Journal of Lipid Research最新文献

{"title":"Global deletion of COX-2 attenuates hepatic inflammation but impairs metabolic homeostasis in diet-induced obesity.","authors":"Jeyakumar Balakrishnan, Cyrus Desouza, Rishikesh Thakare, Yazen Alnouti, Viswanathan Saraswathi","doi":"10.1016/j.jlr.2025.100823","DOIUrl":"10.1016/j.jlr.2025.100823","url":null,"abstract":"<p><p>The role of cyclooxygenase-2 (COX-2), a well-known pharmacological target for attenuating inflammation, in regulating obesity and its comorbidities remains unclear. We sought to determine the role of COX-2 in modulating metabolic inflammation and systemic metabolic homeostasis in obesity. Male WT and COX-2 KO mice were fed a chow diet or a high fat diet (HF, 45% fat) for 13 weeks. While the body weight gain did not alter, the visceral adipose tissue mass was significantly higher in KO-HF mice than in WT-HF mice. Plasma triglycerides and total cholesterol levels were higher in KO-HF mice than in WT-HF mice. Total body fat mass was higher with a concomitant reduction in lean mass in KO-HF mice than in WT-HF mice. Paradoxically, hepatic steatosis was reduced in KO-HF mice. While liver triglycerides were reduced, the liver cholesterol was increased in KO-HF mice. Bile acids and markers of cholesterol biosynthesis were unaltered between WT-HF and KO-HF groups. The mRNA and/or protein levels of autophagy markers were significantly decreased in KO-HF mice compared to WT-HF mice, indicating that a reduction in autophagy may increase cholesterol levels in these mice. The liver inflammatory markers were significantly increased only in WT mice fed a HF diet but not in KO-HF fed mice compared to their respective controls. Visceral adipose tissue showed a reduction in inflammatory markers in spite of an increase in adiposity. These data suggest that despite being effective in attenuating the inflammatory processes, inhibition of COX-2 exerts undesirable consequences on metabolic homeostasis.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100823"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stearoyl-CoA desaturase 1 deficiency drives saturated lipid accumulation and increases liver and plasma acylcarnitines.","authors":"Mugagga Kalyesubula, Helaina Von Bank, Jessica W Davidson, Maggie S Burhans, Madelaine M Becker, Ahmed Aljohani, Judith Simcox, James M Ntambi","doi":"10.1016/j.jlr.2025.100824","DOIUrl":"10.1016/j.jlr.2025.100824","url":null,"abstract":"<p><p>Stearoyl-CoA desaturase-1 (SCD1) is a critical regulator of lipogenesis that catalyzes the synthesis of MUFAs, mainly oleate (18:1n-9) and palmitoleate (16:1n-7) from saturated fatty acids, stearoyl-CoA (18:0) and palmitoyl-CoA (16:0), respectively. Elevated SCD1 expression and its products are associated with obesity, metabolic dysfunction-associated steatotic liver disease, insulin resistance, and cancer. Conversely, Scd1 deficiency diminishes de novo lipogenesis and protects mice against adiposity, hepatic steatosis, and hyperglycemia. Yet, the comprehensive impact of Scd1 deficiency on hepatic and circulating lipids remains incompletely understood. To further delineate the effects of SCD1 on lipid metabolism, we employed lipidomics on the liver from mice under a lipogenic high carbohydrate, very low-fat diet. We found that Scd1 deficiency leads to an accumulation of saturated lipids and an increase in hepatic and plasma acylcarnitines. Remarkably, transgenic replenishment of de novo oleate synthesis by human SCD5 in the liver of Scd1-deficient mice not only restored hepatic lipid desaturation levels but also attenuated acylcarnitine accumulation, highlighting the distinct role of SCD1 and oleate in regulating intracellular lipid homeostasis.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100824"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plaat1 deficiency reduces cardiac cardiolipin content and impairs exercise tolerance.","authors":"Ashkan Hashemi, Ming Rong Liu, John Z Chan, Antonia N Berdeklis, Alex D Cocco, Michelle V Tomczewski, Douglas Strathdee, Ken D Stark, Robin E Duncan","doi":"10.1016/j.jlr.2025.100822","DOIUrl":"10.1016/j.jlr.2025.100822","url":null,"abstract":"<p><p>Phospholipase A and acyltransferase 1 (PLAAT1) catalyzes O-transacylase, N-transacylase, and phospholipase A_1/2 reactions. We have demonstrated that PLAAT1 has O-transacylase activity in vitro using phosphatidylcholine as an acyl donor and monolysocardiolipin (MLCL) as an acyl acceptor, generating cardiolipin. However, a role for PLAAT1 in cardiolipin regulation in vivo has not yet been reported. We generated Plaat1-deficient (Plaat1^-/-) mice and studied males and females for gross morphological differences, food intakes, respiratory gas exchange, total energy expenditure, and voluntary activity. We also evaluated cardiac cardiolipin contents, levels of mitochondrial proteins, and exercise capacity. Sex-matched Plaat1^-/- mice had highly similar body weights to their wild-type (Wt) littermates, although male Plaat1^-/- mice ate less. Male and female Plaat1^-/- hearts were 14.2% and 10.6% smaller, respectively. Cardiac cardiolipin levels were ∼one-third lower in male and female Plaat1^-/- mice compared to their sex-matched Wt littermates, largely due to lower cardiolipin linoleate. Levels of the mitochondrial protein succinate dehydrogenase complex flavoprotein subunit A were 13.8% and 16.3% lower in male and female Plaat1^-/- mice, respectively. Both male and female Plaat1^-/- mice had significantly lower oxygen consumption, carbon dioxide production, and total energy expenditure, and male Plaat1^-/- mice had lower rearing activity than their sex-matched Wt littermates. While other measures of voluntary activity, including locomotion and ambulation did not differ significantly between genotypes, both males and females had reduced exercise tolerance. This work demonstrates a critical role for PLAAT1 in cardiac cardiolipin content and the regulation of energy metabolism and exercise tolerance in vivo.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100822"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apolipoprotein A1 deficiency increases macrophage apoptosis and necrotic core development in atherosclerotic plaques in a Bim-dependent manner.","authors":"Alexander S Qian, George E G Kluck, Pei Yu, Leticia Gonzalez, Elizabeth Balint, Bernardo L Trigatti","doi":"10.1016/j.jlr.2025.100782","DOIUrl":"10.1016/j.jlr.2025.100782","url":null,"abstract":"<p><p>In advanced atherosclerotic lesions, macrophage apoptosis contributes to plaque progression and the formation of necrotic cores, rendering plaques vulnerable to rupture. The proapoptotic protein B-cell lymphoma 2 [Bcl-2] interacting mediator of cell death (Bim) plays a crucial role in mediating apoptosis in macrophages under prolonged endoplasmic reticulum stress. HDL has been shown to suppress macrophage apoptosis induced by endoplasmic reticulum stressors. To investigate the impact of apolipoprotein A1 (ApoA1) deficiency, associated with reduced HDL levels, on necrotic core growth and plaque apoptosis, we introduced ApoA1 deficiency into low-density lipoprotein receptor (LDLR) knockout mice and fed them a high-fat diet for 10 weeks. ApoA1-deficient Ldlr KO mice developed advanced plaques characterized by large necrotic cores, increased apoptosis, and elevated Bim expression in macrophages within the plaques. To assess whether deletion of Bim could mitigate this development, mice underwent bone marrow transplantation with bone marrow from either Bim-deficient mice or from mice with a deletion of myeloid-derived Bim driven by LyzM-cre. Inhibiting Bim in all bone marrow-derived cells led to leukocytosis, reductions in plasma cholesterol and triglyceride levels, and decreased plaque apoptosis, necrotic core, and plaque sizes in ApoA1 and Ldlr double-KO mice but not in Ldlr KO mice. Likewise, conditional deletion of Bim in the myeloid compartment of ApoA1 and Ldlr double-KO mice also reduced apoptosis, necrotic core sizes, and plaque sizes, without inducing leukocytosis or lowering plasma cholesterol levels. These findings suggest that ApoA1 deficiency triggers apoptosis in myeloid cells through a Bim-dependent pathway, significantly contributing to the development of necrotic cores and the progression of atherosclerotic plaques.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100782"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum and plasma sphingolipids as biomarkers of chemotherapy-induced cardiotoxicity in female patients with breast cancer.","authors":"Samia Mohammed, Andreas P Kalogeropoulos, Victoria Alvarado, Michelle Weisfelner-Bloom, Christopher J Clarke","doi":"10.1016/j.jlr.2025.100798","DOIUrl":"10.1016/j.jlr.2025.100798","url":null,"abstract":"<p><p>Although effective as a chemotherapeutic, the utility of Doxorubicin (Dox) is hampered by cardiotoxicity. Despite this, the ability to predict and guide monitoring of patients receiving Dox is hampered by a lack of effective biomarkers to identify susceptible patients and detect early signs of subclinical cardiotoxicity. Based on their well-established roles in the response to Dox and other chemotherapies, we performed a retrospective analysis of serum and plasma sphingolipids (SLs) from female patients with breast cancer (BC) undergoing anthracycline-containing therapy, correlating with cardiac parameters assessed by echocardiography. Results showed substantial changes in both plasma and serum SL species during therapy including ceramide (Cer), deoxydihydroCer, and dihydrosphingosine with reversion toward baseline after treatment. Linear mixed-effects model analysis revealed that baseline levels of a number of SLs correlated with adverse cardiac outcomes. Here, serum sphingosine-1-phosphate (S1P), dihydroS1P, and plasma Cer performed comparably to the prognostic value of pro-NT-BNP, an established biomarker of cardiotoxicity. Intriguingly, while pro-NT-BNP had no predictive value at mid- and post-therapy timepoints, serum S1P and dihydroS1P, and plasma Cer levels showed a correlation with adverse outcomes, particularly at the post-therapy timepoint. Finally, analysis of plasma and serum C16:C24-Cer ratios-previously linked with adverse cardiac outcomes-showed no correlation in the context of chemotherapy treatment. Overall, this pilot study provides initial evidence that plasma and serum SLs may have benefits as both prognostic and diagnostic biomarkers for female BC patients undergoing anthracycline-containing chemotherapy. Consequently, diagnostic SL measurements-recently implemented for metabolic-associated cardiac disorders-could have wider utility.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100798"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12127548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diet-induced obesity dampens the temporal oscillation of hepatic mitochondrial lipids.","authors":"Rashi Jain, Rajprabu Rajendran, Sona Rajakumari","doi":"10.1016/j.jlr.2025.100790","DOIUrl":"10.1016/j.jlr.2025.100790","url":null,"abstract":"<p><p>Mitochondria play a pivotal role in energy homeostasis and regulate several metabolic pathways. The inner and outer membrane of mitochondria comprises unique lipid composition and proteins that are essential to form electron transport chain complexes, orchestrate oxidative phosphorylation, β-oxidation, ATP synthesis, etc. As known, diet-induced obesity affects mitochondrial function, dynamics, and mitophagy, which are governed by circadian clock machinery. Though DIO impairs the interplay between circadian oscillation and lipid metabolism, the impact of DIO on mitochondrial membrane lipid composition and their temporal oscillation is unknown. Thus, we investigated the diurnal oscillation of liver mitochondrial lipidome at various Zeitgeber times using quantitative lipidomics. Our data suggested that obesity disrupted lipid accumulation profiles and diminished the oscillating lipid species in the hepatic mitochondria. Strikingly, HFD manifested a more homogenous temporal oscillation pattern in phospholipids regardless of possessing different fatty acyl-chain lengths and degrees of unsaturation. In particular, DIO impaired the circadian rhythmicity of phosphatidyl ethanolamine, phosphatidyl choline, phosphatidyl serine, and ether-linked phosphatidyl ethanolamine. Also, DIO altered the rhythmic profile of PE/PC, ePE/PC, PS/PC ratio, and key proteins related to mitochondrial function, dynamics, and quality control. Since HFD dampened lipid oscillation, we examined whether the diurnal oscillation of mitochondrial lipids synchronized with mitochondrial function. Also, our data emphasized that acrophase of mitochondrial lipids synchronized with increased oxygen consumption rate and Parkin levels at ZT16 in chow-fed mice. Our study revealed that obesity altered the mitochondrial lipid composition and hampered the rhythmicity of mitochondrial lipids, oxygen consumption rate, and Parkin levels in the liver.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100790"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12127559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Statin effects on the lipidome: Predicting statin usage and implications for cardiovascular risk prediction.","authors":"Changyu Yi, Kevin Huynh, Yvette Schooneveldt, Gavriel Olshansky, Amy Liang, Tingting Wang, Habtamu B Beyene, Aleksandar Dakic, Jingqin Wu, Michelle Cinel, Natalie A Mellett, Gerald F Watts, Joseph Hung, Jennie Hui, John Beilby, Joanne E Curran, John Blangero, Eric K Moses, John Simes, Andrew M Tonkin, Leonard Kritharides, David Sullivan, Jonathan E Shaw, Dianna J Magliano, Agus Salim, Corey Giles, Peter J Meikle","doi":"10.1016/j.jlr.2025.100800","DOIUrl":"10.1016/j.jlr.2025.100800","url":null,"abstract":"<p><p>Statin therapy is a highly successful and cost-effective strategy for the prevention and treatment of cardiovascular diseases (CVD). Adjusting for statin usage is crucial when exploring the association of the lipidome with CVD to avoid erroneous conclusions. However, practical challenges arise in real-world scenarios due to the frequent absence of statin usage information. To address this limitation, we demonstrate that statin usage can be accurately predicted using lipidomic data. Using three large population datasets and a longitudinal clinical study, we show that lipidomic-based statin prediction models exhibit high prediction accuracy in external validation. Furthermore, we introduce a re-weighted model, designed to overcome a ubiquitous limitation of prediction models, namely the need for predictor alignment between training and target data. We demonstrated that the re-weighted models achieved comparable prediction accuracy to ad hoc models which use the aligned predictor between training and target data. This innovation holds promise for significantly enhancing the transferability of statin prediction and other 'omics prediction models, especially in situations where predictor alignment is incomplete. Our statin prediction model now allows for the inclusion of statin usage in lipidomic analyses of cohorts even where statin use is not available, improving the interpretability of the resulting analyses.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":"66 5","pages":"100800"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S-adenosylmethionine deficit disrupts very low-density lipoprotein metabolism promoting liver lipid accumulation in mice.","authors":"María R Luque-Urbano, David Fernández-Ramos, Fernando Lopitz-Otsoa, Virginia Gutiérrez de Juan, Maider Bizkarguenaga, Lia Castro-Espadas, Uxue Hermoso-Martínez, Lucía Barbier-Torres, Shelly C Lu, Oscar Millet, José M Mato","doi":"10.1016/j.jlr.2025.100794","DOIUrl":"10.1016/j.jlr.2025.100794","url":null,"abstract":"<p><p>Hepatic deletion of methionine adenosyltransferase-1a (Mat1a) in mice reduces S-adenosylmethionine (SAMe), a key methyl donor essential for many biological processes, which promotes the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Hyperglycemia and reduced MAT1A expression, along with low SAMe levels, are common in MASLD patients. This study explores how Mat1a-knockout (KO) hepatocytes respond to prolonged high glucose conditions, focusing on glucose metabolism and lipid accumulation. Hepatocytes from methionine adenosyltransferase-1a-knockout (Mat1a-KO) mice were incubated in high glucose conditions overnight, allowing for analysis of key metabolic intermediates and gene expression related to glycolysis, gluconeogenesis, glyceroneogenesis, phospholipid synthesis, and very low density lipoprotein (VLDL) secretion. SAMe deficiency in Mat1a-KO hepatocytes led to reduced protein methyltransferase-1 activity, resulting in increased expression of glycolytic enzymes (glucokinase, phosphofructokinase, and pyruvate kinase) and decreased expression of gluconeogenic enzymes (phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase). These alterations led to a reduction in dihydroxyacetone phosphate (DHAP), which subsequently inhibited mammalian target of rapamycin complex 1 (mTORC1) activity. This inhibition resulted in decreased phosphatidylcholine synthesis via the CDP-choline pathway and impaired VLDL secretion, ultimately causing lipid accumulation. Thus, under high glucose conditions, SAMe deficiency in hepatocytes depletes DHAP, inhibits mTORC1 activity, and promotes lipid buildup.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100794"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in the lipid profiles of visceral adipose tissue with obesity and gonadectomy.","authors":"Mita Varghese, Rajendiran Thekkelnaycke, Tanu Soni, Jiayu Zhang, Krishnarao Maddipati, Kanakadurga Singer","doi":"10.1016/j.jlr.2025.100803","DOIUrl":"10.1016/j.jlr.2025.100803","url":null,"abstract":"<p><p>In obesity, adipose tissue (AT) expansion is accompanied by chronic inflammation. Altered lipid composition in the visceral or gonadal white AT (GWAT) directly drive AT macrophage accumulation and activation to a proinflammatory phenotype. Sex steroid hormones modulate visceral versus subcutaneous lipid accumulation that correlates with metabolic syndrome, especially in men and postmenopausal women who are more prone to abdominal obesity. Prior studies demonstrated sex differences in GWAT lipid species in HFD-fed mice, but the role of sex hormones is still unclear. We hypothesized that sex hormone alterations with gonadectomy (GX) would further impact lipid composition in the obese GWAT. Untargeted lipidomics of obese GWAT identified sex differences in phospholipids, sphingolipids, sterols, fatty acyls, saccharolipids and prenol lipids. Males had significantly more precursor fatty acids (palmitic, oleic, linoleic, and arachidonic acid) than females and GX mice. Targeted lipidomics for fatty acids and oxylipins in the HFD-fed male and female GWAT stromal vascular fraction identified higher omega-6 to omega-3 free fatty acid profile in males and differences in PUFAs-derived prostaglandins, thromboxanes, and leukotrienes. Both obese male and female GWAT stromal vascular fraction showed increased levels of arachidonic acid-derived oxylipins compared to their lean counterparts. Bulk RNA-seq of sorted GWAT AT macrophages highlighted sex and diet differences in PUFA and oxylipin metabolism genes. These findings of sexual dimorphism in both stored lipid species and PUFA-derived mediators with diet and GX emphasize sex differences in lipid metabolism pathways that drive inflammation responses and metabolic disease risk in obesity.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100803"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidized LDL stimulates PKM2-mediated mtROS production and phagocytosis.","authors":"Jue Zhang, Jackie Chang, Vaya Chen, Mirza Ahmar Beg, Wenxin Huang, Lance Vick, Yaxin Wang, Heng Zhang, Erin Yttre, Ankan Gupta, Mark Castleberry, Ziyu Zhang, Wen Dai, Jieqing Zhu, Shan Song, Moua Yang, Ashley Kaye Brown, Zhen Xu, Yan-Qing Ma, Brian C Smith, Jacek Zielonka, James G Traylor, Cyrine Ben Dhaou, A Wayne Orr, Weiguo Cui, Yiliang Chen","doi":"10.1016/j.jlr.2025.100809","DOIUrl":"10.1016/j.jlr.2025.100809","url":null,"abstract":"<p><p>Oxidized low-density lipoprotein (oxLDL) promotes proatherogenic phenotypes in macrophages, accelerating the progression of atherosclerosis. Our previous studies demonstrated that oxLDL binds to its receptor CD36, stimulating mitochondrial reactive oxygen species (mtROS), which are critical in atherosclerosis development. However, the mechanisms underlying mtROS induction and their effects on macrophage cellular functions remain poorly understood. Macrophages rely on phagocytosis to clear pathogens, apoptotic cells, or other particles, a process critical for tissue homeostasis. Dysregulated or excessive particle ingestion, a key step in phagocytosis, can lead to lipid overloading and foam cell formation, a hallmark of atherosclerosis. In this study, we showed that macrophages pretreated with oxLDL exhibit increased particle ingestion, a phagocytic response significantly attenuated in Cd36-null macrophages. Further investigations revealed that oxLDL-induced phagocytosis depends on mtROS, as their suppression inhibited the process. In vivo, atherosclerosis-prone Apoe-null mice on a high-fat diet exhibited increased mtROS levels and enhanced phagocytic activity in aortic foamy macrophages compared to those from chow diet-fed mice, supporting a role of mtROS in promoting lesional macrophage phagocytosis. Mechanistically, we identified a novel signaling pathway whereby oxLDL/CD36 interaction induces the translocation of the cytosolic enzyme pyruvate kinase muscle 2 (PKM2) to mitochondria. Disruption of PKM2 mitochondrial translocation using siRNA knockdown or a specific chemical inhibitor reduced mtROS production and attenuated oxLDL-induced phagocytosis. In conclusion, our findings reveal a novel oxLDL-CD36-PKM2 signaling axis that drives mtROS production and phagocytosis in atherogenic macrophages.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100809"},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}