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A targeted proteomics method for quantifying plasma apolipoprotein kinetics in individual mice using stable isotope labeling J. Lipid Res. (IF 6.5) Pub Date : 2024-03-13 Baohai Shao, Masami Shimizu-Albergine, Farah Kramer, Jenny E. Kanter, Jay W. Heinecke, Tomas Vaisar, Bettina Mittendorfer, Bruce W. Patterson, Karin E. Bornfeldt
Altered apolipoprotein kinetics play a critical role in promoting dyslipidemia and atherogenesis. Human apolipoprotein kinetics have been extensively evaluated, but similar studies in mice are hampered by the lack of robust methods suitable for the small amounts of blood that can be collected at sequential time points from individual mice. We describe a targeted liquid chromatography tandem mass spectrometry
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Apolipoprotein A1 and high-density lipoprotein limit low-density lipoprotein transcytosis by binding SR-B1 J. Lipid Res. (IF 6.5) Pub Date : 2024-03-12 Karen Y.Y. Fung, Tse Wing Winnie Ho, Zizhen Xu, Dante Neculai, Catherine A.A. Beauchemin, Warren L. Lee, Gregory D. Fairn
Atherosclerosis results from the deposition and oxidation of low-density lipoprotein (LDL) and immune cell infiltration in the sub-arterial space leading to arterial occlusion. Studies have shown that transcytosis transports circulating LDL across endothelial cells lining blood vessels. LDL transcytosis is initiated by binding to either Scavenger Receptor B1 (SR-B1) or Activin A receptor-like kinase
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Causal association of blood lipids with all-cause and cause-specific mortality risk: a Mendelian randomization study. J. Lipid Res. (IF 6.5) Pub Date : 2024-03-06 Jiawen Lu, Zhenqian Wang, Jiaying Zhang, Feng Jiao, Chenfeng Zou, Liyuan Han, Guozhi Jiang
Dyslipidemia has long been implicated in elevating mortality risk; yet the precise associations between lipid traits and mortality remained undisclosed. Our study aimed to explore the causal effects of lipid traits on both all-cause and cause-specific mortality. One-sample Mendelian randomization (MR) with linear and nonlinear assumptions was conducted in a cohort of 407,951 European participants from
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Hepatic FOXA3 overexpression prevents Western diet-induced obesity and MASH through TGR5 J. Lipid Res. (IF 6.5) Pub Date : 2024-03-04 Raja Gopoju, Jiayou Wang, Xiaoli Pan, Shuwei Hu, Li Lin, Alyssa Clark, Yanyong Xu, Liya Yin, Xinwen Wang, Yanqiao Zhang
Forkhead transcription factor 3 (FOXA3) has been shown to regulate metabolism and development. Hepatic FOXA3 is reduced in obesity and fatty liver disease. However, the role of hepatic FOXA3 in regulating obesity or steatohepatitis remains to be investigated. In this work, C57BL/6 mice were i.v. injected with AAV8-ALB-FOXA3 or the control virus. The mice were then fed a chow or Western diet for 16
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Characterization of sexual dimorphism in ANGPTL4 levels and function J. Lipid Res. (IF 6.5) Pub Date : 2024-02-29 Mingjuan Deng, Sander Kersten
ANGPTL4 is an attractive pharmacological target for lowering plasma triglycerides and cardiovascular risk. Since most preclinical studies on ANGPTL4 were performed in male mice, little is known about sexual dimorphism in ANGPTL4 regulation and function. Here, we aimed to study potential sexual dimorphism in ANGPTL4 mRNA and protein levels and ANGPTL4 function. Additionally, we performed exploratory
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Mining cholesterol genes from thousands of mouse livers identifies aldolase C as a regulator of cholesterol biosynthesis J. Lipid Res. (IF 6.5) Pub Date : 2024-02-28 James A. Votava, Steven V. John, Zhonggang Li, Shuyang Chen, Jing Fan, Brian W. Parks
The availability of genome-wide transcriptomic and proteomic datasets is ever-increasing and often not used beyond initial publication. Here, we applied module-based coexpression network analysis to a comprehensive catalog of 35 mouse genome-wide liver expression datasets (encompassing more than 3800 mice) with the goal of identifying and validating unknown genes involved in cholesterol metabolism
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PCSK9 vaccines: a promising new strategy for the treatment of hypercholesterolemia? J. Lipid Res. (IF 6.5) Pub Date : 2024-02-17 Bryce Chackerian, Alan T. Remaley
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A fluorogenic substrate for the detection of lipid amidases in intact cells J. Lipid Res. (IF 6.5) Pub Date : 2024-02-17 Mireia Casasampere, Johnson Ung, Alejandro Iñáñez, Carine Dufau, Kazuhito Tsuboi, Josefina Casas, Su-Fern Tan, David J. Feith, Nathalie Andrieu-Abadie, Bruno Segui, Thomas P. Loughran Jr., José Luis Abad, Gemma Fabrias
Lipid amidases of therapeutic relevance include acid ceramidase (AC), -acylethanolamine-hydrolyzing acid amidase, and fatty acid amide hydrolase (FAAH). Although fluorogenic substrates have been developed for the three enzymes and high-throughput methods for screening have been reported, a platform for the specific detection of these enzyme activities in intact cells is lacking. In this article, we
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Decreased sarcoplasmic reticulum phospholipids in human skeletal muscle are associated with metabolic syndrome J. Lipid Res. (IF 6.5) Pub Date : 2024-02-13 Samantha E. Adamson, Sangeeta Adak, Max C. Petersen, Dustin Higgins, Larry D. Spears, Rong Mei Zhang, Andrea Cedeno, Alexis McKee, Aswathi Kumar, Sudhir Singh, Fong-Fu Hsu, Janet B. McGill, Clay F. Semenkovich
Metabolic syndrome affects more than one in three adults and is associated with increased risk of diabetes, cardiovascular disease, and all-cause mortality. Muscle insulin resistance is a major contributor to the development of the metabolic syndrome. Studies in mice have linked skeletal muscle sarcoplasmic reticulum (SR) phospholipid composition to sarcoplasmic/endoplasmic reticulum Ca-ATPase activity
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Loss of function and reduced levels of sphingolipid desaturase DEGS1 variants are both relevant in disease mechanism J. Lipid Res. (IF 6.5) Pub Date : 2024-02-10 Michele Dei Cas, Linda Montavoci, Claudia Pasini, Anna Caretti, Sara Penati, Carla Martinelli, Umberto Gianelli, Sara Casati, Francesca Nardecchia, Annalaura Torella, Nicola Brunetti-Pierri, Marco Trinchera
The last step of ex novo ceramide biosynthesis consists of the conversion of dihydroceramide into ceramide catalyzed by sphingolipid Δ4-desaturase DEGS1. DEGS1 variants were found to be responsible for heterogeneous clinical pictures belonging to the family of hypomyelinating leukodystrophies. To investigate the mechanisms making such variants pathogenic, we designed a procedure for the efficient detection
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Elovl4b knockout zebrafish as a model for ocular very-long-chain PUFA deficiency J. Lipid Res. (IF 6.5) Pub Date : 2024-02-10 Uzoamaka Nwagbo, Saba Parvez, J. Alan Maschek, Paul S. Bernstein
Very-long-chain PUFAs (VLC-PUFAs) are a group of lipids with chain lengths >24 carbons, and the ELOVL4 (elongation of very-long-chain FA-4) enzyme is responsible for vertebrate VLC-PUFA biosynthesis. Studies on the role of VLC-PUFAs in vision have been hindered because of the need for adequate animal models to capture the global loss of VLC-PUFAs. Since homozygous ablation is lethal in neonatal mice
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Plasma C24:0- and C26:0-lysophosphatidylcholines are Reliable Biomarkers for the Diagnosis of Peroxisomal β-Oxidation Disorders. J. Lipid Res. (IF 6.5) Pub Date : 2024-02-04 Blai Morales-Romero, José Manuel González de Aledo-Castillo, Cristina Fernández Sierra, Carmen Martínez Carreira, Carles Zaragoza Bonet, Rosa Fernández Bonifacio, Maria Antònia Caro Miró, Ana Argudo-Ramírez, Rosa María López Galera, Judit García-Villoria
The gold-standard diagnostic test for peroxisomal disorders (PDs) is plasma concentration analysis of very long-chain fatty acids (VLCFA). However, this method's time-consuming nature and limitations in cases which present normal VLCFA levels necessitates alternative approaches. The analysis of C26:0-lysophosphatydylcholine (C26:0-LPC) in dried blood spot samples by tandem-mass spectrometry (MS/MS)
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Evaluation of antisense oligonucleotide therapy targeting Hsd17b13 in a fibrosis mice model J. Lipid Res. (IF 6.5) Pub Date : 2024-02-02 Yanling Ma, Hong Cai, Julia Smith, Ching-Hsuen Chu, Stephen E. Mercer, Stephanie Boehm, Ivar Mcdonald, Bradley Zinker, Dong Cheng
Human genetic evidence suggests a protective role of loss-of-function variants in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) for liver fibrotic diseases. Although there is limited preclinical experimental data on Hsd17b13 antisense oligonucleotide (ASO) or siRNA in a fibrosis model, several ASO and siRNA approaches are being tested clinically as potential therapies for nonalcoholic steatohepatitis
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Geranylgeranyl Isoprenoids and Hepatic Rap1a Regulate Basal and Statin-Induced Expression of PCSK9. J. Lipid Res. (IF 6.5) Pub Date : 2024-02-01 Yating Wang, Brea Tinsley, Stefano Spolitu, John A Zadroga, Heena Agarwal, Amesh K Sarecha, Lale Ozcan
Low-density lipoprotein cholesterol (LDL-C) lowering is the main goal of atherosclerotic cardiovascular disease prevention, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is now a validated therapeutic strategy that lowers serum LDL-C and reduces coronary events. Ironically, the most widely used medicine to lower cholesterol, statins, has been shown to increase circulating PCSK9
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Bacterial lipopolysaccharide forms aggregates with apolipoproteins in male and female rat brains after ethanol binges. J. Lipid Res. (IF 6.5) Pub Date : 2024-01-29 L López-Valencia, M Moya, B Escudero, B García-Bueno, L Orio
Alcohol binge drinking allows the translocation of bacterial lipopolysaccharide (LPS) from the gut to the blood, which activates the peripheral immune system with consequences in neuroinflammation. A possible access/direct signaling of LPS to/in the brain has not yet been described under alcohol abuse conditions. Apolipoproteins are compounds altered by alcohol with high affinity to LPS which may be
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Histone demethylase KDM1A promotes hepatic steatosis and inflammation by increasing chromatin accessibility in NAFLD. J. Lipid Res. (IF 6.5) Pub Date : 2024-01-29 Zifeng Yang, Siyao Zhang, Xiang Liu, Rui Shu, Wei Shi, Weiyi Qu, Dianyu Liu, Zhiwei Cai, Ye Wang, Xu Cheng, Yemao Liu, Xiao-Jing Zhang, Lan Bai, Hongliang Li, Zhi-Gang She
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease without specific FDA-approved drugs. Recent advances suggest that chromatin remodeling and epigenetic alteration contribute to the development of NAFLD. The functions of the corresponding molecular modulator in NAFLD, however, are still elusive. KDM1A, commonly known as LSD1 (lysine-specific histone demethylase 1)
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PI(4,5)P2 binding sites in the Ebola virus matrix protein VP40 modulate assembly and budding. J. Lipid Res. (IF 6.5) Pub Date : 2024-01-29 Kristen A Johnson, Melissa R Budicini, Nisha Bhattarai, Tej Sharma, Sarah Urata, Bernard S Gerstman, Prem P Chapagain, Sheng Li, Robert V Stahelin
Ebolavirus (EBOV) causes severe hemorrhagic fever in humans and is lethal in a large percentage of those infected. The EBOV matrix protein VP40 is a peripheral binding protein that forms a shell beneath the lipid bilayer in virions and virus-like particles (VLPs). VP40 is required for virus assembly and budding from the host cell plasma membrane. VP40 is a dimer that can rearrange into oligomers at
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Glucosylceramide flippases contribute to cellular glucosylceramide homeostasis. J. Lipid Res. (IF 6.5) Pub Date : 2024-01-25 Natsuki Kita, Asuka Hamamoto, Siddabasave Gowda B Gowda, Hiroyuki Takatsu, Kazuhisa Nakayama, Makoto Arita, Shu-Ping Hui, Hye-Won Shin
Lipid transport is an essential cellular process with importance to human health, disease development, and therapeutic strategies. Type IV P-type ATPases (P4-ATPases) have been identified as membrane lipid flippases by utilizing nitrobenzoxadiazole (NBD)-labeled lipids as substrates. Among the 14 human P4-ATPases, ATP10D was shown to flip NBD-glucosylceramide (GlcCer) across the plasma membrane. Here
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Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes. J. Lipid Res. (IF 6.5) Pub Date : 2024-01-25 Masato Komai, Yuka Noda, Atsuya Ikeda, Nanaka Kaneshiro, Yuji Kamikubo, Takashi Sakurai, Takashi Uehara, Nobumasa Takasugi
The link between changes in astrocyte function and the pathological progression of Alzheimer's disease (AD) has attracted considerable attention. Interestingly, activated astrocytes in AD show abnormalities in their lipid content and metabolism. In particular, the expression of ApoE, a lipid transporter, is decreased. Because ApoE has anti-inflammatory and amyloid β (Aβ)-metabolizing effects, the nuclear
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Finasteride delays atherosclerosis progression in mice and is associated with a reduction in plasma cholesterol in men. J. Lipid Res. (IF 6.5) Pub Date : 2024-01-23 Patrick McQueen, Donald Molina, Ivan Pinos, Samuel Krug, Anna J Taylor, Michael R LaFrano, Maureen A Kane, Jaume Amengual
Finasteride is commonly prescribed to treat benign prostate hyperplasia and male-pattern baldness in cis men and, more recently, trans individuals. However, the effect of finasteride on cardiovascular disease remains elusive. We evaluated the role of finasteride on atherosclerosis using low-density lipoprotein (LDL) receptor-deficient (Ldlr-/-) mice. Next, we examined the relevance to humans by analysing
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The role of N-terminal phosphorylation of DGK-θ J. Lipid Res. (IF 6.5) Pub Date : 2024-01-23 Millie X. Barbernitz, Lauren R. Devine, Robert N. Cole, Daniel M. Raben
Diacylglycerol kinases (DGKs) are lipid kinases that mediate the phosphorylation of diacylglycerol (DAG) leading to the production of phosphatidic acid (PtdOH). To examine the role of phosphorylation on DGK-θ, we first identified the phosphorylated sites on endogenous DGK-θ from mouse brain and found four sites: S15, S17, which we refer to phosphomotif-1 sites, and S22 and S26 which we refer to as
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Changes in Soluble LDL Receptor and Lipoprotein Fractions in Response to Diet in the DIETFITS Weight Loss Study. J. Lipid Res. (IF 6.5) Pub Date : 2024-01-19 Ronald M Krauss, Lois M Fisher, Sarah M King, Christopher D Gardner
Circulating levels of the soluble ligand binding ectodomain of the LDL receptor (sLDLR) that is proteolytically cleaved from the cell surface have been shown to correlate with plasma triglycerides, but the lipid and lipoprotein effects of longitudinal changes in sLDLR have not been examined. We sought to assess associations between changes in sLDLR and detailed lipoprotein measurements between baseline
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Spatial Lipidomics of Coronary Atherosclerotic Plaque Development in a Familial Hypercholesterolemia Swine Model. J. Lipid Res. (IF 6.5) Pub Date : 2024-01-19 Nuria Slijkhuis, Francesca Razzi, Suze-Anne Korteland, Bram Heijs, Kim van Gaalen, Dirk J Duncker, Antonius F W van der Steen, Volkert van Steijn, Heleen M M van Beusekom, Gijs van Soest
Coronary atherosclerosis is caused by plaque build-up, with lipids playing a pivotal role in its progression. However, lipid composition and distribution within coronary atherosclerosis remain unknown. This study aims to characterize lipids and investigate differences in lipid composition across disease stages to aid in the understanding of disease progression. Matrix-assisted laser desorption/ionization
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ANGPTL3 deficiency impairs lipoprotein production and produces adaptive changes in hepatic lipid metabolism. J. Lipid Res. (IF 6.5) Pub Date : 2024-01-12 Kendall H Burks, Yan Xie, Michael Gildea, In-Hyuk Jung, Sandip Mukherjee, Paul Lee, Upasana Pudupakkam, Ryan Wagoner, Ved Patel, Katherine Santana, Arturo Alisio, Ira J Goldberg, Brian N Finck, Edward A Fisher, Nicholas O Davidson, Nathan O Stitziel
Angiopoietin-like protein 3 (ANGPTL3) is a hepatically secreted protein and therapeutic target for reducing plasma triglyceride-rich lipoproteins (TRL) and low-density lipoprotein cholesterol (LDL). Although ANGPTL3 modulates the metabolism of circulating lipoproteins, its role in TRL assembly and secretion remains unknown. CRISPR-associated protein 9 (CRISPR/Cas9) was used to target ANGPTL3 in HepG2
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The oxidized phospholipid PGPC impairs endothelial function by promoting endothelial cell ferroptosis via FABP3. J. Lipid Res. (IF 6.5) Pub Date : 2024-01-11 Si Chen, Jian-Jun Gao, Yu-Jia Liu, Zhi-Wei Mo, Fang-Yuan Wu, Zuo-Jun Hu, Yue-Ming Peng, Xiao-Qin Zhang, Zhen-Sheng Ma, Ze-Long Liu, Jian-Yun Yan, Zhi-Jun Ou, Yan Li, Jing-Song Ou
Ferroptosis is a novel cell death mechanism that is mediated by iron-dependent lipid peroxidation. It may be involved in atherosclerosis development. Products of phospholipid oxidation play a key role in atherosclerosis. 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) is a phospholipid oxidation product present in atherosclerotic lesions. It remains unclear whether PGPC causes atherosclerosis
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APOE genotype dictates lipidomic signatures in primary human hepatocytes. J. Lipid Res. (IF 6.5) Pub Date : 2024-01-10 Francisco C Almeida, Kalicharan Patra, Andreas Giannisis, Anezka Niesnerova, Renu Nandakumar, Ewa Ellis, Tiago Gil Oliveira, Henrietta M Nielsen
Apolipoprotein E (APOE) genetic variants are most notably known for their divergent impact on the risk of developing Alzheimer's disease. While APOE genotype has been consistently shown to modulate lipid metabolism in a variety of cellular contexts, the effect of APOE alleles on the lipidome in hepatocytes is unknown. In this study, we investigated the contribution of APOE alleles to lipidomic profiles
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VXX-401, a novel anti-PCSK9 vaccine, reduces LDL-C in cynomolgus monkeys. J. Lipid Res. (IF 6.5) Pub Date : 2024-01-10 Madeline M Vroom, Hanxin Lu, Maggie Lewis, Brett A Thibodeaux, Jeanne K Brooks, Matthew S Longo, Martina M Ramos, Jaya Sahni, Jonathan Wiggins, Justin D Boyd, Shuang Ding, Michael Hellerstein, Valorie Ryan, Peter Powchik, Jean-Cosme Dodart
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disease burden in the world and is highly correlated with chronic elevations of low-density lipoprotein cholesterol (LDL-C). LDL-C lowering drugs such as statins or monoclonal antibodies (mAbs) against proprotein convertase subtilisin/kexin type 9 (PCSK9) are known to reduce the risk of cardiovascular diseases, however statins
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A Historical, Evidence-Based, and Narrative Review on Commonly Used Dietary Supplements in Lipid-Lowering. J. Lipid Res. (IF 6.5) Pub Date : 2023-12-23 Jelani K Grant, Michael Dangl, Chiadi E Ndumele, Erin D Michos, Seth S Martin
Dietary supplements augment the nutritional value of everyday food intake and originate from the historical practices of ancient Egyptian (Ebers papyrus), Chinese (Pen Ts'ao by Shen Nung), Indian (Ayurveda), Greek (Hippocrates), and Arabic herbalists. In modern-day medicine, the use of dietary supplements continues to increase in popularity with greater than 50% of the US population reporting taking
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Unmasking Crucial Residues in Adipose Triglyceride Lipase (ATGL) for Co-Activation with Comparative Gene Identification-58 (CGI-58). J. Lipid Res. (IF 6.5) Pub Date : 2023-12-20 Natalia Kulminskaya, Carlos Francisco Rodriguez Gamez, Peter Hofer, Ines Kathrin Cerk, Noopur Dubey, Roland Viertlmayr, Theo Sagmeister, Tea Pavkov-Keller, Rudolf Zechner, Monika Oberer
Lipolysis is an essential metabolic process that releases unesterified fatty acids from neutral lipid stores to maintain energy homeostasis in living organisms. Adipose triglyceride lipase (ATGL) plays a key role in intracellular lipolysis and can be co-activated upon interaction with the protein comparative gene identification-58 (CGI-58). The underlying molecular mechanism of ATGL stimulation by
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Wide-scope targeted analysis of bioactive lipids in human plasma by LC/MS/MS. J. Lipid Res. (IF 6.5) Pub Date : 2023-12-20 Kohta Nakatani, Yoshihiro Izumi, Hironobu Umakoshi, Maki Yokomoto-Umakoshi, Tomoko Nakaji, Hiroki Kaneko, Hiroshi Nakao, Yoshihiro Ogawa, Kazutaka Ikeda, Takeshi Bamba
Quantitative information on blood metabolites can be used in developing advanced medical strategies such as early detection and prevention of disease. Monitoring bioactive lipids such as steroids, bile acids, and polyunsaturated fatty acid (PUFA) metabolites could be a valuable indicator of health status. However, a method for simultaneously measuring these bioactive lipids has not yet been developed
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Unravelling the genetic background of individuals with a clinical Familial Hypercholesterolemia phenotype. J. Lipid Res. (IF 6.5) Pub Date : 2023-12-18 Ana Margarida Medeiros, Ana Catarina Alves, Beatriz Miranda, Joana Rita Chora, Mafalda Bourbon
Familial Hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, ABCG8), polygenic hypercholesterolemia and hyper-Lp(a) can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical
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Phosphatidylthreonine is a procoagulant lipid detected in human blood and elevated in coronary artery disease. J. Lipid Res. (IF 6.5) Pub Date : 2023-12-14 Ali A Hajeyah, Majd B Protty, Divyani Paul, Daniela Costa, Nader Omidvar, Bethan Morgan, Yugo Iwasaki, Beth McGill, P Vincent Jenkins, Zaheer Yousef, Keith Allen-Redpath, Shin Soyama, Anirban Choudhury, Rito Mitra, Parveen Yaqoob, James H Morrissey, Peter W Collins, Valerie B O'Donnell
Aminophospholipids (aPL) such as phosphatidylserine (PS) are essential for supporting the activity of coagulation factors, circulating platelets and blood cells. Phosphatidylthreonine (PT) is an aPL previously reported in eukaryotic parasites and animal cell cultures, but not yet in human tissues. Here, we evaluated whether PT is present in blood cells and characterized its ability to support coagulation
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Effects of apolipoprotein H downregulation on lipid metabolism, fatty liver disease, and gut microbiota dysbiosis. J. Lipid Res. (IF 6.5) Pub Date : 2023-12-13 Yaming Liu, Yiqun Zhao, Qiusong Liu, Binbin Li, Vineeth D Poovannalil, Binbin Chen, Zeyi Wu
Apolipoprotein H (APOH) downregulation can cause hepatic steatosis and gut microbiota dysbiosis. However, the mechanism by which APOH-regulated lipid metabolism contributes to metabolic dysfunction associated steatotic liver disease (MASLD) remains undetermined. Herein, we aim to explore the regulatory effect of APOH, mediated through various pathways, on metabolic homeostasis and MASLD pathogenesis
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Functional characterization of missense variants affecting the extracellular domains of ABCA1 using a fluorescence-based assay. J. Lipid Res. (IF 6.5) Pub Date : 2023-12-03 Marianne Teigen, Åsa Schawlann Ølnes, Katrine Bjune, Trond P Leren, Martin Prøven Bogsrud, Thea Bismo Strøm
Excess cholesterol originating from non-hepatic tissues is transported within high-density lipoprotein (HDL) particles to the liver for metabolism and excretion. Cholesterol efflux is initiated by lipid-free or lipid-poor apolipoprotein A1 (ApoA1) interacting with the transmembrane protein adenosine triphosphate-binding cassette transporter A1 (ABCA1), a key player in cholesterol homeostasis. Defective
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Human HDL subclasses modulate energy metabolism in skeletal muscle cells. J. Lipid Res. (IF 6.5) Pub Date : 2023-11-24 Jenny Lund,Emilia Lähteenmäki,Tiia Eklund,Hege G Bakke,G Hege Thoresen,Eija Pirinen,Matti Jauhiainen,Arild C Rustan,Maarit Lehti
In addition to its anti-atherogenic role, HDL reportedly modulates energy metabolism at the whole-body level. HDL functionality is associated with its structure and composition, and functional activities can differ between HDL subclasses. Therefore, we studied if HDL2 and HDL3, the two major HDL subclasses, are able to modulate energy metabolism of skeletal muscle cells. Differentiated mouse and primary
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Lipid structure matters in lysosomal storage disease. J. Lipid Res. (IF 6.5) Pub Date : 2023-11-14 Roger Sandhoff
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JLR-D-23-00401-R1 Dissecting cell type-specific impact in lysosomal acid lipase deficiency-associated disorders. J. Lipid Res. (IF 6.5) Pub Date : 2023-11-14 Marit Westerterp,Fang Li,Hanrui Zhang
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Apolipoprotein C3: Form begets function. J. Lipid Res. (IF 6.5) Pub Date : 2023-11-14 Karin E Bornfeldt
Increased circulating levels of apolipoprotein C3 (APOC3) predict cardiovascular disease (CVD) risk in humans, and APOC3 promotes atherosclerosis in mouse models. APOC3's mechanism of action is due in large part to its ability to slow the clearance of triglyceride-rich lipoproteins (TRLs) and their remnants when APOC3 is carried by these lipoproteins. However, different pools and forms of APOC3 exert
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The Role of KLF2 in Regulating Hepatic Lipogenesis and Blood Cholesterol Homeostasis via the SCAP/SREBP Pathway. J. Lipid Res. (IF 6.5) Pub Date : 2023-11-08 Yuhong Huang, Yi Fan Wang, Xiong-Zhong Ruan, Chi Wai Lau, Li Wang, Yu Huang
Liver steatosis is a common metabolic disorder resulting from imbalanced lipid metabolism, which involves various processes such as de novo lipogenesis, fatty acid uptake, fatty acid oxidation, and VLDL secretion. In this study, we discovered that KLF2, a transcription factor, plays a crucial role in regulating lipid metabolism in the liver. Overexpression of KLF2 in the liver of db/db mice, C57BL/6J
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Ola1p trafficking indicates an interaction network between mitochondria, Lipid droplets and stress granules in times of stress. J. Lipid Res. (IF 6.5) Pub Date : 2023-11-08 Melanie Kovacs, Florian Geltinger, Lukas Schartel, Simon Pöschl, Peter Briza, Manuel Paschinger, Kitti Boros, Thomas Klaus Felder, Herbert Wimmer, Jutta Duschl, Mark Rinnerthaler
Protein aggregates arise naturally under normal physiological conditions, but their formation is accelerated by age or stress-induced protein misfolding. When the stressful event dissolves, these aggregates are removed by mechanisms such as aggrephagy, chaperone-mediated autophagy, refolding attempts, or the proteasome. It was recently shown that mitochondria in yeast cells may support these primarily
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Identification of genetic drivers of plasma lipoprotein size in the Diversity Outbred mouse population. J. Lipid Res. (IF 6.5) Pub Date : 2023-11-07 Tara R Price, Christopher H Emfinger, Kathryn L Schueler, Sarah King, Rebekah Nicholson, Tim Beck, Brian S Yandell, Scott A Summers, William L Holland, Ronald M Krauss, Mark P Keller, Alan D Attie
Despite great progress in understanding lipoprotein physiology, there is still much to be learned about the genetic drivers of lipoprotein abundance, composition, and function. We used ion mobility spectrometry to survey 16 plasma lipoprotein subfractions in 500 Diversity Outbred (DO) mice maintained on a Western-style diet. We identified 21 quantitative trait loci (QTL) affecting lipoprotein abundance
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Lipidomic analysis of Porphyromonas gingivalis reveals novel glycerol bisphosphoceramide, phosphatidyl- and phosphoglycerol dipeptide lipid families. J. Lipid Res. (IF 6.5) Pub Date : 2023-11-02 Brian A Kleiboeker,Cheryl Frankfater,Mary E Davey,Fong-Fu Hsu
Porphyromonas gingivalis, like other members of the phylum Bacteroidetes (synonym Bacteroidota), synthesizes several classes of dihydroceramides and peptidolipids. Using a similar strategy as that recently used to delimit the lipidome of its close relative Bacteroides fragilis, we applied linear ion-trap (LIT) multiple-stage mass spectrometry (LIT MSn) with high resolution mass spectrometry (HRMS)
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Sterol interactions influence the function of Wsc sensors. J. Lipid Res. (IF 6.5) Pub Date : 2023-11-02 Lukas Bernauer,Paula Berzak,Leonie Lehmayer,Julia Messenlehner,Gustav Oberdorfer,Günther Zellnig,Heimo Wolinski,Christoph Augustin,Melanie Baeck,Anita Emmerstorfer-Augustin
The Wsc1, Wsc2, and Wsc3 proteins are essential cell surface sensors that respond to cell wall perturbation by activating the cell wall integrity pathway (CWIP). We show here that in situ production of cholesterol (in place of ergosterol) induces hyper-phosphorylation of Slt2, the MAPK of the CWIP, and upregulates cell wall biosynthesis. Deletion of all three Wsc genes in K. phaffii reverts these phenotypes
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Microbial products linked to steatohepatitis are reduced by deletion of nuclear hormone receptor SHP in mice. J. Lipid Res. (IF 6.5) Pub Date : 2023-11-02 Ryan Mifflin,Jung Eun Park,Mikang Lee,Prasant Kumar Jena,Yu-Jui Yvonne Wan,Hazel A Barton,Mirjavid Aghayev,Takhar Kasumov,Li Lin,Xinwen Wang,Robert Novak,Feng Li,He Huang,Leah P Shriver,Yoon-Kwang Lee
Deletion of the nuclear hormone receptor small heterodimer partner (Shp) ameliorates the development of obesity and nonalcoholic steatohepatitis (NASH) in mice. Liver-specific SHP plays a significant role in this amelioration. The gut microbiota has been associated with these metabolic disorders, and the interplay between bile acids (BAs) and gut microbiota contributes to various metabolic disorders
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Imaging the ANGPTL3/8-mediated regulation of lipoprotein lipase in the heart. J. Lipid Res. (IF 6.5) Pub Date : 2023-10-26 Ye Yang,Hyesoo Jung,Robert J Konrad,Loren G Fong,Stephen G Young
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The atypical sphingolipid SPB 18:1(14Z);O2 is a biomarker for DEGS1 related hypomyelinating leukodystrophy. J. Lipid Res. (IF 6.5) Pub Date : 2023-10-25 Andreas J Hülsmeier, Sandra P Toelle, Peter Bellstedt, Christian Wentzel, Angela Bahr, Konstantinos Kolokotronis, Thorsten Hornemann
Sphingolipids (SL) represent a structurally diverse class of lipids that are central to cellular physiology and neuronal development and function. Defects in the sphingolipid metabolism are typically associated with nervous system disorders. The C4-dihydroceramide desaturase (DEGS1) catalyzes the conversion of dihydroceramide to ceramide, the final step in the SL de-novo synthesis. Loss of function
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TMEM241 is a UDP-N-acetylglucosamine transporter required for M6P modification of NPC2 and cholesterol transport. J. Lipid Res. (IF 6.5) Pub Date : 2023-10-25 Nan Zhao, Gang Deng, Pei-Xin Yuan, Ya-Fen Zhang, Lu-Yi Jiang, Xiaolu Zhao, Bao-Liang Song
Accurate intracellular cholesterol traffic plays crucial roles. Niemann Pick type C (NPC) proteins NPC1 and NPC2, are two lysosomal cholesterol transporters that mediate the cholesterol exit from lysosomes. However, other proteins involved in this process remain poorly defined. Here we find that the previously unannotated protein TMEM241 is required for cholesterol egressing from lysosomes through
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Sialidase NEU3 action on GM1 ganglioside is neuroprotective in GM1 gangliosidosis. J. Lipid Res. (IF 6.5) Pub Date : 2023-10-21 Maria L Allende,Y Terry Lee,Colleen Byrnes,Cuiling Li,Galina Tuymetova,Jenna Y Bakir,Elena-Raluca Nicoli,Virginia K James,Jennifer S Brodbelt,Cynthia J Tifft,Richard L Proia
GM1 gangliosidosis is a neurodegenerative disorder caused by mutations in the GLB1 gene, which encodes lysosomal β-galactosidase. The enzyme deficiency blocks GM1 ganglioside catabolism, leading to accumulation of GM1 ganglioside and asialo-GM1 ganglioside (GA1 glycolipid) in brain. This disease can present in varying degrees of severity, with the level of residual β-galactosidase activity primarily
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Cooperation of acylglycerol hydrolases in neuronal lipolysis. J. Lipid Res. (IF 6.5) Pub Date : 2023-10-21 Liqing Yu
Genetic and biochemical evidence has established DDHD-domain containing 2 (DDHD2) as the principal triacylglycerol (TAG) hydrolase in neuronal lipolysis of cytosolic lipid droplets. In this issue of Journal of Lipid Research, Hofer et al. report that DDHD2 cooperates with adipose triglyceride lipase, the principal TAG hydrolase in adipose lipolysis, contributing to cytosolic hydrolysis of both TAG
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Altered hepatic lipid droplet morphology and lipid metabolism in fasted Plin2 null mice. J. Lipid Res. (IF 6.5) Pub Date : 2023-10-14 Atanaska I Doncheva, Yuchuan Li, Prabhat Khanal, Marit Hjorth, Svein O Kolset, Frode A Norheim, Alan R Kimmel, Knut Tomas Dalen
Perilipin 2 (Plin2) binds to the surface of hepatic lipid droplets (LDs) with expression levels that correlate with triacylglyceride (TAG) content. We investigated if Plin2 is important for hepatic LD storage in fasted or high-fat diet-induced obese Plin2+/+ and Plin2-/- mice. Plin2-/- mice had comparable body weights, metabolic phenotype, glucose tolerance, and circulating TAG and total cholesterol
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Maternal DHA intake in mice increased DHA metabolites in the pup brain and ameliorated MeHg-induced behavioral disorder. J. Lipid Res. (IF 6.5) Pub Date : 2023-10-12 Ami Oguro,Taichi Fujiyama,Yasuhiro Ishihara,Chisato Kataoka,Megumi Yamamoto,Komyo Eto,Yoshihiro Komohara,Susumu Imaoka,Toshihide Sakuragi,Mayumi Tsuji,Eiji Shibata,Yaichiro Kotake,Takeshi Yamazaki
Although pregnant women's fish consumption is beneficial for the brain development of the fetus due to the DHA in fish, seafood also contains methylmercury (MeHg), which adversely affects fetal brain development. Epidemiological studies suggest that high DHA levels in pregnant women's sera may protect the fetal brain from MeHg-induced neurotoxicity, but the underlying mechanism is unknown. Our earlier
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Deep generative models of LDLR protein structure to predict variant pathogenicity. J. Lipid Res. (IF 6.5) Pub Date : 2023-10-11 Jose K James,Kristjan Norland,Angad S Johar,Iftikhar J Kullo
The complex structure and function of low density lipoprotein receptor (LDLR) makes classification of protein-coding missense variants challenging. Deep generative models, including Evolutionary model of Variant Effect (EVE), Evolutionary Scale Modeling (ESM), and AlphaFold 2 (AF2), have enabled significant progress in the prediction of protein structure and function. ESM and EVE directly estimate
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Cooperative lipolytic control of neuronal triacylglycerol by spastic paraplegia-associated enzyme DDHD2 and ATGL. J. Lipid Res. (IF 6.5) Pub Date : 2023-10-11 Peter Hofer, Gernot F Grabner, Mario König, Hao Xie, Dominik Bulfon, Anton E Ludwig, Heimo Wolinski, Robert Zimmermann, Rudolf Zechner, Christoph Heier
Intracellular lipolysis - the enzymatic breakdown of lipid droplet (LD)-associated triacylglycerols (TAGs) - depends on the cooperative action of several hydrolytic enzymes and regulatory proteins, together designated as lipolysome. Adipose triglyceride lipase (ATGL) acts as a major cellular TAG hydrolase and core effector of the lipolysome in many peripheral tissues. Neurons initiate lipolysis independent
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Serum opacity factor normalizes erythrocyte morphology in Scarb1-/- mice in an HDL-free cholesterol-dependent way. J. Lipid Res. (IF 6.5) Pub Date : 2023-10-10 Ziyi Wang,Dedipya Yelamanchili,Jing Liu,Antonio M Gotto,Corina Rosales,Baiba K Gillard,Henry J Pownall
Compared with WT mice, HDL receptor-deficient (Scarb1-/-) mice have higher plasma levels of free cholesterol (FC)-rich HDL and exhibit multiple pathologies associated with a high mol% FC in ovaries, platelets, and erythrocytes, which are reversed by lowering HDL. Bacterial serum opacity factor (SOF) catalyzes the opacification of plasma by targeting and quantitatively converting HDL to neo HDL (HDL
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Metabolic switch from glycogen to lipid in the liver maintains glucose homeostasis in neonatal mice. J. Lipid Res. (IF 6.5) Pub Date : 2023-10-10 Liangkui Li, Haoyu Zhou, Jinhui Wang, Jiaxin Li, Xuchao Lyu, Wenshan Wang, Chengting Luo, He Huang, Dawang Zhou, Xiaowei Chen, Li Xu, Peng Li
Neonates strive to acquire energy when the continuous transplacental nutrient supply ceases at birth, whereas milk consumption takes hours to start. Using murine models, we report the metabolic switches in the first days of life, with an unexpected discovery of glucose as the universal fuel essential for neonatal life. Blood glucose quickly drops as soon as birth, but immediately rebounds even before
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Deletion of hepatic Small Heterodimer Partner ameliorates development of nonalcoholic steatohepatitis in mice. J. Lipid Res. (IF 6.5) Pub Date : 2023-10-10 Yoon-Kwang Lee, Jung Eun Park, Mikang Lee, Ryan Mifflin, Yang Xu, Robert Novak, Yanqiao Zhang, James P Hardwick
Small heterodimer partner (SHP, Nr0b2) is an orphan nuclear receptor that regulates bile acid, lipid, and glucose metabolism. Shp-/- mice are resistant to diet-induced obesity and hepatic steatosis. In this study, we explored the potential role of SHP in the development of nonalcoholic steatohepatitis (NASH). A six-month Western diet (WD) regimen was used to induce NASH. Shp deletion protected mice
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LC-MS based simultaneous profiling of adrenal hormones of steroids, catecholamines, and metanephrines. J. Lipid Res. (IF 6.5) Pub Date : 2023-10-06 Jongsung Noh, Chaelin Lee, Jung Hee Kim, Seung Woon Myung, Man Ho Choi
Metabolic changes in adrenocortical steroids and medullary catecholamines characterize adrenal tumors, but they are measured using different analytical protocols. To increase bioanalytical validity while maintaining sample homogeneity, liquid chromatography-mass spectrometry (LC-MS)-based profiling of 29 cortical steroids and 6 medullary amines, including catecholamines and metanephrines, in a single
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Exogenous oxygen is required for prostanoid induction under brain ischemia as evidence for a novel regulatory mechanism. J. Lipid Res. (IF 6.5) Pub Date : 2023-09-30 Drew R Seeger, Brennon Schofield, Derek Besch, Svetlana A Golovko, Peddanna Kotha, Meredith Parmer, Shahram Solaymani-Mohammadi, Mikhail Y Golovko
Previously, we and others reported a rapid and dramatic increase in brain prostanoids (PG), including prostaglandins, prostacyclins, and thromboxanes, under ischemia that is traditionally explained through the activation of esterified arachidonic acid (20:4n6) release by phospholipases as a substrate for cyclooxygenases (COX). However, the availability of another required COX substrate, oxygen, has
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LDL binding to cell receptors and extracellular matrix is proatherogenic in obesity but improves after bariatric surgery. J. Lipid Res. (IF 6.5) Pub Date : 2023-09-28 Shobini Jayaraman, Antonio Pérez, Inka Miñambres, Jose Luis Sánchez-Quesada, Olga Gursky
Obesity is a major global public health issue involving dyslipidemia, oxidative stress, inflammation, and increased risk of cardiovascular disease (CVD). Weight loss reduces this risk, but the biochemical underpinnings are unclear. We explored how obesity and weight loss after bariatric surgery influence LDL interactions that trigger pro-atherogenic vs. anti-atherogenic processes. LDL was isolated
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Sphingosine Kinase 1 is Involved in Triglyceride Breakdown by Maintaining Lysosomal Integrity in Brown Adipocytes. J. Lipid Res. (IF 6.5) Pub Date : 2023-09-24 Jun-Ichi Morishige, Kazuaki Yoshioka, Hiroki Nakata, Kazuhiro Ishimaru, Naoto Nagata, Tamotsu Tanaka, Yoh Takuwa, Hitoshi Ando
Sphingosine 1-phosphate (S1P) has been implicated in brown adipose tissue (BAT) formation and energy consumption; however, the mechanistic role of sphingolipids, including S1P, in BAT remains unclear. Here, we showed that, in mice, BAT activation by cold exposure upregulated mRNA and protein expression of the S1P-synthesizing enzyme sphingosine kinase 1 (SphK1), and S1P production in BAT. Treatment