Journal of Lipid Research最新文献

{"title":"Corrigendum to: [Activation of JNK/c-Jun is required for the proliferation, survival, and angiogenesis induced by EET in pulmonary artery endothelial cells].","authors":"Jun Ma, Lei Zhang, Weina Han, Tingting Shen, Cui Ma, Yun Liu, Xiaowei Nie, Mengmeng Liu, Yajuan Ran, Daling Zhu","doi":"10.1016/j.jlr.2024.100691","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100691","url":null,"abstract":"","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":"65 12","pages":"100691"},"PeriodicalIF":5.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675989","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":"Development and application of an LC-MS/MS method for the combined quantification of oxysterols and bile acids.","authors":"Martin Roumain, Giulio G Muccioli","doi":"10.1016/j.jlr.2024.100697","DOIUrl":"10.1016/j.jlr.2024.100697","url":null,"abstract":"<p><p>Oxysterols and bile acids are interconnected bioactive lipids playing pivotal roles in diverse physiological and pathological processes. For this reason, they are increasingly studied together for their implications in various diseases. However, due to analytical challenges inherent to the nature of these analytes, very few methods have been developed for the simultaneous analysis of these lipids. We here report the development of a sensitive LC-MS/MS method for the combined quantification of 18 oxysterols, 11 unconjugated, 15 conjugated bile acids, and 1 bile acid precursor, using 8 isotope-labeled internal standards, addressing the need for a more comprehensive analysis of these interesting lipid families. During the method development, we investigated different extraction protocols, set up a purification step and achieved chromatographic separation for these lipids, overcoming challenges such as the large number of analytes, isomers, and wide range of polarity across the analytes. Finally, the method was successfully applied to the analysis of preclinical and clinical samples, quantifying 12 oxysterols and 14 bile acids in human plasma, 10 oxysterols and 18 bile acids in mouse plasma from the vena cava, and 10 oxysterols and 20 bile acids in mouse plasma from the portal vein within a single chromatographic run.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100697"},"PeriodicalIF":5.0,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667849","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":"Novel Loci for Triglyceride / High-density Lipoprotein Cholesterol Ratio Longitudinal Change among Subjects without Type 2 Diabetes.","authors":"Lihua Wang, Siyu Wang, Jason A Anema, Vaha A Moghaddam, Yanli Lu, Shiow Lin, E Warwick Daw, Allison L Kuipers, Iva Miljkovic, Michael Brent, Gary J Patti, Bharat Thygarajan, Joseph M Zmuda, Michael A Province, Ping An","doi":"10.1016/j.jlr.2024.100702","DOIUrl":"10.1016/j.jlr.2024.100702","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Triglyceride (TG) /High density lipoprotein cholesterol (HDL-C) ratio (THR) is a surrogate predictor of hyperinsulinemia. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among non-diabetic Europeans from the Long Life Family Study (LLFS, n=1384).</p><p><strong>Methods: </strong>Subjects with diabetes or on dyslipidemia medications were excluded. ΔTHR was derived using growth curve modeling, and adjusted for age, sex, field centers, and principal components (PCs). GWAS used a linear mixed model accounting for familial relatedness. GWLS employed haplotype-based IBD estimation with 0.5 cM average spacing.</p><p><strong>Results: </strong>Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the LPL (p=1.58e-9) for ΔTHR; this locus has been reported before influencing baseline THR levels. Our GWLS found significant linkage with a logarithm of the odds (LODs) exceeding 3 on 3q28 (LODs=4.1). Using a subset of 25 linkage enriched families, we assessed sequence elements under 3q28 and identified two novel variants (EIF4A2/ADIPOQ-rs114108468, p=5e-6, MAF=1.8%; TPRG1-rs16864075, p=3e-6, MAF=8%; accounted for ∼28% and ∼29% of the linkage, respectively). While the former variant was associated with EIF4A2 (p=7e-5) / ADIPOQ (p=3.49e-2) transcriptional levels, the latter variant was not associated with TPRG1 (p=0.23) transcriptional levels. Replication in the Framingham Heart Study Offspring Cohort (FOS) observed modest effect of these loci on ΔTHR.</p><p><strong>Conclusions: </strong>Our approach discovered two novel gene variants EIF4A2/ADIPOQ-rs114108468 and TPRG1-rs16864075 on 3q28 for ΔTHR among subjects without diabetes. Our findings provided novel insights into the molecular regulation of insulin resistance.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100702"},"PeriodicalIF":5.0,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667857","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":"ApoB100 Remodeling and Stiffened Cholesteryl Ester Core Raise LDL Aggregation in Familial Hypercholesterolemia Patients.","authors":"M T La Chica Lhoëst, A Martínez, E Garcia, J Dandurand, A Polishchuk, A Benitez-Amaro, A Cenarro, F Civeira, A Bernabé, D Vilades, J C Escola-Gil, V Samouillan, Cortés V Llorente","doi":"10.1016/j.jlr.2024.100703","DOIUrl":"10.1016/j.jlr.2024.100703","url":null,"abstract":"<p><p>Patients with familial hypercholesterolemia (FH) exhibit a significant residual cardiovascular risk. A new cardiovascular risk factor is the susceptibility of individual LDL particles to aggregation. This study examined LDL aggregation and its relationship with LDL lipid composition and biophysical properties in patients with FH compared to controls. LDL aggregation was measured as the change in particle size, assessed by dynamic light scattering (DLS), after exposure to sphingomyelinase (SMase), which breaks down sphingomyelin in the LDL phospholipid layer. DLS and transmission electron microscopy (TEM) showed that LDL in FH patients exhibited smaller size and greater susceptibility to aggregation. Biochemical analyses revealed a higher cholesteryl ester (CE)/ApoB100 ratio in LDL from FH patients. Differential Scanning Calorimetry (DSC) showed that LDL from FH patients had higher transition temperatures, indicating a more ordered CE core. Fourier-transform infrared (FTIR) spectroscopy revealed fewer flexible α-helices (1658 cm⁻¹) and more stable α-helices (1651 cm⁻¹) in ApoB100 of LDL from FH patients. These structural changes correlated with higher CE content and increased LDL aggregation. In conclusion, a more ordered CE core in smaller LDL particles, combined with a higher proportion of stable α-helices in ApoB100, promotes LDL aggregation in FH patients. These findings suggest new potential therapeutic targets within LDL to reduce cardiovascular risk in FH patients.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100703"},"PeriodicalIF":5.0,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667846","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":"Corrigendum to: Protein kinase C activation stabilizes LDL receptor mRNA via the JNK pathway in HepG2 cells [Journal of Lipid Research 50/3 (2008) 386-397].","authors":"Noelle B Vargas, Brandy Y Brewer, Terry B Rogers, Gerald M Wilson","doi":"10.1016/j.jlr.2024.100661","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100661","url":null,"abstract":"","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":"65 11","pages":"100661"},"PeriodicalIF":5.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644340","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":"Metallothionein 1B attenuates inflammation and hepatic steatosis in MASH by inhibiting the AKT/PI3K pathway.","authors":"Canghai Guan, Xinlei Zou, Wujiang Shi, Jianjun Gao, Chengru Yang, Yifei Ge, Zhaoqiang Xu, Shaowu Bi, Xiangyu Zhong","doi":"10.1016/j.jlr.2024.100701","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100701","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH) is a severe form of metabolic dysfunction-associated fatty liver disease (MAFLD), characterized by hepatic steatosis, inflammation, and fibrosis. This study investigates the role and potential mechanisms of metallothionein 1B (MT1B) in MASH through bioinformatics analysis and experimental validation. qRT-PCR and western blot analyses confirm that MT1B expression is significantly downregulated in liver tissues of MASH patients, in high-fat diet (HFD)-induced mouse models, and in hepatocytes induced by free fatty acids (FFA). Further functional experiments show that upregulation of MT1B reduces intracellular triglycerides and total cholesterol levels, lipid droplet formation, and pro-inflammatory factors. In vivo experiments demonstrate that specific downregulation of hepatic MT1B expression via AAV8-shMT1B injection significantly increases triglyceride and total cholesterol levels, exacerbates lipid accumulation, and markedly elevates liver fibrosis and inflammatory factor expression. RNA-seq and bioinformatics analyses show that the AKT/PI3K pathway is significantly suppressed in MT1B-overexpressing cells. Further experiments indicate that AKT inhibition can reverse the lipid metabolism disorders and inflammatory responses caused by MT1B downregulation. Additionally, Zinc can promote the nuclear translocation of MTF1, leading to its binding to the MT1B promoter, thereby upregulating MT1B expression and ultimately mitigating MASH progression. These findings suggest that zinc-regulated MT1B plays a critical role in lipid metabolism and inflammatory responses by regulating the AKT/PI3K signaling pathway, influencing MASH progression.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100701"},"PeriodicalIF":5.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648208","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":"Prophages divert Staphylococcus aureus defenses against host lipids.","authors":"Biyang Zhou, Amit Pathania, Deepak Pant, David Halpern, Philippe Gaudu, Patrick Trieu-Cuot, Andressa Dias-Leao, Charlotte Pagot, Audrey Solgadi, Alexandra Gruss, Karine Gloux","doi":"10.1016/j.jlr.2024.100693","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100693","url":null,"abstract":"<p><p>Phages are ubiquitous in bacteria, including clinical Staphylococcus aureus, where Sfi 21/Sa3 phages often integrate into the hlb gene, which encodes Hlb sphingomyelinase. This integration acts as a rapid regulatory switch for Hlb production. Our findings suggest that Sfi 21/Sa3 prophages and Hlb activity influence S. aureus fitness by modulating the incorporation of the toxic linoleic acid (C18:2) from serum into the bacterial membrane. This process relies on C18:2 derived from 1,3-diglyceride, facilitated by the FakB1 kinase subunit. Palmitic acid (C16), primarily released from serum through Hlb activity, competes with C18:2 for FakB1. This mechanism contributes to adaptation to AFN-1252, an antibiotic inhibiting the fatty acid synthesis pathway (anti-FASII). Since S. aureus relies on exogenous fatty acids for growth, AFN-1252 treatment leads to increased proportion of C18:2 in the membrane. Furthermore, Hlb inhibition, whether by prophage insertion, gene inactivation, or enzyme inhibition, delays S. aureus adaptation, resulting in a higher proportion of C18:2 in the membrane. This study sheds light on the role of lipid environments in infections and may contribute to the accurate prediction of infection risks and therapeutic efficacy. Moreover, since both anti-FASII agent and Hlb inhibitor enhance C18:2 incorporation, they represent potential candidates for combined strategies against S. aureus.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100693"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590914","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":"Deducing formation routes of oxylipins by quantitative multiple heart-cutting achiral-chiral 2D-LC-MS.","authors":"Nadja Kampschulte, Rebecca Kirchhoff, Ariane Löwen, Nils Helge Schebb","doi":"10.1016/j.jlr.2024.100694","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100694","url":null,"abstract":"<p><p>Several oxylipins are regulators of inflammation. They are formed by enzymes such as lipoxygenases or cyclooxygenases, but also stereorandomly by autoxidation. Reversed-phase liquid chromatography-tandem-mass-spectrometry (LC-MS/MS) methods for oxylipin quantification do not separate enantiomers. Here, we combine sensitive and selective oxylipin analysis with chiral separation using two-dimensional (2D)-LC-MS/MS. By multiple heart-cutting, the oxylipin peaks are transferred onto a chiral column. 45 enantiomeric pairs of (di-)hydroxy-fatty acids are separated with full gradient elution within 1.80min, yielding lower limits of quantification <1pg on column. Concentrations as well as enantiomeric fractions of oxylipins can be determined, even at low concentrations or at high enantiomeric excess of one isomer. The developed achiral-chiral multiple heart-cutting 2D-LC-MS/MS method offers unprecedented selectivity, enabling a better understanding of the formation route of these lipid mediators. This is demonstrated by distinguishing the formation of hydroxy-fatty acids by (acetylated) cyclooxygenase-2 and radical-mediated autoxidation. Applying the method to human M2-like-macrophages, we show that the so-called specialized pro-resolving mediators (SPM) 5,15-DiHEPE and 7,17-DiHDHA as well as 5,15-DiHETE were present as (S,S)-enantiomers, supporting their enzymatic formation. In contrast, at least eight isomers (including protectin DX but not neutroprotectin D1) of 10,17-DiHDHA are present in immune cells, indicating formation by autoxidation. In human plasma of healthy subjects, none of these dihydroxy-fatty acids are not present. However, we demonstrate that all four isomers quickly form via autoxidation if the samples are stored improperly. Thus, dihydroxy-FA should only be reported as SPM, such as resolvin D5 or resolvin E4, if an enantioselective analysis has been carried out.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100694"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590890","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":"Humanized Monoacylglycerol Acyltransferase 2 Mice Develop Metabolic Dysfunction-Associated Steatohepatitis.","authors":"Jose Corbalan, Pranavi Jagadeesan, Karla K Frietze, Rulaiha Taylor, Grace L Gao, Grant Gallagher, Joseph T Nickels","doi":"10.1016/j.jlr.2024.100695","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100695","url":null,"abstract":"<p><p>Mice lacking monoacylglycerol acyltransferase 2 (mMGAT2¹) are resistant to diet-induced fatty liver, suggesting hMOGAT2 inhibition is a viable option for treating metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). We generated humanized hMOGAT2 mice (HuMgat2) for use in pre-clinical studies testing the efficacy of hMOGAT2 inhibitors for treating MASLD/MASH. HuMgat2 mice developed MASH when fed a steatotic diet. Computer-aided histology revealed the presence of hepatocyte cell ballooning, immune cell infiltration, and fibrosis. Hepatocytes accumulated Mallory-Denk bodies containing phosphorylated p62/sequestosome-1-ubiquintinated protein aggregates likely caused by defects in autophagy. Metainflammation and apoptotic cell death were seen in the livers of HuMgat2 mice. Treating HuMgat2 mice with elafibranor reduced several MASH phenotypes. RNASeq analysis predicted changes in bile acid transporter expression that correlated with altered bile acid metabolism indicative of cholestasis. Our results suggest that HuMgat2 mice will serve as a pre-clinical model for testing hMOGAT2 inhibitor efficacy and toxicity and allow for the study of hMOGAT2 in the context of MASH.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100695"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590909","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":"Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARα activation in liver cells.","authors":"Camilla Moliterni, Francesco Vari, Emily Schifano, Stefano Tacconi, Eleonora Stanca, Marzia Friuli, Serena Longo, Maria Conte, Stefano Salvioli, Davide Gnocchi, Antonio Mazzocca, Daniela Uccelletti, Daniele Vergara, Luciana Dini, Anna Maria Giudetti","doi":"10.1016/j.jlr.2024.100692","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100692","url":null,"abstract":"<p><p>Lipotoxicity refers to the harmful effects of excess fatty acids on metabolic health, and it can vary depending on the type of fatty acids involved. Saturated and unsaturated fatty acids exhibit distinct effects, though the precise mechanisms behind these differences remain unclear. Here, we investigated the lipotoxicity of palmitic acid (PA), a saturated fatty acid, compared with oleic acid (OA), a monounsaturated fatty acid, in the hepatic cell line HuH7. Our results demonstrated that PA, unlike OA, induces lipotoxicity, endoplasmic reticulum (ER) stress, and autophagy inhibition. Compared with OA, PA treatment leads to less lipid droplet (LD) accumulation and a significant reduction in the mRNA and protein level of diacylglycerol acyltransferase 1 (DGAT1), a key enzyme of triacylglycerol synthesis. Using modulators of ER stress and autophagy, we established that DGAT1 downregulation by PA is closely linked to these cellular pathways. Notably, the ER stress inhibitor 4-phenylbutyrate can suppress PA-induced DGAT1 downregulation. Furthermore, knockdown of DGAT1 by siRNA or with A922500, a specific DGAT1 inhibitor, resulted in cell death, even with OA. Both PA and OA increased the oxygen consumption rate; however, the increase associated with PA was only partially coupled to ATP synthesis. Importantly, treatment with GW7647 a specific PPARα agonist mitigated the lipotoxic effects of PA, restoring PA-induced ER stress, autophagy block, and DGAT1 suppression. In conclusion, our study highlights the crucial role of DGAT1 in PA-induced lipotoxicity, broadening the knowledge of the mechanisms underlying hepatic lipotoxicity and providing the basis for potential therapeutic interventions.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100692"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590911","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}