HCA, HDCA and OCA, and their relative proportions were increased by the type of bile acid (CDCA or OCA) given enterally. High doses of OCA increased the total NR1H4-agonistic bile acid profile in the liver and intestine above 50% total bile acids. Both CDCA and OCA treatments suppressed hepatic cyp7a1 expression, but only OCA increased hepatobiliary transporters, ABCB11, ABCC4 and ABCB1. Plasma phytosterol levels were reduced and biliary levels were increased by CDCA and OCA and hepatic sterol transporters, abcg5/8, expression were increased by OCA. Both CDCA and OCA increased plasma FGF19 and OCA increased intestinal FGF19, FABP6, and SLC51A. Both CDCA and OCA increased intestinal mucosal growth, whereas CDCA increased the plasma GLP-2, GLP-1 and GIP. Enteral OCA prevented cholestasis and phytosterolemia by increased hepatic bile acid and sterol transport via induction of hepatobiliary transporter NR1H4 target genes and not by suppression of bile acid synthesis genes. We also showed an intestinal trophic action of OCA that demonstrates a dual clinical benefit of NR1H4 agonism in the prevention of PNALD in pigs.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100919"},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apolipoprotein A5 Reduces Clearance of Very Low-density Lipoprotein by Altering Apolipoprotein E Content.","authors":"Pheruza Tarapore, Debi Swertfeger, Jamie Morris, Yi He, Snigdha Sarkar, John T Melchior, Amy S Shah, Min Liu, W Sean Davidson","doi":"10.1016/j.jlr.2025.100917","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100917","url":null,"abstract":"<p><p>Apolipoprotein A-V (APOA5) is a critical regulator of circulating triglyceride (TG) levels. Its deletion leads to elevated plasma TG concentrations by altering the metabolism of very low-density lipoprotein (VLDL) particles in vivo. One way APOA5 exerts its effects is through modulation of lipoprotein lipase (LPL) activity, specifically by disrupting inhibitory interactions between LPL and angiopoietin-like proteins (ANGPTLs). However, the impact of APOA5 on VLDL composition and its potential to alter VLDL metabolism in other ways remains poorly understood. To address this, we investigated the influence of APOA5 on the VLDL proteome, LPL activation, and hepatic remnant uptake. Using VLDL from Apoa5 knockout (KO) and wild-type (WT) mice, we found no evidence that APOA5 directly enhances LPL activity in purified or plasma systems. However, VLDL from Apoa5 KO mice was cleared significantly more slowly by cultured hepatocytes. VLDL proteomics experiments from two independent laboratories identified altered contents of 23 proteins involved in lipoprotein metabolism, inflammation, and immune response in Apoa5 KO VLDL, including reductions in APOE and serum amyloid A1 (SAA1). Remarkably, reintroduction of recombinant mouse APOA5 to the KO plasma partially restored the WT VLDL proteome, including APOE, and normalized VLDL uptake by hepatocytes without altering LPL lipolysis. These findings reveal that APOA5 influences hepatic clearance of VLDL remnants by modulating particle composition, particularly APOE content. This study expands the functional scope of APOA5 in TG metabolism and underscores its role in VLDL remodeling and remnant clearance, offering new insights with implications for understanding hypertriglyceridemia and its roles in inflammation and immune response.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100917"},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma oxylipin profiling reveals the step-wise activation of ARA/5-HETE metabolism in diabetic kidney disease.","authors":"Chunyu Zhou, Xianhui Liang, Jiao Wang, Jia Guo, Qing Zhang, Pei Wang","doi":"10.1016/j.jlr.2025.100918","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100918","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is a highly prevalent complication of diabetes concomitant with disordered oxylipin metabolism. Our study characterize the plasma oxylipins associated with the step-wise progression of DKD. An ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was performed to quantify 141 kinds of oxylipins in plasma samples of patients with DKD or T2DM and healthy individuals, both in the test cohort (n=40 for each group) and the validation cohort (n=20 for each group). The key oxylipins associated with DKD were identified by orthogonal partial least-squares discriminant analysis (OPLS-DA) and receiver-operating characteristic (ROC) curve. Polynomial regression, Pearson's correlation and logistic regression analyses were performed to assess their correlation with the clinical indicators reflecting DKD progression, as well as their diagnostic abilities. Our oxylipin profiling presented the significant alterations of 55 kinds in the test cohort and 42 kinds in the validation cohort. ARA, 5-HETE, 5-oxoETE, 12-HETE and 13(S)-HpODE in the test cohort, as well as ARA, 5-HETE, 5-oxoETE, 20-hydroxyPGF2α and 8,9-EET in the validation cohort were screened as the key oxylipins distinguishing DKD group. The increased plasma levels of ARA, 5-HETE and 5-oxoETE were strongly correlated with estimated glomerular filtration rate (eGFR). The diagnostic model combining the plasma levels of ARA, 5-HETE and 5-oxoETE indicated an excellent diagnostic performance for DKD. Collectively, our study disclosed the profiling of oxylipin metabolism, implicating the activation of ARA/5-HETE metabolism associated with the step-wise progression of DKD, which provide the basis for early identification and therapeutic strategies for DKD.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100918"},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare skin disease helps uncover mechanisms of acyl ceramide biosynthesis.","authors":"Susanne Tollinger, Daniela Ortner, Thomas Trafoier, Verena Moosbrugger-Martinz, Robert Gruber, Matthias Schmuth","doi":"10.1016/j.jlr.2025.100916","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100916","url":null,"abstract":"","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100916"},"PeriodicalIF":4.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"1-Linoleoylglycerophosphocholine stimulates UCP1-dependent thermogenesis and mitochondrial respiration to combat obesity.","authors":"Rui Wang, Tianfu Zhu, Jingxian Lu, Mengke Cheng, Xingyun Wang, Xirong Guo, Shan Huang, Jianfang Gao","doi":"10.1016/j.jlr.2025.100914","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100914","url":null,"abstract":"<p><p>Obesity leads to numerous illnesses and metabolic disorders, with lysophosphatidylcholine (LPC) levels declining in obese patients. However, the physiological role of LPC and the regulatory mechanisms involved in modulating obesity remain largely unknown. Here, we provide evidence that 1-linoleoylglycerophosphocholine (1-LGPC) promotes adipocyte energy expenditure by activating the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (KEAP1-NRF2) axis. Metabolomic analyses identified 1-LGPC as a characteristic metabolite that declined in the peripheral blood of obese patients. Treatment with 1-LGPC effectively alleviated high-fat diet-induced lipid accumulation in zebrafish larvae and human adipocytes. Elevated expression levels, increased oxygen consumption rates, and enhanced transcript levels indicated that uncoupling protein 1-dependent thermogenesis and mitochondrial respiration were significantly boosted. Furthermore, NRF2 expression and nuclear translocation were induced by 1-LGPC, and NRF2 inhibition triggered UCP1 downregulation and lipid accumulation restoration, confirming the KEAP1-NRF2 axis's involvement in 1-LGPC-induced energy expenditure. These findings offer preliminary insights into physiological roles and mechanisms by which 1-LGPC modulates lipid and energy metabolism, providing potential strategies for obesity intervention using clinically identified compounds.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100914"},"PeriodicalIF":4.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary phospholipid carriers of DHA do not increase brain DHA levels: A replication study.","authors":"Brinley J Klievik, Yan Fu, Aidan D Tyrrell, Chuck T Chen, Adam H Metherel, Richard P Bazinet","doi":"10.1016/j.jlr.2025.100913","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100913","url":null,"abstract":"<p><p>DHA is primarily found in fish and seafood as triacylglycerides (TAG) and phospholipids (PL). Oral administration of PL DHA forms, sn-1 lysophosphatidylcholine-DHA (sn-1 LPC-DHA), and di-DHA phosphatidylcholine (di-DHA-PC) have been suggested to increase brain DHA levels by 100% (relative percent) and up to 500% (concentration) compared to controls. In contrast, TAG-DHA and non-esterified (NE)-DHA do not produce increases in brain DHA when provided in the diet. However, a subsequent study using a higher dose of sn-1 LPC-DHA did not confirm these findings and reported no significant increase in brain DHA. To address these inconsistencies, we aimed to replicate previous investigations of PL-DHA forms (LPC and PC) and their impact on brain DHA levels. Mice were randomly divided into one of four groups and received a daily gavage for 30 days of 80 μL of either corn oil alone (control) or corn oil containing 1mg of DHA as NE-DHA, sn-1 LPC-DHA, or di-DHA-PC. DHA relative percent and concentrations were determined in brain regions (cortex, cerebellum, hippocampus, amygdala, striatum, remainder of brain) and plasma using gas chromatography-flame ionization detection. Following treatment, no significant differences in DHA percent or concentration were observed between control and/or treatment groups in any brain region. Relative percent of plasma DHA was significantly elevated in all DHA-treated groups compared to the control group, confirming systemic absorption of the supplemented DHA. Our results demonstrate that dietary DHA provided as sn-1 LPC-DHA or di-DHA-PC does not increase brain DHA levels compared to NE-DHA or the control group, failing to reproduce prior reports.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100913"},"PeriodicalIF":4.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial lipidomics reveals demyelination and remyelination dynamics in the mouse brain.","authors":"Mikolaj Opielka, Krzysztof Urbanowicz, Klaudia Konieczna-Wolska, Elisabeth Müller, Oliwier Krajewski, Maureen Feucherolles, Qiuqin Zhou, Michal Bienkowski, Gilles Frache, Carsten Hopf, Lucas Schirmer, Aleksandra Rutkowska, Ryszard T Smolenski","doi":"10.1016/j.jlr.2025.100912","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100912","url":null,"abstract":"<p><p>Myelin pathology in demyelinating diseases is accompanied by lipid remodeling that remains challenging to characterize at spatial level using traditional mass spectrometry. We developed an optimized AP-MALDI-Orbitrap MSI pipeline, incorporating sample preparation improvements and mass recalibration, to investigate lipid dynamics in the cuprizone (CPZ) mouse model of demyelination. Dual-modality, untargeted lipid profiling was performed to map spatially resolved lipid alterations during demyelination and spontaneous remyelination in two key brain areas of male mice: corpus callosum (CC) and cortex (Ctx), with lipid identifications benchmarked against 4D-LC-TIMS-MS/MS. Demyelinated regions were identified using Black Gold II staining. Using 1 ppm mass tolerance, we annotated 154 and 133 lipids at the sum-composition level in CC and Ctx, respectively, with 60% validated by LC-MS/MS. Spatial lipid profiling revealed CPZ-induced alterations in sphingolipids, sulfatides, and glycerophospholipids, supported by reanalysis of a published snRNA-seq dataset from a mouse CPZ model. Long-chain ceramides (Cer) and hexosylceramides (HexCer) were reduced in demyelinated regions, with partial, region-specific recovery during remyelination. Short-chain sulfatides (SHexCer), sphingomyelins (SM) and seminolipids transiently increased in the CC during demyelination, while long-chain sulfatides decreased in both CC and Ctx. Additionally, we observed demyelination-induced upregulation of polyunsaturated glycerophospholipids in CC and phosphatidylinositols (PI) in cortex. Lipid subclass changes emerged as reliable markers of both demyelination and remyelination in the mouse brain. Region-specific alterations in lipid metabolism provide new insights into the processes of de- and remyelination. Notably, remyelinated fibers have a distinct lipid profile compared to intact myelin, suggesting that lipid-based therapeutic strategies could improve myelin repair.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100912"},"PeriodicalIF":4.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial cardiolipin remodeling facilitates efficient myoblast differentiation.","authors":"Yohsuke Ohba, Chinami Fujiwara, Makoto Arita","doi":"10.1016/j.jlr.2025.100909","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100909","url":null,"abstract":"<p><p>During myoblast differentiation, mitochondria undergo dynamic changes in their morphology and function. Although the mitochondrial membrane lipid environment is closely related to mitochondrial integrity, how mitochondrial lipid composition changes during myoblast differentiation and whether it is involved in efficient differentiation remains unclear. In this study, we applied LC-MS/MS-based untargeted lipidomics to the mitochondria isolated from C2C12 murine myoblasts and found that the proportion of linoleic acid (C18:2)-containing cardiolipin (CL) increased during the early stages of differentiation. In parallel, the expression of tafazzin, a mitochondrial CL remodeling enzyme, increased in line with myoblast differentiation. Notably, the increase in C18:2-containing CL was not suppressed by the knockdown of MyoD, a master transcription factor for myoblast differentiation. In contrast, the inhibition of CL biosynthesis and remodeling significantly suppressed differentiation progression, which was partially rescued by exogenous supplementation with C18:2. Similar trends in CL remodeling were observed when primary stem cells isolated from mouse skeletal muscle differentiated into myotubes. These results demonstrate that mitochondrial CL remodeling at an early stage is required to promote efficient myoblast differentiation.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100909"},"PeriodicalIF":4.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphingomyelin Synthase Related Protein Is a Regulator of Serine Palmitoyltransferase.","authors":"Xiang Li, Zhiqiang Li, Yeun-Po Chiang, Tilla Worgall, Tade Souaiaia, Xian-Cheng Jiang","doi":"10.1016/j.jlr.2025.100908","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100908","url":null,"abstract":"<p><p>Sphingomyelin synthase related protein (SMSr) belongs to SMS family, however, it cannot synthesize SM. We reported that SMSr is a phosphatidylethanolamine-specific phospholipase C which is associated with metabolic dysfunction-associated fatty liver disease (MAFLD). However, the mechanism is unknown. Based on hierarchical clustering of the samples from human Genotype-Tissue Expression project, we found that SMSr and serine palmitoyltransferase (SPT), the key enzyme for sphingolipid biosynthesis, as well as certain sphingolipid metabolism related genes belong to the same co-expression cluster in the liver and adipose tissues. We also found that Smsr expression is positively associated with Sptlc1 and Sptlc2 expression in both tissues of both genders. In mouse study, we found that Smsr overexpression induced while Smsr knockout (KO) (under a high fat diet) reduced SPT activity, thus, influencing most of tested sphingolipids. Further, we found that PE treatment reversed Smsr overexpression-mediated SPTLC2 upregulation. PE supplement also reduced liver microsome SPT activity in a dose-dependent manner. Furthermore, we demonstrated that SMSr interacts with SPTLC2 in vivo. Thus, SMSr, as a member in sphingolipid biosynthesis pathway, regulates SPT. Perturbation of SPT activity has been linked to the prevention of MAFLD and cardiovascular diseases. However, the approach to finding a SPT-specific inhibitor, as a drug, has not been successful so far. Importantly, global Smsr KO mice are viable and healthy; therefore, inhibiting SPT activity by reducing PE, mediated by SMSr/PE-PLC activity, could provide a novel approach for preventing and treating MAFLD.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100908"},"PeriodicalIF":4.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}