Journal of Lipid Research

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ISSN / EISSN : 0022-2275 / 1539-7262
Published by: Elsevier BV (10.1016)
Total articles ≅ 18,311
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Oleg Kovrov, Fredrik Landfors, Valeria Saar-Kovrov, Ulf Näslund,
Published: 25 October 2021
Journal of Lipid Research; https://doi.org/10.1016/j.jlr.2021.100144

Abstract:
Lipoprotein lipase (LPL) is a key player in plasma triglyceride metabolism. Consequently, LPL is regulated by several proteins during synthesis, folding, secretion, and transport to its site of action at the luminal side of capillaries, as well as during the catalytic reaction. Some proteins are well known, while others have been identified but are still not fully understood. We set out to study the effects of the natural variations in the plasma levels of all known LPL regulators on the activity of purified LPL added to samples of fasted plasma taken from 117 individuals. The enzymatic activity was measured at 25° C using isothermal titration calorimetry. This method allows quantification of the ability of an added fixed amount of exogenous LPL to hydrolyze triglyceride-rich lipoproteins in plasma samples by measuring the heat produced. Our results indicate that, under the conditions used, the normal variation in the endogenous levels of apolipoprotein C1, C2 and C3, or the levels of angiopoietin-like proteins 3, 4, and 8 in the fasted plasma samples had no significant effect on the recorded activity of the added LPL. Instead, the key determinant for the LPL activity was a lipid signature strongly correlated to the average size of the VLDL particles. The signature involved several lipoprotein and plasma lipid parameters, but also apolipoprotein A5 levels. While the measurements cannot fully represent the action of LPL when attached to the capillary wall, our study provides knowledge on the interindividual variation of LPL lipolysis rates in human plasma.
Monika Lakk, Grace F. Hoffmann, Aruna Gorusupudi, Eric Enyong, , Paul S. Bernstein, , Nanna MacAulay, Michael H. Elliott,
Published: 25 October 2021
Journal of Lipid Research; https://doi.org/10.1016/j.jlr.2021.100145

Abstract:
Despite the association of cholesterol with debilitating pressure-related diseases such as glaucoma, heart disease, and diabetes, its role in mechanotransduction is not well understood. We investigated the relationship between mechanical strain, free membrane cholesterol, actin cytoskeleton, and the stretch-activated TRPV4 (transient receptor potential vanilloid isoform 4) channel in human trabecular meshwork (TM) cells. Physiological levels of cyclic stretch resulted in time-dependent decreases in membrane cholesterol/phosphatidylcholine ratio and upregulation of stress fibers. Depleting free membrane cholesterol with m-β-cyclodextrin (MβCD) augmented TRPV4 activation by the agonist GSK1016790A, swelling and strain, with the effects reversed by cholesterol supplementation. MβCD increased membrane expression of TRPV4, caveolin-1, and flotillin. TRPV4 did not colocalize or interact with caveolae or lipid rafts, apart from a truncated ∼75 kDa variant partially precipitated by a caveolin-1 antibody. MβCD induced currents in TRPV4-expressing Xenopus laevis oocytes. Thus, membrane cholesterol regulates trabecular transduction of mechanical information, with TRPV4 channels mainly located outside of cholesterol-enriched membrane domains. Moreover, the biomechanical milieu itself shapes the lipid content of TM membranes. Diet, cholesterol metabolism, and mechanical stress might modulate the conventional outflow pathway and intraocular pressure in glaucoma and diabetes.
Jiangang Zhang, Shuai Yang, Jingchun Wang, Yanquan Xu, Huakan Zhao, Juan Lei, Yu Zhou, Yu Chen, Lei Wu, Mingyue Zhou, et al.
Published: 25 October 2021
Journal of Lipid Research; https://doi.org/10.1016/j.jlr.2021.100143

Abstract:
Free fatty acids (FFAs) display pleiotropic functions in human diseases. Short-, medium-, and long-chain fatty acids (SCFAs, MCFAs, and LCFAs) are derived from different origins, and precise quantification of these FFAs is critical for revealing their roles in biological processes. However, accessing stable isotope-labeled internal standards (SIL-IS) is difficult, and different chain lengths of FFAs challenge the chromatographic coverage. Here, we developed a metabolomics strategy to analyze FFAs based on isotope-free liquid chromatography-mass spectrometry-multiple reaction monitoring (LC-MS-MRM) integrated with dual derivatization. Samples and dual derivatization internal standards (DD-ISs) were synthesized using 2-dimethylaminoethylamine (DMED) or dansylhydrazine (Dns-Hz) as a "light" label under mild and efficient reaction conditions, and N, N-diethyl ethylene diamine (DEEA) or N, N-diethyldansulfonyl hydrazide (Dens-HZ) as a "heavy" label. General MRM parameters were designed to analyze these FFAs. The limit of detection (LOD) of SCFAs varied from 0.5 to 3 nM. Furthermore, we show this approach exhibits good linearity (R2=0.99374 to 0.99929), there is no serious substrate interference, and no quench steps are required, confirming the feasibility and reliability of the method. Using this method, we successfully quantified 15 types of SCFAs in fecal samples from hepatocellular carcinoma (HCC) patients and healthy individuals; among these, propionate, butyrate, isobutyrate, and 2-methylbutyrate were significantly decreased in the HCC group compared to the healthy control group. These results indicate that the integrated LC-MS metabolomics with isotope-free and dual derivatization is an efficient approach for quantifying FFAs, and may be useful for identifying lipid biomarkers of cancer.
, , Maho Tsuda, Yasuhiro Takenouchi, Hironobu Ishimaru, Yasuo Okamoto
Published: 18 October 2021
Journal of Lipid Research; https://doi.org/10.1016/j.jlr.2021.100141

Abstract:
Lysophosphatidic acid (LPA) is a lipid mediator that regulates various processes, including cell migration and cancer progression. Autotaxin (ATX) is a lysophospholipase D (lyso-PLD)-type exoenzyme that produces extracellular LPA. In contrast, glycerophosphodiesterase (GDE) family members GDE4 and GDE7 are intracellular lyso-PLDs that form LPA, depending on Mg2+ and Ca2+, respectively. Since no fluorescent substrate for these GDEs has been reported, in the present study we examined whether a fluorescent ATX substrate, FS-3, could be applied to study GDE activity. We found that the membrane fractions of human GDE4- and GDE7-overexpressing HEK293T cells hydrolyzed FS-3 in a manner almost exclusively dependent on Mg2+ and Ca2+, respectively. Using these assay systems, we found that several ATX inhibitors, including BrP-LPA and 3-carbacyclic phosphatidic acid, also potently inhibited GDE4 and GDE7 activities. In contrast, the ATX inhibitor S32826 hardly inhibited these activities. Furthermore, FS-3 was hydrolyzed in a Mg2+-dependent manner by the membrane fraction of human prostate cancer LNCaP cells that express GDE4 endogenously, but not by those of GDE4-deficient LNCaP cells. Similar Ca2+-dependent GDE7 activity was observed in human breast cancer MCF-7 cells but not in GDE7-deficient MCF-7 cells. Finally, our assay system could selectively measure GDE4 and GDE7 activities in a mixture of the membrane fractions of GDE4- and GDE7-overexpressing HEK293T cells in the presence of S32826. These findings allow high-throughput assays of GDE4 and GDE7 activities, which could lead to the development of selective inhibitors and stimulators as well as a better understanding of the biological roles of these enzymes.
Narasimha Anaganti, Sujith Rajan,
Published: 17 October 2021
Journal of Lipid Research; https://doi.org/10.1016/j.jlr.2021.100136

Abstract:
Microsomal triglyceride transfer protein (MTP) is essential for the assembly and secretion of apolipoprotein B-containing lipoproteins. MTP transfers diverse lipids such as triacylglycerol (TAG) and phospholipids (PL) between vesicles in vitro. Previously, we described methods to measure these transfer activities using N-7-nitro-2-1,3-benzoxadiazol-4-yl (NBD)-labeled lipids. The NBD-TAG transfer assay is sensitive and can measure MTP activity in cell and tissue homogenates. In contrast, the NBD-PL transfer assay shows high background and is less sensitive; therefore, purified MTP is required to measure its PL transfer activity. Here, we optimized the assay to measure also the PL transfer activity of MTP in cell and tissue homogenates. We found that donor vesicles containing dioleoylphosphoethanolamine and palmitoyloleoylphosphoethanolamine result in a low background signal and are suitable to assay the PL transfer activity of MTP. This assay was capable of measuring protein- and substrate-dependent saturation kinetics. Furthermore, the MTP inhibitor lomitapide blocked this transfer activity. One drawback of the PL transfer assay is that it is less sensitive at physiological temperature than at room temperature, and it requires longer incubation times than the TAG transfer assay. Nevertheless, this significantly improved, sensitive assay is simple and easy to perform, involves few steps, can be conducted at room temperature, and is suitable for high-throughput screening to identify inhibitors. This assay can be adapted to measure other phospholipid transfer proteins and to address biological and physiological importance of these activities.
, Whitney L. Stutts, Morgan M. Ritter, Kenneth P. Garrard, Seth W. Kullman
Published: 17 October 2021
Journal of Lipid Research; https://doi.org/10.1016/j.jlr.2021.100142

Abstract:
Vitamin D is well known for its traditional role in bone mineral homeostasis; however, recent evidence suggests that vitamin D also plays a significant role in metabolic control. This study served to investigate putative linkages between vitamin D deficiency (VDD) and metabolic disruption of bioactive lipids by mass spectrometry imaging (MSI). Our approach employed infrared-matrix-assisted laser desorption electrospray ionization (IR-MALDESI) MSI for lipid metabolite profiling in 6-month-old zebrafish fed either a vitamin D-deficient (VDD) or a vitamin D-sufficient (VDS) diet. Using a lipidomics pipeline, we found that VDD zebrafish had a greater abundance of bioactive lipids (N-acyls, endocannabinoids (ECs), diacylglycerols/triacylglycerols, bile acids/bile alcohols, and vitamin D derivatives) suggestive of increased endocannabinoid tone compared to VDS zebrafish. Tandem mass spectrometry (MS2) was performed on several differentially expressed metabolites with sufficient ion abundances to aid in structural elucidation and provide additional support for MS1 annotations. To confirm activation of the EC pathways, we subsequently examined expression of genes involved in EC biosynthesis, metabolism, and receptor signaling in adipose tissue and liver from VDD and VDS zebrafish. Gene expression changes were congruent with increased endocannabinoid tone, with VDD zebrafish demonstrating increased synthesis and metabolism of anandamide compared to VDS zebrafish. Taken together, our data suggest that VDD may promote accumulation of bioactive lipids and increased endocannabinoid tone in zebrafish.
Marta Futema, Alison Taylor-Beadling, Maggie Williams,
Published: 16 October 2021
Journal of Lipid Research; https://doi.org/10.1016/j.jlr.2021.100139

Abstract:
In the early 1980s, the Nobel Prize winning cellular and molecular work of Mike Brown and Joe Goldstein led to the identification of the Low Density Lipoprotein Receptor (LDLR) gene as the first gene where mutations cause the Familial Hypercholesterolaemia (FH) phenotype. We now know that autosomal dominant monogenic FH can be caused by pathogenic variants of three additional genes (APOB/PCSK9/APOE), and that the plasma LDL-C concentration and risk of premature Coronary Heart Disease (CHD) differs according to the specific locus and associated molecular cause. It is now possible to use Next Generation Sequencing (NGS) to sequence all exons of all four genes, processing 96 patient samples in one sequencing run, increasing the speed of test results and reducing costs. This has resulted in the identification of many novel FH-causing variants, but also some "Variants of Unknown Significance (VUSs)" which require further evidence to classify as pathogenic or benign. The identification of the FH-causing variant in an index case can be used as an unambiguous and rapid test for other family members. An FH-causing variant can be found in 20%-40% of patients with the FH phenotype, and we now appreciate that in the majority of patients without a monogenic cause, a polygenic aetiology for their phenotype is highly likely. Compared to those with a monogenic cause, these patients have significantly lower risk of future CHD. The use of these molecular genetic diagnostic methods in the characterization of FH is a prime example of the utility of precision or personalised medicine.
, Robert Ahrends, , Kim Ekroos, , , , Markus R. Wenk,
Published: 15 October 2021
Journal of Lipid Research; https://doi.org/10.1016/j.jlr.2021.100138

Abstract:
In the last two decades, lipidomics has become one of the fastest expanding scientific disciplines in biomedical research. With an increasing number of new research groups to the field, it is even more important to design guidelines for assuring high standards of data quality. The Lipidomics Standards Initiative (LSI) is a community-based endeavor for the coordination of development of these best practice guidelines in lipidomics, and is embedded within the International Lipidomics Society (ILS). It is the intention of this review to highlight the most quality-relevant aspects of the lipidomics workflow, including preanalytics, sample preparation, mass spectrometry, and lipid species identification and quantitation. Furthermore, this review does not just highlight examples of best practice, but also sheds light on strengths, drawbacks, and pitfalls in the lipidomic analysis workflow. While this review is not designed to be a step-by-step protocol by itself, nor to be dedicated to a specific application of lipidomics, it should nevertheless provide the interested reader with links and original publications to obtain a comprehensive overview concerning the state of the art practices in the field.
Ronald M. Krauss
Published: 9 October 2021
Journal of Lipid Research, Volume 62; https://doi.org/10.1016/j.jlr.2021.100116

Abstract:
Trudy M. Forte, a leader in the field of lipoprotein research, died in June 2021 (Fig. 1). Trudy was a Senior Scientist at Lawrence Berkeley National Laboratory and a Scientist at Children’s Hospital Oakland Research Institute (CHORI). She grew up on the farm where her father worked in Wayne, Pennsylvania, a pastoral experience that shaped her in many ways and fostered her love of biologic science. After graduating magna cum laude from Immaculata College, she went on to receive a PhD in biology from the University of Pennsylvania and did postdoctoral fellowships in biochemistry at the University of Southern California and biophysics at the University of California, Berkeley. In 1969, she took a position at Lawrence Berkeley National Laboratory, where she joined the lipoprotein research group at Donner Lab founded by John Gofman, a pioneer of this field. There, she applied her skills to perfecting electron microscopic techniques for determining structural features of lipoprotein particles. Her seminal accomplishments with this methodology included the use of model systems, in collaboration with Alex Nichols, to demonstrate the metabolic transformation of nascent discoidal HDL to mature spherical particles (Fig. 2). Trudy’s interest in HDL structure and function led to a series of studies investigating the role of the apolipoprotein A-I primary sequence in HDL assembly and function, most notably with regard to recruitment of membrane cholesterol and interactions with the antiatherogenic enzymes lecithin:cholesterol acyltransferase and paraoxonase. This work formed one of the main pillars of an NIH Program Project grant based at Donner Lab for many years. Subsequently, together with Robert Ryan at CHORI, Trudy investigated structure-function relationships of the recently discovered apolipoprotein apoA-V that bear on its key involvement in triglyceride metabolism and atherogenesis. In 2004, Trudy moved to CHORI, where, with Dr Ryan, she continued her studies of apoA-V and launched a productive new research direction aimed at developing and testing lipid nanoparticles for drug delivery.Fig. 1Gertrude (Trudy) M. Forte, PhD. February 25, 1937 to June 9, 2021.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 2Negatively stained preparation of the density 1.063–1.21 g/ml fraction ultracentrifugally isolated from a sonified mixture of ApoA-I-lecithin-unesterified cholesterol before (A) and after (B) incubation with the plasma d > 1.21 g/ml fraction containing lecithin:cholesterol acyltransferase. Magnification, 212,000×. Adapted from Forte TM, et al. (1Forte T.M. Nichols A.V. Gong E.L. Levy R.I. Lux S. Electron microscopic study on reassembly of plasma high density apoprotein with various lipids.Biochim. Biophys. Acta. 1971; 248: 381-386Crossref PubMed Scopus (85) Google Scholar).View Large Image Figure ViewerDownload Hi-res image Download (PPT)
, Anna V. Mathew, Carissa Thornock,
Published: 8 October 2021
Journal of Lipid Research; https://doi.org/10.1016/j.jlr.2021.100135

Abstract:
Patients with chronic kidney disease (CKD) are at high risk for cardiovascular disease (CVD). However, traditional lipid risk factors, including low HDL levels, cannot completely explain the increased risk. Altered HDL proteome is linked with both CVD and CKD, but the role of HDL proteins in incident CVD events in patients with CKD is unknown. In this prospective case-control study, we used targeted proteomics to quantify 31 HDL proteins in 92 subjects (46 incident new CVD and 46 one-to-one matched controls) at various stages of CKD. We tested associations of HDL proteins with incident CVD using matched logistic regression analysis. In the model fully adjusted for clinical confounders, lipid levels, CRP, and proteinuria, no significant associations were found for HDL-C, but we observed inverse associations between levels of HDL proteins PON1, PON3, and LCAT and incident CVD. Odds ratios (per 1-SD) were 0.38 (0.18-0.97, P=0.042), 0.42 (0.20-0.92, P=0.031), and 0.30 (0.11-0.83, P=0.020) for PON1, PON3, and LCAT, respectively. APOA4 remained associated with incident CVD in CKD patients in models adjusted for clinical confounders and lipid levels, but lost significance with the addition of CRP and proteinuria to the model. In conclusion, levels of four HDL proteins, PON1, PON3, LCAT, and APOA4, were found to be inversely associated with incident CVD events in CKD patients. Our observations indicate that HDL's protein cargo, but not HDL-C levels, can serve as a marker—and perhaps mediator—for elevated CVD risk in CKD patients.
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