Role of angiopoietin-like protein 3 in sugar-induced dyslipidemia in rhesus macaques: suppression by fish oil or RNAi [Research Articles]
Angiopoietin-like protein 3 (ANGPTL3) inhibits lipid clearance and is a promising target for managing cardiovascular disease. Here we investigated the effects of a high-sugar (high-fructose) diet on circulating ANGPTL3 concentrations in rhesus macaques. Plasma ANGPTL3 concentrations increased ~30% to 40% after 1 and 3 months of a high-fructose diet (both P < 0.001 vs. baseline). During fructose-induced metabolic dysregulation, plasma ANGPTL3 concentrations were positively correlated with circulating indices of insulin resistance [assessed with fasting insulin and the homeostatic model assessment of insulin resistance (H...
Source: The Journal of Lipid Research - February 29, 2020 Category: Lipidology Authors: Butler, A. A., Graham, J. L., Stanhope, K. L., Wong, S., King, S., Bremer, A. A., Krauss, R. M., Hamilton, J., Havel, P. J. Tags: Research Articles Source Type: research
Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice [Research Articles]
Atherosclerosis-related CVD causes nearly 20 million deaths annually. Most patients are treated after plaques develop, so therapies must regress existing lesions. Current therapies reduce plaque volume, but targeting all apoB-containing lipoproteins with intensive combinations that include alirocumab or evinacumab, monoclonal antibodies against cholesterol-regulating proprotein convertase subtilisin/kexin type 9 and angiopoietin-like protein 3, may provide more benefit. We investigated the effect of such lipid-lowering interventions on atherosclerosis in APOE*3-Leiden.CETP mice, a well-established model for hyperlipidemia....
Source: The Journal of Lipid Research - February 29, 2020 Category: Lipidology Authors: Pouwer, M. G., Pieterman, E. J., Worms, N., Keijzer, N., Jukema, J. W., Gromada, J., Gusarova, V., Princen, H. M. G. Tags: Research Articles Source Type: research
Role of pyruvate kinase M2 in oxidized LDL-induced macrophage foam cell formation and inflammation [Research Articles]
Pyruvate kinase M2 (PKM2) links metabolic and inflammatory dysfunction in atherosclerotic coronary artery disease; however, its role in oxidized LDL (Ox-LDL)-induced macrophage foam cell formation and inflammation is unknown and therefore was studied. In recombinant mouse granulocyte-macrophage colony-stimulating factor-differentiated murine bone marrow-derived macrophages, early (1–6 h) Ox-LDL treatment induced PKM2 tyrosine 105 phosphorylation and promotes its nuclear localization. PKM2 regulates aerobic glycolysis and inflammation because PKM2 shRNA or Shikonin abrogated Ox-LDL-induced hypoxia-inducible factor-1&a...
Source: The Journal of Lipid Research - February 29, 2020 Category: Lipidology Authors: Kumar, A., Gupta, P., Rana, M., Chandra, T., Dikshit, M., Barthwal, M. K. Tags: Research Articles Source Type: research
Hepatic PLIN5 signals via SIRT1 to promote autophagy and prevent inflammation during fasting [Research Articles]
Lipid droplets (LDs) are energy-storage organelles that are coated with hundreds of proteins, including members of the perilipin (PLIN) family. PLIN5 is highly expressed in oxidative tissues, including the liver, and is thought to play a key role in uncoupling LD accumulation from lipotoxicity; however, the mechanisms behind this action are incompletely defined. We investigated the role of hepatic PLIN5 in inflammation and lipotoxicity in a murine model under both fasting and refeeding conditions and in hepatocyte cultures. PLIN5 ablation with antisense oligonucleotides triggered a pro-inflammatory response in livers from ...
Source: The Journal of Lipid Research - February 29, 2020 Category: Lipidology Authors: Zhang, E., Cui, W., Lopresti, M., Mashek, M. T., Najt, C. P., Hu, H., Mashek, D. G. Tags: Research Articles Source Type: research
Serum amyloid A is not incorporated into HDL during HDL biogenesis [Research Articles]
In this study, we investigated SAA lipidation by hepatocytes and how this lipidation relates to the formation of nascent HDL particles. We also examined hepatocyte-mediated clearance of lipid-free and HDL-associated SAA. We prepared hepatocytes from mice injected with lipopolysaccharide or an SAA-expressing adenoviral vector. Alternatively, we incubated primary hepatocytes from SAA-deficient mice with purified SAA. We analyzed conditioned media to determine the lipidation status of endogenously produced and exogenously added SAA. Examining the migration of lipidated species, we found that SAA is lipidated and forms nascent...
Source: The Journal of Lipid Research - February 29, 2020 Category: Lipidology Authors: Ji, A., Wang, X., Noffsinger, V. P., Jennings, D., de Beer, M. C., de Beer, F. C., Tannock, L. R., Webb, N. R. Tags: Research Articles Source Type: research
Model systems for studying the assembly, trafficking, and secretion of apoB lipoproteins using fluorescent fusion proteins [Research Articles]
apoB exists as apoB100 and apoB48, which are mainly found in hepatic VLDLs and intestinal chylomicrons, respectively. Elevated plasma levels of apoB-containing lipoproteins (Blps) contribute to coronary artery disease, diabetes, and other cardiometabolic conditions. Studying the mechanisms that drive the assembly, intracellular trafficking, secretion, and function of Blps remains challenging. Our understanding of the intracellular and intraorganism trafficking of Blps can be greatly enhanced, however, with the availability of fusion proteins that can help visualize Blp transport within cells and between tissues. We designe...
Source: The Journal of Lipid Research - February 29, 2020 Category: Lipidology Authors: Walsh, M. T., Celestin, O. M., Thierer, J. H., Rajan, S., Farber, S. A., Hussain, M. M. Tags: Research Articles Source Type: research
Composition-function analysis of HDL subpopulations: influence of lipid composition on particle functionality [Research Articles]
The composition-function relationship of HDL particles and its effects on the mechanisms driving coronary heart disease (CHD) is poorly understood. We tested the hypothesis that the functionality of HDL particles is significantly influenced by their lipid composition. Using a novel 3D-separation method, we isolated five different-sized HDL subpopulations from CHD patients who had low preβ-1 functionality (low-F) (ABCA1-dependent cholesterol-efflux normalized for preβ-1 concentration) and controls who had either low-F or high preβ-1 functionality (high-F). Molecular numbers of apoA-I, apoA-II, and eight major...
Source: The Journal of Lipid Research - February 29, 2020 Category: Lipidology Authors: Niisuke, K., Kuklenyik, Z., Horvath, K. V., Gardner, M. S., Toth, C. A., Asztalos, B. F. Tags: Research Articles Source Type: research
A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice [Research Articles]
Bile acids (BAs) facilitate intestinal absorption of lipid-soluble nutrients and modulate various metabolic pathways through the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5. These receptors are targets for therapy in cholestatic and metabolic diseases. However, dissimilarities in BA metabolism between humans and mice complicate translation of preclinical data. Cytochrome P450 family 2 subfamily c polypeptide 70 (CYP2C70) was recently proposed to catalyze the formation of rodent-specific muricholic acids (MCAs). With CRISPR/Cas9-mediated somatic genome editing, we generated an acute hepatic Cyp2c70 kn...
Source: The Journal of Lipid Research - February 29, 2020 Category: Lipidology Authors: de Boer, J. F., Verkade, E., Mulder, N. L., de Vries, H. D., Huijkman, N., Koehorst, M., Boer, T., Wolters, J. C., Bloks, V. W., van de Sluis, B., Kuipers, F. Tags: Research Articles Source Type: research
Tissue-specific analysis of lipid species in Drosophila during overnutrition by UHPLC-MS/MS and MALDI-MSI [Research Articles]
Diets high in calories can be used to model metabolic diseases, including obesity and its associated comorbidities, in animals. Drosophila melanogaster fed high-sugar diets (HSDs) exhibit complications of human obesity including hyperglycemia, hyperlipidemia, insulin resistance, cardiomyopathy, increased susceptibility to infection, and reduced longevity. We hypothesize that lipid storage in the high-sugar-fed fly’s fat body (FB) reaches a maximum capacity, resulting in the accumulation of toxic lipids in other tissues or lipotoxicity. We took two approaches to characterize tissue-specific lipotoxicity. Ultra-HPLC-MS...
Source: The Journal of Lipid Research - February 29, 2020 Category: Lipidology Authors: Tuthill, B. F., Searcy, L. A., Yost, R. A., Musselman, L. P. Tags: Research Articles Source Type: research
ANGPTL3, PCSK9, and statin therapy drive remarkable reductions in hyperlipidemia and atherosclerosis in a mouse model [Commentary]
(Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - February 29, 2020 Category: Lipidology Authors: Hurt-Camejo, E. Tags: Commentary Source Type: research
Is CYP2C70 the key to new mouse models to understand bile acids in humans? [Commentary]
(Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - February 29, 2020 Category: Lipidology Authors: Guo, G. L., Chiang, J. Y. L. Tags: Commentary Source Type: research
Erratum: FTY720/fingolimod decreases hepatic steatosis and expression of fatty acid synthase in diet-induced nonalcoholic fatty liver disease in mice [Errata]
(Source: The Journal of Lipid Research)
Source: The Journal of Lipid Research - January 31, 2020 Category: Lipidology Authors: Rohrbach, T. D., Asgharpour, A., Maczis, M. A., Montefusco, D., Cowart, L. A., Bedossa, P., Sanyal, A. J., Spiegel, S. Tags: Errata Source Type: research
Plasma membrane asymmetry of lipid organization: fluorescence lifetime microscopy and correlation spectroscopy analysis [Methods]
A fundamental feature of the eukaryotic cell membrane is the asymmetric arrangement of lipids in its two leaflets. A cell invests significant energy to maintain this asymmetry and uses it to regulate important biological processes, such as apoptosis and vesiculation. The dynamic coupling of the inner or cytoplasmic and outer or exofacial leaflets is a challenging open question in membrane biology. Here, we combined fluorescence lifetime imaging microscopy (FLIM) with imaging total internal reflection fluorescence correlation spectroscopy (ITIR-FCS) to differentiate the dynamics and organization of the two leaflets of live ...
Source: The Journal of Lipid Research - January 31, 2020 Category: Lipidology Authors: Gupta, A., Korte, T., Herrmann, A., Wohland, T. Tags: Methods Source Type: research
Functional recombinant apolipoprotein A5 that is stable at high concentrations at physiological pH [Methods]
APOA5 is a low-abundance exchangeable apolipoprotein that plays critical roles in human triglyceride (TG) metabolism. Indeed, aberrations in the plasma concentration or structure of APOA5 are linked to hypertriglyceridemia, hyperchylomicronemia, myocardial infarction risk, obesity, and coronary artery disease. While it has been successfully produced at low yield in bacteria, the resulting protein had limitations for structure-function studies due to its low solubility under physiological buffer conditions. We hypothesized that the yield and solubility of recombinant APOA5 could be increased by: i) engineering a fusion prot...
Source: The Journal of Lipid Research - January 31, 2020 Category: Lipidology Authors: Castleberry, M., Davis, X., Liu, M., Thompson, T. B., Tso, P., Davidson, W. S. Tags: Methods Source Type: research
Metallopeptidase Stp1 activates the transcription factor Sre1 in the carotenogenic yeast Xanthophyllomyces dendrorhous [Research Articles]
Xanthophyllomyces dendrorhous is a basidiomycete yeast known as a natural producer of astaxanthin, a carotenoid of commercial interest because of its antioxidant properties. Recent studies indicated that X. dendrorhous has a functional SREBP pathway involved in the regulation of isoprenoid compound biosynthesis, which includes ergosterol and carotenoids. SREBP is a major regulator of sterol metabolism and homeostasis in mammals; characterization in fungi also provides information about its role in the hypoxia adaptation response and virulence. SREBP protease processing is required to activate SREBP pathway functions in fun...
Source: The Journal of Lipid Research - January 31, 2020 Category: Lipidology Authors: Gomez, M., Gutierrez, M. S., Gonzalez, A. M., Garate-Castro, C., Sepulveda, D., Barahona, S., Baeza, M., Cifuentes, V., Alcaino, J. Tags: Research Articles Source Type: research
