scholarly journals Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Xin Rong ◽  
Bo Wang ◽  
Merlow M Dunham ◽  
Per Niklas Hedde ◽  
Jinny S Wong ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Membrane Lipid ◽  
Membrane Composition ◽  
Critical Determinant ◽  
Triglyceride Secretion ◽  
Key Factor

The role of specific phospholipids (PLs) in lipid transport has been difficult to assess due to an inability to selectively manipulate membrane composition in vivo. Here we show that the phospholipid remodeling enzyme lysophosphatidylcholine acyltransferase 3 (Lpcat3) is a critical determinant of triglyceride (TG) secretion due to its unique ability to catalyze the incorporation of arachidonate into membranes. Mice lacking Lpcat3 in the intestine fail to thrive during weaning and exhibit enterocyte lipid accumulation and reduced plasma TGs. Mice lacking Lpcat3 in the liver show reduced plasma TGs, hepatosteatosis, and secrete lipid-poor very low-density lipoprotein (VLDL) lacking arachidonoyl PLs. Mechanistic studies indicate that Lpcat3 activity impacts membrane lipid mobility in living cells, suggesting a biophysical basis for the requirement of arachidonoyl PLs in lipidating lipoprotein particles. These data identify Lpcat3 as a key factor in lipoprotein production and illustrate how manipulation of membrane composition can be used as a regulatory mechanism to control metabolic pathways.

Glucose-stimulated insulin secretion suppresses hepatic triglyceride-rich lipoprotein and apoB production

2000 ◽  
Vol 279 (5) ◽  
pp. E1003-E1011 ◽  
Author(s):  
Doru V. Chirieac ◽  
Lucian R. Chirieac ◽  
James P. Corsetti ◽  
Joanne Cianci ◽  
Charles E. Sparks ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Serum Triglyceride ◽  
Hepatic Triglyceride ◽  
Triglyceride Secretion ◽  
Triglyceride Rich Lipoprotein ◽  
Apob Secretion ◽  
Glucose Stimulated Insulin Secretion

The current study assessed in vivo the effect of insulin on triglyceride-rich lipoprotein (TRL) production by rat liver. Hepatic triglyceride and apolipoprotein B (apoB) production were measured in anesthetized, fasted rats injected intravenously with Triton WR-1339 (400 mg/kg). After intravascular catabolism was blocked by detergent treatment, glucose (500 mg/kg) was injected to elicit insulin secretion, and serum triglyceride and apoB accumulation were monitored over the next 3 h. In glucose-injected rats, triglyceride secretion averaged 22.5 ± 2.1 μg · ml−1· min−1, which was significantly less by 30% than that observed in saline-injected rats, which averaged 32.1 ± 1.4 μg · ml−1· min−1. ApoB secretion was also significantly reduced by 66% in glucose-injected rats. ApoB immunoblotting indicated that both B100 and B48 production were significantly reduced after glucose injection. Results support the conclusion that insulin acts in vivo to suppress hepatic very low density lipoprotein (VLDL) triglyceride and apoB secretion and strengthen the concept of a regulatory role for insulin in VLDL metabolism postprandially.

scholarly journals Scavenger Receptor CD36 Directs Nonclassical Monocyte Patrolling Along the Endothelium During Early Atherogenesis

2017 ◽  
Vol 37 (11) ◽  
pp. 2043-2052 ◽  
Author(s):  
Paola M. Marcovecchio ◽  
Graham D. Thomas ◽  
Zbigniew Mikulski ◽  
Erik Ehinger ◽  
Karin A.L. Mueller ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Adaptor Protein ◽  
Fold Increase ◽  
Vascular Wall ◽  
Western Diet ◽  
Oxidized Lipoprotein

Objective— Nonclassical monocytes (NCM) function to maintain vascular homeostasis by crawling or patrolling along the vessel wall. This subset of monocytes responds to viruses, tumor cells, and other pathogens to aid in protection of the host. In this study, we wished to determine how early atherogenesis impacts NCM patrolling in the vasculature. Approach and Results— To study the role of NCM in early atherogenesis, we quantified the patrolling behaviors of NCM in ApoE −/− (apolipoprotein E) and C57BL/6J mice fed a Western diet. Using intravital imaging, we found that NCM from Western diet–fed mice display a 4-fold increase in patrolling activity within large peripheral blood vessels. Both human and mouse NCM preferentially engulfed OxLDL (oxidized low-density lipoprotein) in the vasculature, and we observed that OxLDL selectively induced NCM patrolling in vivo. Induction of patrolling during early atherogenesis required scavenger receptor CD36, as CD36 −/− mice revealed a significant reduction in patrolling activity along the femoral vasculature. Mechanistically, we found that CD36-regulated patrolling was mediated by a SFK (src family kinase) through DAP12 (DNAX activating protein of 12KDa) adaptor protein. Conclusions— Our studies show a novel pathway for induction of NCM patrolling along the vascular wall during early atherogenesis. Mice fed a Western diet showed increased NCM patrolling activity with a concurrent increase in SFK phosphorylation. This patrolling activity was lost in the absence of either CD36 or DAP12. These data suggest that NCM function in an atheroprotective manner through sensing and responding to oxidized lipoprotein moieties via scavenger receptor engagement during early atherogenesis.

scholarly journals Polar phospholipids from bovine endogenously oxidized low density lipoprotein interfere with follicular thecal function

2005 ◽  
Vol 35 (3) ◽  
pp. 531-545 ◽  
Author(s):  
B Löhrke ◽  
T Viergutz ◽  
B Krüger
Keyword(s):  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Ldl Oxidation ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Steroidogenic Enzymes ◽  
Cox 2

The role of endogenously oxidized low density lipoprotein (oxLDL) in follicular steroidogenic regulation is unknown. Information may be important in order to elucidate ovulatory dysregulation in disordered lipid metabolism. To obtain specific data, we studied the effect of polar phospholipids (PL) isolated from oxLDL with different endogenous levels of lipohydroperoxides (LHP) on the thecal expression of mRNA encoding steroidogenic enzymes and cyclooxygenase 2 (COX-2), and on the thecal production of superoxide and progesterone. Large (preovulatory) bovine follicles were used and analyses of thecal fragments from single follicles were performed by radioimmunoassays, chemiluminescence assays and quantitative RT-PCR. Basal concentration of mRNA for several lipoprotein receptors exceeded by about 10-times the basal level of mRNA encoding steroidogenic enzymes, suggesting that preovulatory theca receptors may favour uptake of oxLDL. PL (5–11 pmol phosphorus/ml) decreased (up to 0.5-times the control) progesterone synthesis, production of superoxide and levels of P450 cholesterol side chain cleavage (P450 scc), 3β-hydroxysteroid dehydrogenase and COX-2 mRNA. Abundance of COX-2 transcripts in thecal tissue incubated with forskolin depended on the progesterone/17β-oestradiol ratio of the follicle fluid, i.e. the previous microenvironment in vivo. PL effects were mimicked by the platelet-activating factor (PAF). WEB 2086, a PAF receptor blocker, did not always abolish these responses, suggesting that the effects were not mediated solely by this receptor. PAF interfered dose-dependently with LH-induced responses, indicating interference with LH signalling. PL from mildly oxidized LDL (0.5 nmol/ml LHP) tended to exert greater effects than PL from oxLDL containing 1.5 nmol/ml LHP. In consideration of the known physiologic role of progesterone, COX-2 and possibly superoxide, these results provide evidence for a potential of PL from oxLDL to induce ovulatory dysregulation and suggest that the extent of the LDL oxidation seems to be important for interfering with thecal responses to the preovulatory LH surge.

scholarly journals Wide Biological Role of Hydroxytyrosol: Possible Therapeutic and Preventive Properties in Cardiovascular Diseases

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1932
Author(s):  
Chiara D’Angelo ◽  
Sara Franceschelli ◽  
José Luis Quiles ◽  
Lorenza Speranza
Keyword(s):  
Cardiovascular Health ◽  
Biological Effects ◽  
Low Density Lipoprotein ◽  
Antioxidant Properties ◽  
Density Lipoprotein ◽  
In Vivo Models ◽  
And Oxidative Stress

The growing incidence of cardiovascular disease (CVD) has promoted investigations of natural molecules that could prevent and treat CVD. Among these, hydroxytyrosol, a polyphenolic compound of olive oil, is well known for its antioxidant, anti-inflammatory, and anti-atherogenic effects. Its strong antioxidant properties are due to the scavenging of radicals and the stimulation of synthesis and activity of antioxidant enzymes (SOD, CAT, HO-1, NOS, COX-2, GSH), which also limit the lipid peroxidation of low-density lipoprotein (LDL) cholesterol, a hallmark of atherosclerosis. Lowered inflammation and oxidative stress and an improved lipid profile were also demonstrated in healthy subjects as well as in metabolic syndrome patients after hydroxytyrosol (HT) supplementation. These results might open a new therapeutic scenario through personalized supplementation of HT in CVDs. This review is the first attempt to collect together scientific literature on HT in both in vitro and in vivo models, as well as in human clinical studies, describing its potential biological effects for cardiovascular health.

scholarly journals Bisflavonoids fraction from Araucaria bidwilli Hook., reverses hyperlipidemia induced atherosclerosis in high-fat diet induced hyperlipidemia

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Rahimullah Siddiqui ◽  
Haja Nazeer Ahamed ◽  
Ismail Yusuff
Keyword(s):  
High Fat Diet ◽  
Leaf Extract ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Heart Tissue ◽  
High Fat ◽  
Anti Oxidant ◽  
Aortic Wall Thickness

Abstract Background Hyperlipidemia is a major cause for atherosclerosis which is a frontline cause for mortality in the world. Bisflavonoids are dimeric flavonoids abundant in few medicinal herbs with various pharmacological effects. However, in vivo anti-hyperlipidemic role of bisflavonoids (BFR) is limited. The present investigation is aimed to study BFR from the leaf extract of Araucaria bidwillii Hook. in rat model of hyperlipidemia. Results Administration of HFD was significantly (p < 0.0001) shown to increase total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TG) associated with decrease in HDL. BFR at two doses significantly decreased TC, LDL, and TG in HFD-fed rats. In addition, BFR significantly (p < 0.0001) decreased the MDA and significantly (p < 0.0001) increased the impaired anti-oxidant enzyme SOD and CAT in heart tissue induced by HFD. Further, 28 days administration of BFR significantly (p < 0.001) decreased HFD-induced aortic wall thickness. Conclusion It can be concluded that bisflavonoids from A. bidwillii Hook. leaf extract administered to high fat-fed rats showed beneficial anti-hyperlipidemic effect by reducing lipid profiles and protecting the heart tissue from oxidative stress.

scholarly journals Arterial heparin deposition: role of diffusion, convection, and extravascular space

1998 ◽  
Vol 275 (6) ◽  
pp. H2236-H2242 ◽  
Author(s):  
Mark A. Lovich ◽  
Mike Philbrook ◽  
Sean Sawyer ◽  
Ed Weselcouch ◽  
Elazer R. Edelman
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Perivascular Space ◽  
Low Density ◽  
Pressure Gradients ◽  
Extravascular Space ◽  
Diffusion Convection

Transvascular transport has been studied with atherogenic, tracer, and inert compounds such as low-density lipoprotein, horseradish peroxidase, and albumin, respectively. Few studies used vasoactive compounds, and virtually all studies examined entry from the lumen and not from the perivascular space. We compared several mechanisms that govern arterial heparin deposition after administration to the perivascular and endovascular aspects of the calf carotid artery in vitro and the rabbit iliac artery in vivo. In the absence of transmural hydrostatic pressure gradients, heparin deposition following endovascular administration was unaffected by deendothelialization and was indistinguishable from perivascular delivery. Deposition in the former was enhanced by the addition of a pressure gradient and to a greater extent in denuded arteries, indicating that convection influences transport but is dampened by the endothelium. Neither the endothelium nor the adventitia pose significant resistances to heparin. Deposition in vivo was greater following endovascular hydrogel release than perivascular application from similar devices to native or denuded arteries. The loss of drug to extra-arterial microvessels exceeded the loss of drug to the lumen flow. These findings are essential for describing vascular pharmacokinetics and for implementing local pharmacotherapies.

Role of receptor-mediated endocytosis in the antiangiogenic effects of human T lymphoblastic cell-derived microparticles

2012 ◽  
Vol 302 (8) ◽  
pp. R941-R949 ◽  
Author(s):  
Chun Yang ◽  
Wei Xiong ◽  
Qian Qiu ◽  
Zuo Shao ◽  
David Hamel ◽  
...  
Keyword(s):  
Cell Growth ◽  
Protein Expression ◽  
Therapeutic Potential ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Vascular Density ◽  
Receptor Mediated Endocytosis

Microparticles possess therapeutic potential regarding angiogenesis. We have demonstrated the contribution of apoptotic human CEM T lymphocyte-derived microparticles (LMPs) as inhibitors of angiogenic responses in animal models of inflammation and tumor growth. In the present study, we characterized the antivascular endothelial growth factor (VEGF) effects of LMPs on pathological angiogenesis in an animal model of oxygen-induced retinopathy and explored the role of receptor-mediated endocytosis in the effects of LMPs on human retinal endothelial cells (HRECs). LMPs dramatically inhibited cell growth of HRECs, suppressed VEGF-induced cell migration in vitro experiments, and attenuated VEGF-induced retinal vascular leakage in vivo. Intravitreal injections of fluorescently labeled LMPs revealed accumulation of LMPs in retinal tissue, with more than 60% reductions of the vascular density in retinas of rats with oxygen-induced neovascularization. LMP uptake experiments demonstrated that the interaction between LMPs and HRECs is dependent on temperature. In addition, endocytosis is partially dependent on extracellular calcium. RNAi-mediated knockdown of low-density lipoprotein receptor (LDLR) reduced the uptake of LMPs and attenuated the inhibitory effects of LMPs on VEGF-A protein expression and HRECs cell growth. Intravitreal injection of lentivirus-mediated RNA interference reduced LDLR protein expression in retina by 53% and significantly blocked the antiangiogenic effects of LMPs on pathological vascularization. In summary, the potent antiangiogenic LMPs lead to a significant reduction of pathological retinal angiogenesis through modulation of VEGF signaling, whereas LDLR-mediated endocytosis plays a partial, but pivotal, role in the uptake of LMPs in HRECs.

scholarly journals Role of R-spondin 2 in arterial lymphangiogenesis and atherosclerosis

2020 ◽  
Author(s):  
Bhupesh Singla ◽  
Hui-Ping Lin ◽  
Alex Chen ◽  
WonMo Ahn ◽  
Pushpankur Ghoshal ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cholesterol Efflux ◽  
Matrix Protein ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lymphatic Drainage ◽  
Control Treatment

Abstract Aims Impaired lymphatic drainage of the arterial wall results in intimal lipid accumulation and atherosclerosis. However, the mechanisms regulating lymphangiogenesis in atherosclerotic arteries are not well understood. Our studies identified elevated levels of matrix protein R-spondin 2 (RSPO2) in atherosclerotic arteries. In this study, we investigated the role of RSPO2 in lymphangiogenesis, arterial cholesterol efflux into lesion-draining lymph nodes (LNs) and development of atherosclerosis. Methods and results The effect of RSPO2 on lymphangiogenesis was investigated using human lymphatic endothelial cells (LEC) in vitro and implanted Matrigel plugs in vivo. Cellular and molecular approaches, pharmacological agents, and siRNA silencing of RSPO2 receptor LGR4 were used to investigate RSPO2-mediated signalling in LEC. In vivo low-density lipoprotein (LDL) tracking and perivascular blockade of RSPO2–LGR4 signalling using LGR4-extracellular domain (ECD) pluronic gel in hypercholesterolemic mice were utilized to investigate the role of RSPO2 in arterial reverse cholesterol transport and atherosclerosis. Immunoblotting and imaging experiments demonstrated increased RSPO2 expression in human and mouse atherosclerotic arteries compared to non-atherosclerotic controls. RSPO2 treatment inhibited lymphangiogenesis both in vitro and in vivo. LGR4 silencing and inhibition of RSPO2–LGR4 signalling abrogated RSPO2-induced inhibition of lymphangiogenesis. Mechanistically, we found that RSPO2 suppresses PI3K-AKT-endothelial nitric oxide synthase (eNOS) signalling via LGR4 and inhibits activation of the canonical Wnt-β-catenin pathway. ApoE−/− mice treated with LGR4-ECD developed significantly less atherosclerosis compared with control treatment. Finally, increased arterial lymphatic vessel density and improved lymphatic drainage of fluorescently labelled LDL to deep cervical LNs were observed in LGR4-ECD-treated mice. Conclusion These findings demonstrate that RSPO2 inhibits lymphangiogenesis via LGR4 and downstream impairment of AKT-eNOS-nitric oxide signalling. These results may also inform new therapeutic strategies to promote lymphangiogenesis and improve cholesterol efflux from atherosclerotic arteries.

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