Erratum: Docosahexaenoic acid is both a product of and a precursor to tetracosahexaenoic acid in the rat [Errata]
(Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - December 2, 2019 Category: Lipidology Authors: Metherel, A. H., Lacombe, R. J. S., Chouinard-Watkins, R., Bazinet, R. P. Tags: Errata Source Type: research

A genome-wide search for gene-by-obesity interaction loci of dyslipidemia in Koreans shows diverse genetic risk alleles [Patient-Oriented and Epidemiological Research]
Dyslipidemia is a well-established risk factor for CVD. Studies suggest that similar fat accumulation in a given population might result in different levels of dyslipidemia risk among individuals; for example, despite similar or leaner body composition compared with Caucasians, Asians of Korean descent experience a higher prevalence of dyslipidemia. These variations imply a possible role of gene-obesity interactions on lipid profiles. Genome-wide association studies have identified more than 500 loci regulating plasma lipids, but the interaction structure between genes and obesity traits remains unclear. We hypothesized th...
Source: The Journal of Lipid Research - December 2, 2019 Category: Lipidology Authors: Kang, M., Sung, J. Tags: Patient-Oriented and Epidemiological Research Source Type: research

Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis [Patient-Oriented and Epidemiological Research]
It is postulated that lipoprotein (a) [Lp(a)] inhibits fibrinolysis, but this hypothesis has not been tested in humans due to the lack of specific Lp(a) lowering agents. Patients with elevated Lp(a) were randomized to antisense oligonucleotide [IONIS-APO(a)Rx] directed to apo(a) (n = 7) or placebo (n = 10). Ex vivo plasma lysis times and antigen concentrations of plasminogen, factor XI, plasminogen activator inhibitor 1, thrombin activatable fibrinolysis inhibitor, and fibrinogen at baseline, day 85/92/99 (peak drug effect), and day 190 (3 months off drug) were measured. The mean ± SD baseline Lp(a) levels were 477....
Source: The Journal of Lipid Research - December 2, 2019 Category: Lipidology Authors: Boffa, M. B., Marar, T. T., Yeang, C., Viney, N. J., Xia, S., Witztum, J. L., Koschinsky, M. L., Tsimikas, S. Tags: Patient-Oriented and Epidemiological Research Source Type: research

Investigation of diagnostic performance of five urinary cholesterol metabolites for Niemann-Pick disease type C [Patient-Oriented and Epidemiological Research]
In this study, we developed a simultaneous analysis method for five urinary conjugated cholesterol metabolites, which are potential diagnostic biomarkers for a rapid, convenient, and noninvasive chemical diagnosis, using LC/MS/MS. By the method, their urinary concentrations were quantified and the NPC diagnostic performances were evaluated. The developed LC/MS/MS method showed high accuracy and satisfied all analytical method validation criteria. When the urine of healthy controls and patients with NPC was analyzed, three of five urinary conjugated cholesterol metabolite concentrations corrected by urinary creatinine were ...
Source: The Journal of Lipid Research - December 2, 2019 Category: Lipidology Authors: Maekawa, M., Jinnoh, I., Narita, A., Iida, T., Saigusa, D., Iwahori, A., Nittono, H., Okuyama, T., Eto, Y., Ohno, K., Clayton, P. T., Yamaguchi, H., Mano, N. Tags: Patient-Oriented and Epidemiological Research Source Type: research

Insights into lipid accumulation in skeletal muscle in dysferlin-deficient mice [Research Articles]
Loss of dysferlin (DYSF) protein in humans results in limb-girdle muscular dystrophy 2B, characterized by progressive loss of muscles in the distal limbs with impaired locomotion. The DYSF-null (Bla/J) mouse develops severe steatotic muscles upon aging. Here, we report a marked increase in adipocytes, especially in the psoas and gluteus muscles but not in the soleus and tibialis anterior muscles in aged Bla/J mice compared with WT mice. There was a robust upregulation in the mRNA expression of enzymes involved in lipogenesis and triacylglycerol (TAG) synthesis pathways in the steatotic skeletal muscles. Lipidomic analysis ...
Source: The Journal of Lipid Research - December 2, 2019 Category: Lipidology Authors: Agarwal, A. K., Tunison, K., Mitsche, M. A., McDonald, J. G., Garg, A. Tags: Research Articles Source Type: research

Transfer of glucose hydrogens via acetyl-CoA, malonyl-CoA, and NADPH to fatty acids during de novo lipogenesis [Research Articles]
Deuterated water (2H2O) is widely used for measuring de novo lipogenesis (DNL). 2H is incorporated into fatty acids via exchange between body water and the hydrogens of acetyl-CoA, malonyl-CoA, and NADPH. Previous studies concluded that these exchanges are incomplete; therefore, fatty acid 2H enrichment requires correcting. In mice, we measured the 2H enrichment of fatty acid positions 2 and 3 and methyl hydrogens from [U-2H7]glucose to determine 2H transfer from glucose to fatty acid via malonyl-CoA, NADPH, and acetyl-CoA, respectively. Positional fatty acid 2H enrichments were compared with 13C enrichment of the same sit...
Source: The Journal of Lipid Research - December 2, 2019 Category: Lipidology Authors: Belew, G. D., Silva, J., Rito, J., Tavares, L., Viegas, I., Teixeira, J., Oliveira, P. J., Macedo, M. P., Jones, J. G. Tags: Research Articles Source Type: research

Decreased {omega}-6:{omega}-3 PUFA ratio attenuates ethanol-induced alterations in intestinal homeostasis, microbiota, and liver injury [Research Articles]
Ethanol (EtOH)-induced alterations in intestinal homeostasis lead to multi-system pathologies, including liver injury. -6 PUFAs exert pro-inflammatory activity, while -3 PUFAs promote anti-inflammatory activity that is mediated, in part, through specialized pro-resolving mediators [e.g., resolvin D1 (RvD1)]. We tested the hypothesis that a decrease in the -6:-3 PUFA ratio would attenuate EtOH-mediated alterations in the gut-liver axis. -3 FA desaturase-1 (fat-1) mice, which endogenously increase -3 PUFA levels, were protected against EtOH-mediated downregulation of intestinal tight junction proteins in organoid cultures an...
Source: The Journal of Lipid Research - December 2, 2019 Category: Lipidology Authors: Warner, D. R., Warner, J. B., Hardesty, J. E., Song, Y. L., King, T. N., Kang, J. X., Chen, C.-Y., Xie, S., Yuan, F., Prodhan, M. A. I., Ma, X., Zhang, X., Rouchka, E. C., Maddipati, K. R., Whitlock, J., Li, E. C., Wang, G. P., McClain, C. J., Kirpich, I. Tags: Research Articles Source Type: research

CXCL12 promotes atherosclerosis by downregulating ABCA1 expression via the CXCR4/GSK3{beta}/{beta}-cateninT120/TCF21 pathway [Research Articles]
CXC chemokine ligand 12 (CXCL12) is a member of the CXC chemokine family and mainly acts on cell chemotaxis. CXCL12 also elicits a proatherogenic role, but the molecular mechanisms have not been fully defined yet. We aimed to reveal if and how CXCL12 promoted atherosclerosis via regulating lipid metabolism. In vitro, our data showed that CXCL12 could reduce ABCA1 expression, and it mediated cholesterol efflux from THP-1-derived macrophages to apoA-I. Data from the luciferase reporter gene and chromatin immunoprecipitation assays revealed that transcription factor 21 (TCF21) stimulated the transcription of ABCA1 via binding...
Source: The Journal of Lipid Research - December 2, 2019 Category: Lipidology Authors: Gao, J.-H., He, L.-H., Yu, X.-H., Zhao, Z.-W., Wang, G., Zou, J., Wen, F.-J., Zhou, L., Wan, X.-J., Zhang, D.-W., Tang, C.-K. Tags: Research Articles Source Type: research

The three members of the Vav family proteins form complexes that concur to foam cell formation and atherosclerosis [Research Articles]
In this study we found that Vav2 deficiency in RAW264.7 macrophages significantly diminished oxidized LDL uptake and CD36 signaling, demonstrating that each Vav protein family member was required for foam cell formation. Genetic disruption of Vav2 in ApoE-deficient C57BL/6 mice significantly inhibited the severity of atherosclerosis. Strikingly, we further found that the genetic deletion of each member of the Vav protein family by CRISPR/Cas9 resulted in a similar alteration of transcriptomic profiles of macrophages. The three members of the Vav proteins were found to form complexes, and genetic ablation of each single Vav...
Source: The Journal of Lipid Research - December 2, 2019 Category: Lipidology Authors: Huang, R., Guo, G., Lu, L., Fu, R., Luo, J., Liu, Z., Gu, Y., Yang, W., Zheng, Q., Chao, T., He, L., Wang, Y., Niu, Z., Wang, H., Lawrence, T., Malissen, M., Malissen, B., Liang, Y., Zhang, L. Tags: Research Articles Source Type: research

Epoxyeicosatrienoic acid (EET)-stimulated angiogenesis is mediated by epoxy hydroxyeicosatrienoic acids (EHETs) formed from COX-2 [Research Articles]
This study further defines a role for COX-2 in mediating endothelial EET metabolism promoting angiogenesis. Using human aortic endothelial cells (HAECs), we quantified 8,9-EET-induced tube formation and cell migration as indicators of angiogenic potential in the presence and absence of a COX-2 inducer [phorbol 12,13-dibutyrate (PDBu)]. The angiogenic response to 8,9-EET in the presence of PDBu was 3-fold that elicited by 8,9-EET stabilized with a soluble epoxide hydrolase inhibitor (t-TUCB). Contributing to this response was the COX-2 metabolite of 8,9-EET, the 11-hydroxy-8,9-EET (8,9,11-EHET), which exogenously enhanced a...
Source: The Journal of Lipid Research - December 2, 2019 Category: Lipidology Authors: Rand, A. A., Rajamani, A., Kodani, S. D., Harris, T. R., Schlatt, L., Barnych, B., Passerini, A. G., Hammock, B. D. Tags: Research Articles Source Type: research

Angiotensinogen in hepatocytes contributes to Western diet-induced liver steatosis [Research Articles]
Nonalcoholic fatty liver disease (NAFLD) is considered as a liver manifestation of metabolic disorders. Previous studies indicate that the renin-angiotensin system (RAS) plays a complex role in NAFLD. As the only precursor of the RAS, decreased angiotensinogen (AGT) profoundly impacts RAS bioactivity. Here, we investigated the role of hepatocyte-derived AGT in liver steatosis. AGT floxed mice (hepAGT+/+) and hepatocyte-specific AGT-deficient mice (hepAGT–/–) were fed a Western diet and a normal laboratory diet for 12 weeks, respectively. Compared with hepAGT+/+ mice, Western diet-fed hepAGT–/– mice ...
Source: The Journal of Lipid Research - December 2, 2019 Category: Lipidology Authors: Tao, X.-R., 陶;昕;然;, , Rong, J.-B., 戎;佳;炳;, , Lu, H. S., 吕;红;, , Daugherty, A., Shi, P., 史;鹏;, , Ke, C.-L., 柯;昌;乐;, , Zhang, Z.-C., 张;召;才;, Tags: Research Articles Source Type: research

In Memoriam: Lawrence (Larry) L. Rudel (1941-2019) [Tribute]
(Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - December 2, 2019 Category: Lipidology Authors: Parks, J. S., Sawyer, J. K., Shelness, G. S., Brown, J. M. Tags: Tribute Source Type: research

Erratum: A monoclonal antibody to assess oxidized cholesteryl esters associated with apoAI and apoB-100 lipoproteins in human plasma [Errata]
(Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Gonen, A., Choi, S.-H., Miu, P., Agatisa-Boyle, C., Acks, D., Taylor, A. M., McNamara, C. A., Tsimikas, S., Witztum, J. L., Miller, Y. I. Tags: Errata Source Type: research

Analytical separations for lipids in complex, nonpolar lipidomes using differential mobility spectrometry [Methods]
Secretions from meibomian glands located within the eyelid (commonly known as meibum) are rich in nonpolar lipid classes incorporating very-long (22–30 carbons) and ultra-long (>30 carbons) acyl chains. The complex nature of the meibum lipidome and its preponderance of neutral, nonpolar lipid classes presents an analytical challenge, with typically poor chromatographic resolution, even between different lipid classes. To address this challenge, we have deployed differential mobility spectrometry (DMS)-MS to interrogate the human meibum lipidome and demonstrate near-baseline resolution of the two major nonpolar cla...
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Hancock, S. E., Poad, B. L. J., Willcox, M. D. P., Blanksby, S. J., Mitchell, T. W. Tags: Methods Source Type: research

A new method for measuring cholesterol efflux capacity uses stable isotope-labeled, not radioactive-labeled, cholesterol [Methods]
The incidence of cardiovascular events correlates inversely with cholesterol efflux capacity (CEC) more than with HDL-cholesterol level. The measurement of CEC is used to qualify cardiovascular disease risk and is conventionally performed with radioisotope (RI)-labeled cholesterol. Here, we established a CEC measurement technique using stable isotope-labeled cholesterol as an alternative, and we compared the new method with RI and fluorescence (boron dipyrromethene difluoride-cholesterol) methods in cells and in patient serum. We incubated J774 cells labeled with [d7]cholesterol ([d7]C) with patient serum depleted of apoB,...
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Shimizu, T., Miyazaki, O., Iwamoto, T., Usui, T., Sato, R., Hiraishi, C., Yoshida, H. Tags: Methods Source Type: research

Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia [Patient-Oriented and Epidemiological Research]
Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the cen...
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Dron, J. S., Wang, J., McIntyre, A. D., Cao, H., Robinson, J. F., Duell, P. B., Manjoo, P., Feng, J., Movsesyan, I., Malloy, M. J., Pullinger, C. R., Kane, J. P., Hegele, R. A. Tags: Patient-Oriented and Epidemiological Research Source Type: research

PCSK9 loss-of-function variants and Lp(a) phenotypes among black US adults [Patient-Oriented and Epidemiological Research]
The pharmacologic inhibition of proprotein convertase subtilisin-kexin type 9 (PCSK9) lowers lipoprotein (a) [Lp(a)] concentrations. However, the impact of genetic PCSK9 loss-of-function variants (LOFVs) on Lp(a) is uncertain. We determined the association of PCSK9 LOFVs with Lp(a) measures among black adults. Genotyping for PCSK9 LOFVs was conducted in 10,196 black Reasons for Geographic and Racial Differences in Stroke study participants. Among 241 participants with and 723 randomly selected participants without PCSK9 LOFVs, Lp(a) concentations, apo(a) kringle IV (KIV) repeats (a proxy for isoform size), and oxidized pho...
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Mefford, M. T., Marcovina, S. M., Bittner, V., Cushman, M., Brown, T. M., Farkouh, M. E., Tsimikas, S., Monda, K. L., Lopez, J. A. G., Muntner, P., Rosenson, R. S. Tags: Patient-Oriented and Epidemiological Research Source Type: research

Four nights of sleep restriction suppress the postprandial lipemic response and decrease satiety [Patient-Oriented and Epidemiological Research]
Chronic sleep restriction, or inadequate sleep, is associated with increased risk of cardiometabolic disease. Laboratory studies demonstrate that sleep restriction causes impaired whole-body insulin sensitivity and glucose disposal. Evidence suggests that inadequate sleep also impairs adipose tissue insulin sensitivity and the NEFA rebound during intravenous glucose tolerance tests, yet no studies have examined the effects of sleep restriction on high-fat meal lipemia. We assessed the effect of 5 h time in bed (TIB) per night for four consecutive nights on postprandial lipemia following a standardized high-fat dinner (HFD)...
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Ness, K. M., Strayer, S. M., Nahmod, N. G., Schade, M. M., Chang, A.-M., Shearer, G. C., Buxton, O. M. Tags: Patient-Oriented and Epidemiological Research Source Type: research

Metabolism of cholesterol and progesterone is differentially regulated in primary trophoblastic subtypes and might be disturbed in recurrent miscarriages [Patient-Oriented and Epidemiological Research]
During pregnancy, extravillous trophoblasts (EVTs) invade the maternal decidua and remodel the local vasculature to establish blood supply for the growing fetus. Compromised EVT function has been linked to aberrant pregnancy associated with maternal and fetal morbidity and mortality. However, metabolic features of this invasive trophoblast subtype are largely unknown. Using primary human trophoblasts isolated from first trimester placental tissues, we show that cellular cholesterol homeostasis is differentially regulated in EVTs compared with villous cytotrophoblasts. Utilizing RNA-sequencing, gene set-enrichment analysis,...
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Vondra, S., Kunihs, V., Eberhart, T., Eigner, K., Bauer, R., Haslinger, P., Haider, S., Windsperger, K., Klambauer, G., Schütz, B., Mikula, M., Zhu, X., Urban, A. E., Hannibal, R. L., Baker, J., Knöfler, M., Stangl, H., Pollheimer, J., Ro& Tags: Patient-Oriented and Epidemiological Research Source Type: research

Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice [Research Articles]
In this study, we report the identification of ApoA4 as a novel S1P binding protein. Recombinant ApoA4 bound to S1P, activated multiple S1P receptors, and promoted vascular endothelial barrier function, all reflective of its function as a S1P chaperone in the absence of ApoM and albumin. We suggest that multiple S1P chaperones evolved to support complex and essential extracellular signaling functions of this lysolipid mediator in a redundant manner. (Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Obinata, H., Kuo, A., Wada, Y., Swendeman, S., Liu, C. H., Blaho, V. A., Nagumo, R., Satoh, K., Izumi, T., Hla, T. Tags: Research Articles Source Type: research

Plasma oxyphytosterol concentrations are not associated with CVD status in Framingham Offspring Study participants [Research Articles]
In conclusion, circulating plasma oxyphytosterols are not associated with CVD risk in the Framingham Offspring Study. (Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Baumgartner, S., Ras, R. T., Trautwein, E. A., Konings, M. C. J. M., Mensink, R. P., Plat, J. Tags: Research Articles Source Type: research

Bacterial immunogenic {alpha}-galactosylceramide identified in the murine large intestine: dependency on diet and inflammation [Research Articles]
The glycosphingolipid, α-galactosylceramide (αGalCer), when presented by CD1d on antigen-presenting cells, efficiently activates invariant natural killer T (iNKT) cells. Thereby, it modulates immune responses against tumors, microbial and viral infections, and autoimmune diseases. Recently, the production of αGalCer by Bacteroidetes from the human gut microbiome was elucidated. Using hydrophilic interaction chromatography coupled to MS2, we screened murine intestinal tracts to identify and quantify αGalCers, and we investigated the αGalCer response to different dietary and physiologic conditio...
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: von Gerichten, J., Lamprecht, D., Opalka, L., Soulard, D., Marsching, C., Pilz, R., Sencio, V., Herzer, S., Galy, B., Nordström, V., Hopf, C., Gröne, H.-J., Trottein, F., Sandhoff, R. Tags: Research Articles Source Type: research

Lipid species affect morphology of endoplasmic reticulum: a sea urchin oocyte model of reversible manipulation [Research Articles]
The ER is a large multifunctional organelle of eukaryotic cells. Malfunction of the ER in various disease states, such as atherosclerosis, diabetes, cancer, Alzheimer’s and Parkinson’s and amyotrophic lateral sclerosis, often correlates with alterations in its morphology. The ER exhibits regionally variable membrane morphology that includes, at the extremes, large relatively flat surfaces and interconnected tubular structures highly curved in cross-section. ER morphology is controlled by shaping proteins that associate with membrane lipids. To investigate the role of these lipids, we developed a sea urchin oocy...
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Ulloa, G., Hamati, F., Dick, A., Fitzgerald, J., Mantell, J., Verkade, P., Collinson, L., Arkill, K., Larijani, B., Poccia, D. Tags: Research Articles Source Type: research

ApoF knockdown increases cholesteryl ester transfer to LDL and impairs cholesterol clearance in fat-fed hamsters [Research Articles]
Cholesteryl ester transfer protein (CETP) regulates intravascular lipoprotein metabolism. In vitro studies indicate that ApoF alters CETP function by inhibiting its activity with LDL. To explore in vivo the complexities driving ApoF’s effects on CETP, we developed a siRNA-based hamster model of ApoF knockdown. In both male and female hamsters on chow- or fat-fed diets, we measured lipoprotein levels and composition, determined CETP-mediated transfer of cholesteryl esters (CEs) between lipoproteins, and quantified reverse cholesterol transport (RCT). We found that apoF knockdown in chow-fed hamsters had no effect on l...
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Morton, R. E., Liu, Y., Izem, L. Tags: Research Articles Source Type: research

Role of {beta}-glucosidase 2 in aberrant glycosphingolipid metabolism: model of glucocerebrosidase deficiency in zebrafish [Research Articles]
β-glucosidases [GBA1 (glucocerebrosidase) and GBA2] are ubiquitous essential enzymes. Lysosomal GBA1 and cytosol-facing GBA2 degrade glucosylceramide (GlcCer); GBA1 deficiency causes Gaucher disease, a lysosomal storage disorder characterized by lysosomal accumulation of GlcCer, which is partly converted to glucosylsphingosine (GlcSph). GBA1 and GBA2 also may transfer glucose from GlcCer to cholesterol, yielding glucosylated cholesterol (GlcChol). Here, we aimed to clarify the role of zebrafish Gba2 in glycosphingolipid metabolism during Gba1 deficiency in zebrafish (Danio rerio), which are able to survive total Gba1 ...
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Lelieveld, L. T., Mirzaian, M., Kuo, C.-L., Artola, M., Ferraz, M. J., Peter, R. E. A., Akiyama, H., Greimel, P., van den Berg, R. J. B. H. N., Overkleeft, H. S., Boot, R. G., Meijer, A. H., Aerts, J. M. F. G. Tags: Research Articles Source Type: research

Probing compartment-specific sphingolipids with targeted bacterial sphingomyelinases and ceramidases [Research Articles]
Sphingolipids contribute to the regulation of cell and tissue homeostasis, and disorders of sphingolipid metabolism lead to diseases such as inflammation, stroke, diabetes, and cancer. Sphingolipid metabolic pathways involve an array of enzymes that reside in specific subcellular organelles, resulting in the formation of many diverse sphingolipids with distinct molecular species based on the diversity of the ceramide (Cer) structure. In order to probe compartment-specific metabolism of sphingolipids in this study, we analyzed the Cer and SM species preferentially produced in the inner plasma membrane (PM), Golgi apparatus,...
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Sakamoto, W., Canals, D., Salamone, S., Allopenna, J., Clarke, C. J., Snider, J., Obeid, L. M., Hannun, Y. A. Tags: Research Articles Source Type: research

Novel COX-2 products of n-3 polyunsaturated fatty acid-ethanolamine-conjugates identified in RAW264.7 macrophages [Research Articles]
Cyclooxygenase 2 (COX-2) plays a key role in the regulation of inflammation by catalyzing the oxygenation of PUFAs to prostaglandins (PGs) and hydroperoxides. Next to this, COX-2 can metabolize neutral lipids, including endocannabinoid-like esters and amides. We developed an LC-HRMS-based human recombinant (h)COX-2 screening assay to examine its ability to also convert n-3 PUFA-derived N-acylethanolamines. Our assay yields known hCOX-2-derived products from established PUFAs and anandamide. Subsequently, we proved that eicosapentaenoylethanolamide (EPEA), the N-acylethanolamine derivative of EPA, is converted into PGE3-eth...
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: de Bus, I., Zuilhof, H., Witkamp, R., Balvers, M., Albada, B. Tags: Research Articles Source Type: research

Effects of diet and hyperlipidemia on levels and distribution of circulating lysophosphatidic acid [Research Articles]
We examined the effects of experimental hyperlipidemia on the levels and distribution of circulating LPA in mice. The majority of plasma LPA was associated with albumin in plasma from wild-type mice fed normal chow. LDL-associated LPA was increased in plasma from high-fat Western diet-fed mice that are genetically prone to hyperlipidemia (LDL receptor knockout or activated proprotein convertase subtilisin/kexin type 9-overexpressing C57Bl6). Adipose-specific deficiency of the ENPP2 gene encoding the LPA-generating secreted lysophospholipase D, autotaxin (ATX), attenuated these Western diet-dependent increases in LPA. ATX-d...
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Kraemer, M. P., Mao, G., Hammill, C., Yan, B., Li, Y., Onono, F., Smyth, S. S., Morris, A. J. Tags: Research Articles Source Type: research

Metabolic role of fatty acid binding protein 7 in mediating triple-negative breast cancer cell death via PPAR-{alpha} signaling [Research Articles]
This study provides imperative evidence of metabolic vulnerabilities driven by FABP7 via PPAR-α signaling. (Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Kwong, S. C., Jamil, A. H. A., Rhodes, A., Taib, N. A., Chung, I. Tags: Research Articles Source Type: research

{alpha}-Galactosylceramide: a potent immunomodulator produced by gut microbes [Commentary]
(Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - November 1, 2019 Category: Lipidology Authors: Carr, R. M. Tags: Commentary Source Type: research

DGAT2 partially compensates for lipid-induced ER stress in human DGAT1-deficient intestinal stem cells [Patient-Oriented and Epidemiological Research]
Dietary lipids are taken up as FAs by the intestinal epithelium and converted by diacylglycerol acyltransferase (DGAT) enzymes into triglycerides, which are packaged in chylomicrons or stored in cytoplasmic lipid droplets (LDs). DGAT1-deficient patients suffer from vomiting, diarrhea, and protein losing enteropathy, illustrating the importance of this process to intestinal homeostasis. Previously, we have shown that DGAT1 deficiency causes decreased LD formation and resistance to unsaturated FA lipotoxicity in patient-derived intestinal organoids. However, LD formation was not completely abolished in patient-derived organo...
Source: The Journal of Lipid Research - October 1, 2019 Category: Lipidology Authors: van Rijn, J. M., van Hoesel, M., de Heus, C., van Vugt, A. H. M., Klumperman, J., Nieuwenhuis, E. E. S., Houwen, R. H. J., Middendorp, S. Tags: Patient-Oriented and Epidemiological Research Source Type: research

High FA2H and UGT8 transcript levels predict hydroxylated hexosylceramide accumulation in lung adenocarcinoma [Patient-Oriented and Epidemiological Research]
In this study, we paralleled quantification of sphingolipid species with quantitative (q)PCR analyses of metabolic enzymes in order to identify dysregulated routes of sphingolipid metabolism in different subtypes of lung cancers. Lung samples were submitted to histopathological reexamination in order to confirm cancer type/subtype, which included adenocarcinoma histological subtypes and squamous cell and neuroendocrine carcinomas. Compared with benign lesions and tumor-free parenchyma, all cancers featured decreased sphingosine-1-phosphate and SMs. qPCR analyses evidenced differential mechanisms leading to these alteration...
Source: The Journal of Lipid Research - October 1, 2019 Category: Lipidology Authors: Lemay, A.-M., Courtemanche, O., Couttas, T. A., Jamsari, G., Gagne, A., Bosse, Y., Joubert, P., Don, A. S., Marsolais, D. Tags: Patient-Oriented and Epidemiological Research Source Type: research

Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing [Research Articles]
Sterol-regulated HMG-CoA reductase (HMGCR) degradation and SREBP-2 cleavage are two major feedback regulatory mechanisms governing cholesterol biosynthesis. Reportedly, lanosterol selectively stimulates HMGCR degradation, and cholesterol is a specific regulator of SREBP-2 cleavage. However, it is unclear whether other endogenously generated sterols regulate these events. Here, we investigated the sterol intermediates from the mevalonate pathway of cholesterol biosynthesis using a CRISPR/Cas9-mediated genetic engineering approach. With a constructed HeLa cell line expressing the mevalonate transporter, we individually delet...
Source: The Journal of Lipid Research - October 1, 2019 Category: Lipidology Authors: Chen, L., Ma, M.-Y., Sun, M., Jiang, L.-Y., Zhao, X.-T., Fang, X.-X., Man Lam, S., Shui, G.-H., Luo, J., Shi, X.-J., Song, B.-L. Tags: Research Articles Source Type: research

SAR1B GTPase is necessary to protect intestinal cells from disorders of lipid homeostasis, oxidative stress, and inflammation [Research Articles]
In conclusion, SAR1B and its paralogue are needed not only for CM trafficking but also for lipid homeostasis, prooxidant/antioxidant balance, and protection against inflammatory processes. (Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - October 1, 2019 Category: Lipidology Authors: Sane, A., Ahmarani, L., Delvin, E., Auclair, N., Spahis, S., Levy, E. Tags: Research Articles Source Type: research

Characterization of ANGPTL4 function in macrophages and adipocytes using Angptl4-knockout and Angptl4-hypomorphic mice [Research Articles]
In conclusion, ANGPTL4 deficiency increases lipid uptake and respiration in macrophages without affecting LPL protein levels. Compared with the absence of ANGPTL4, low levels of N-terminal ANGPTL4 mitigate the development of chylous ascites and an acute-phase response in mice. (Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - October 1, 2019 Category: Lipidology Authors: Oteng, A.-B., Ruppert, P. M. M., Boutens, L., Dijk, W., van Dierendonck, X. A. M. H., Olivecrona, G., Stienstra, R., Kersten, S. Tags: Research Articles Source Type: research

In search of a genetic explanation for LDLc variability in an FH family: common SNPs and a rare mutation in MTTP explain only part of LDL variability in an FH family [Research Articles]
We previously identified a highly consanguineous familial hypercholesterolemia (FH) family demonstrating segregation of the JD Bari mutation in the LDL receptor as well as a putative cholesterol-lowering trait. We aimed to identify genes related to the latter effect. LDL cholesterol (LDLc) values were normalized for FH affectation status, age, and gender. Using genome-wide SNP data, we examined whether known SNPs gleaned from a genome-wide association study could explain the variation observed in LDLc. Four individuals with markedly reduced LDL levels underwent whole exome sequencing. After prioritizing all potential mutat...
Source: The Journal of Lipid Research - October 1, 2019 Category: Lipidology Authors: Winther, M., Shpitzen, S., Yaacov, O., Landau, J., Oren, L., Foroozan-Rosenberg, L., Lev Cohain, N., Schurr, D., Meiner, V., Szalat, A., Carmi, S., Hayden, M. R., Leitersdorf, E., Durst, R. Tags: Research Articles Source Type: research

Muscle and adipose tissue insulin resistance: malady without mechanism? [Thematic Reviews]
Insulin resistance is a major risk factor for numerous diseases, including type 2 diabetes and cardiovascular disease. These disorders have dramatically increased in incidence with modern life, suggesting that excess nutrients and obesity are major causes of "common" insulin resistance. Despite considerable effort, the mechanisms that contribute to common insulin resistance are not resolved. There is universal agreement that extracellular perturbations, such as nutrient excess, hyperinsulinemia, glucocorticoids, or inflammation, trigger intracellular stress in key metabolic target tissues, such as muscle and adip...
Source: The Journal of Lipid Research - October 1, 2019 Category: Lipidology Authors: Fazakerley, D. J., Krycer, J. R., Kearney, A. L., Hocking, S. L., James, D. E. Tags: Thematic Reviews Source Type: research

Determinants of body fat distribution in humans may provide insight about obesity-related health risks [Thematic Reviews]
Obesity increases the risks of developing cardiovascular and metabolic diseases and degrades quality of life, ultimately increasing the risk of death. However, not all forms of obesity are equally dangerous: some individuals, despite higher percentages of body fat, are at less risk for certain chronic obesity-related complications. Many open questions remain about why this occurs. Data suggest that the physical location of fat and the overall health of fat dramatically influence disease risk; for example, higher concentrations of visceral relative to subcutaneous adipose tissue are associated with greater metabolic risks. ...
Source: The Journal of Lipid Research - October 1, 2019 Category: Lipidology Authors: Frank, A. P., de Souza Santos, R., Palmer, B. F., Clegg, D. J. Tags: Thematic Reviews Source Type: research

Contributions of innate type 2 inflammation to adipose function [Thematic Reviews]
A critical contributor to the health consequences of the obesity epidemic is dysregulated adipose tissue (AT) homeostasis. While white, brown, and beige AT function is altered in obesity-related disease, white AT is marked by progressive inflammation and adipocyte dysfunction and has been the focus of extensive "immunometabolism" research in the past decade. The exact triggering events initiating and sustaining AT inflammation are still under study, but it has been shown that reducing inflammation improves insulin action in AT. Scientific efforts seeking interventions to mitigate obesity-associated AT inflammatio...
Source: The Journal of Lipid Research - October 1, 2019 Category: Lipidology Authors: Bolus, W. R., Hasty, A. H. Tags: Thematic Reviews Source Type: research

Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication [Thematic Reviews]
The breakthrough discoveries of leptin and adiponectin more than two decades ago led to a widespread recognition of adipose tissue as an endocrine organ. Many more adipose tissue-secreted signaling mediators (adipokines) have been identified since then, and much has been learned about how adipose tissue communicates with other organs of the body to maintain systemic homeostasis. Beyond proteins, additional factors, such as lipids, metabolites, noncoding RNAs, and extracellular vesicles (EVs), released by adipose tissue participate in this process. Here, we review the diverse signaling mediators and mechanisms adipose tissu...
Source: The Journal of Lipid Research - October 1, 2019 Category: Lipidology Authors: Funcke, J.-B., Scherer, P. E. Tags: Thematic Reviews Source Type: research

Introduction to the Thematic Review Series: Adipose Biology [Thematic Reviews]
(Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - October 1, 2019 Category: Lipidology Authors: Gupta, R. K., Attie, A. D. Tags: Thematic Reviews Source Type: research

A wolf in sheeps clothing: unmasking the lanosterol-induced degradation of HMG-CoA reductase [Commentary]
(Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - October 1, 2019 Category: Lipidology Authors: Coates, H. W., Brown, A. J. Tags: Commentary Source Type: research

Withdrawal: Lipase maturation factor 1 is required for endothelial lipase activity [Withdrawals/Retractions]
(Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - September 1, 2019 Category: Lipidology Authors: Ben-Zeev, O., Hosseini, M., Lai, C.-M., Ehrhardt, N., Wong, H., Cefalu, A. B., Noto, D., Averna, M. R., Doolittle, M. H., Peterfy, M. Tags: Withdrawals/Retractions Source Type: research

Erratum: Comprehensive shotgun lipidomics of human meibomian gland secretions using MS/MSall with successive switching between acquisition polarity modes [Errata]
(Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - September 1, 2019 Category: Lipidology Authors: Chen, J., Nichols, K. K. Tags: Errata Source Type: research

Rare DEGS1 variant significantly alters de novo ceramide synthesis pathway [Patient-Oriented and Epidemiological Research]
The de novo ceramide synthesis pathway is essential to human biology and health, but genetic influences remain unexplored. The core function of this pathway is the generation of biologically active ceramide from its precursor, dihydroceramide. Dihydroceramides have diverse, often protective, biological roles; conversely, increased ceramide levels are biomarkers of complex disease. To explore the genetics of the ceramide synthesis pathway, we searched for deleterious nonsynonymous variants in the genomes of 1,020 Mexican Americans from extended pedigrees. We identified a Hispanic ancestry-specific rare functional variant, L...
Source: The Journal of Lipid Research - September 1, 2019 Category: Lipidology Authors: Blackburn, N. B., Michael, L. F., Meikle, P. J., Peralta, J. M., Mosior, M., McAhren, S., Bui, H. H., Bellinger, M. A., Giles, C., Kumar, S., Leandro, A. C., Almeida, M., Weir, J. M., Mahaney, M. C., Dyer, T. D., Almasy, L., VandeBerg, J. L., Williams-Bla Tags: Patient-Oriented and Epidemiological Research Source Type: research

New evidence from plasma ceramides links apoE polymorphism to greater risk of coronary artery disease in Finnish adults [Patient-Oriented and Epidemiological Research]
In conclusion, new evidence from plasma ceramides links apoE polymorphism with an increased risk of CAD and extends our understanding of the role of apoE in health and disease. (Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - September 1, 2019 Category: Lipidology Authors: Karjalainen, J.-P., Mononen, N., Hutri-Kähönen, N., Lehtimäki, M., Hilvo, M., Kauhanen, D., Juonala, M., Viikari, J., Kähönen, M., Raitakari, O., Laaksonen, R., Lehtimäki, T. Tags: Patient-Oriented and Epidemiological Research Source Type: research

Comparative quantitative systems pharmacology modeling of anti-PCSK9 therapeutic modalities in hypercholesterolemia [Patient-Oriented and Epidemiological Research]
The objective of this research is to set the stage for the quantitative benchmarking of two anti-PCSK9 pharmacological modality classes, monoclonal antibodies (mAbs) and small interfering RNA (siRNA). To this end, we developed an integrative mathematical model of lipoprotein homeostasis describing the dynamic interplay between PCSK9, LDL-cholesterol (LDL-C), VLDL-cholesterol, HDL-cholesterol (HDL-C), apoB, lipoprotein a [Lp(a)], and triglycerides (TGs). We demonstrate that LDL-C decreased proportionally to PCSK9 reduction for both mAb and siRNA modalities. At marketed doses, however, treatment with mAbs resulted in an addi...
Source: The Journal of Lipid Research - September 1, 2019 Category: Lipidology Authors: Sokolov, V., Helmlinger, G., Nilsson, C., Zhudenkov, K., Skrtic, S., Hamren, B., Peskov, K., Hurt-Camejo, E., Jansson-Löfmark, R. Tags: Patient-Oriented and Epidemiological Research Source Type: research

Heritability of apolipoprotein (a) traits in two-generational African-American and Caucasian families [Patient-Oriented and Epidemiological Research]
Heritability of LPA allele, apo(a) isoform sizes, and isoform-associated lipoprotein(a) [Lp(a)] levels was studied in 82 Caucasian and African-American families with two parents and two children (age: 6–74 years). We determined: 1) Lp(a) levels; 2) LPA allele sizes; 3) apo(a) isoform sizes; and 4) isoform-specific apo(a) levels (ISLs), the amount of Lp(a) carried by an individual apo(a) isoform. Trait heritability was estimated by mid-parent-offspring analysis. The ethnicity-adjusted heritability estimate for Lp(a) level was 0.95. Heritability for ISLs corresponding to the smaller LPA allele in a given allele-pair wa...
Source: The Journal of Lipid Research - September 1, 2019 Category: Lipidology Authors: Enkhmaa, B., Anuurad, E., Zhang, W., Kim, K., Berglund, L. Tags: Patient-Oriented and Epidemiological Research Source Type: research

Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells [Research Articles]
The combination of daunorubicin (dnr) and cytarabine (Ara-C) is a cornerstone of treatment for acute myelogenous leukemia (AML); resistance to these drugs is a major cause of treatment failure. Ceramide, a sphingolipid (SL), plays a critical role in cancer cell apoptosis in response to chemotherapy. Here, we investigated the effects of chemotherapy selection pressure with Ara-C and dnr on SL composition and enzyme activity in the AML cell line HL-60. Resistant cells, those selected for growth in Ara-C- and dnr-containing medium (HL-60/Ara-C and HL-60/dnr, respectively), demonstrated upregulated expression and activity of g...
Source: The Journal of Lipid Research - September 1, 2019 Category: Lipidology Authors: Kao, L.-P., Morad, S. A. F., Davis, T. S., MacDougall, M. R., Kassai, M., Abdelmageed, N., Fox, T. E., Kester, M., Loughran, T. P., Abad, J. L., Fabrias, G., Tan, S.-F., Feith, D. J., Claxton, D. F., Spiegel, S., Fisher-Wellman, K. H., Cabot, M. C. Tags: Research Articles Source Type: research

Lysophosphatidylcholine-induced mitochondrial fission contributes to collagen production in human cardiac fibroblasts [Research Articles]
Lysophosphatidylcholine (LPC) may accumulate in the heart to cause fibrotic events, which is mediated through fibroblast activation and collagen accumulation. Here, we evaluated the mechanisms underlying LPC-mediated collagen induction via mitochondrial events in human cardiac fibroblasts (HCFs), coupling application of the pharmacologic cyclooxygenase-2 (COX-2) inhibitor, celecoxib, and genetic mutations in FOXO1 on the fibrosis pathway. In HCFs, LPC caused prostaglandin E2 (PGE2)/PGE2 receptor 4 (EP4)-dependent collagen induction via activation of transcriptional activity of forkhead box protein O1 (FoxO1) on COX-2 gene ...
Source: The Journal of Lipid Research - September 1, 2019 Category: Lipidology Authors: Tseng, H.-C., Lin, C.-C., Hsiao, L.-D., Yang, C.-M. Tags: Research Articles Source Type: research