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Sökning: L773:1879 2618 OR L773:1388 1981

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1.
  • Olofsson, Sven-Olof, 1947, et al. (författare)
  • Lipid droplets as dynamic organelles connecting storage and efflux of lipids.
  • 2008
  • Ingår i: Biochimica et biophysica acta. - : Elsevier BV. - 0006-3002. ; 1791:6, s. 448-458
  • Tidskriftsartikel (refereegranskat)abstract
    • Neutral lipids are stored in the cytosol in so-called lipid droplets. These are dynamic organelles with neutral lipids as the core surrounded by a monolayer of amphipathic lipids (phospholipids and cholesterol) and specific proteins (PAT proteins and proteins involved in the turnover of lipids and in the formation and trafficking of the droplets). Lipid droplets are formed at microsomal membranes as primordial droplets with a diameter of 0.1-0.4 microm and increase in size by fusion. In this article, we review the assembly and fusion of lipid droplets, and the processes involved in the secretion of triglycerides. Triglycerides are secreted from cells by two principally different processes. In the mammary gland, lipid droplets interact with specific regions of the plasma membrane and bud off with an envelope consisting of the membrane, to form milk globules. In the liver and intestine, very low-density lipoproteins (VLDL) and chylomicrons are secreted by using the secretory pathway of the cell. Finally, we briefly review the importance of lipid droplets in the development of insulin resistance and atherosclerosis.
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2.
  • Shao, Yangzhen, 1981, et al. (författare)
  • A mouse model reveals an important role for catecholamine-induced lipotoxicity in the pathogenesis of stress-induced cardiomyopathy.
  • 2013
  • Ingår i: European journal of heart failure. - : Wiley. - 1879-0844 .- 1388-9842. ; 15:1, s. 9-22
  • Tidskriftsartikel (refereegranskat)abstract
    • AimStress-induced cardiomyopathy (SIC), also known as takotsubo cardiomyopathy, is an acute cardiac syndrome with substantial morbidity and mortality. The unique hallmark of SIC is extensive ventricular dysfunction (akinesia) involving apical segments with preserved function in basal segments. Adrenergic overstimulation plays an important role in initiating SIC, but the pathomechanisms involved are unknown. We tested the hypothesis that excessive catecholamines cause perturbation of myocardial lipid metabolism and that cardiac lipotoxicity is responsible for the pathogenesis of SIC. METHODS AND RESULTS: A single dose injection of isoprenaline (ISO; 400 mg/kg) induced SIC-like regional akinesia in mice. Oil red O staining revealed severe lipid accumulation in the heart 2 h post-ISO. Both intramyocardial lipid accumulation and cardiac function were normalized within 1 week post-ISO and no significant amount of fibrosis was detected. We found that gene expression of lipid importers and exporters (ApoB lipoprotein) was depressed 2 h post-ISO. These results were confirmed by similar findings in SIC patients and in ISO/patient serum-stressed HL-1 cardiomyocytes. Moreover, overexpression of ApoB in the heart was found to protect against the development of ISO-induced cardiac toxicity and cardiac dysfunction. We also found that ISO-induced intramyocardial lipid accumulation caused electrophysiological disturbance and stunning in ISO/patient serum-stressed HL-1 cardiomyocytes. CONCLUSIONS: The present study demonstrates that lipotoxicity is closely associated with catecholamine-induced myocardial dysfunction, including neurogenic stunning, metabolic stunning, and electrophysiological stunning. Cardiac lipotoxicity may originate from direct inhibition of myocardial ApoB lipoprotein and subsequent decreased lipid export, caused by supraphysiological levels of catecholamines.
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3.
  • Stiernstedt, Fredrik, 1981- (författare)
  • The voices we trust : Public trust in news and information about COVID-19 on Swedish Radio
  • 2021
  • Ingår i: Radio Journal. - : Intellect Ltd.. - 1476-4504 .- 2040-1388. ; 19:2
  • Tidskriftsartikel (refereegranskat)abstract
    • This article explores the question of trust in news and information about the COVID-19 pandemic. The focus of the article is on trust in radio news and the data are collected in Sweden during spring 2020. Two questions are asked: (1) to what extent do people in Sweden express trust in the radio as a medium, and radio news and information as a form of content? (2) How do people themselves explain and discuss their trust in the radio as a medium and in radio news and information? The article draws on both survey data and qualitative interviews in answering these questions. The results show that radio, together with television, is the most trusted medium in the population but that there are differences in the extent of trust within the population that are related to age, economic status and political affiliation. The qualitative interviews showed that the specificities of how radio is organized and the form and mode of expression of radio news can help explain the high trust in the radio medium during the COVID-19 pandemic.
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4.
  • Wang, Xiaodi, 1981-, et al. (författare)
  • Synthesis of uniform quasi-octahedral CeO2 mesocrystals via a surfactant-free route
  • 2011
  • Ingår i: Journal of nanoparticle research. - : Springer Science and Business Media LLC. - 1388-0764 .- 1572-896X. ; 13:11, s. 5879-5885
  • Tidskriftsartikel (refereegranskat)abstract
    • A facile surfactant-free nonaqueous method is presented to prepare uniform quasi-octahedral ceria, CeO 2 , mesocrystals, in which only Ce(NO 3 ) 3 and octanol were used as the reactants at a reaction temperature of 150 °C. CeO 2 sample synthesized using this technique consists of well-dispersed quasi-octahedrons and exhibits an uniform size and morphology. Based on structural characterization, it is proposed that the CeO 2 mesostructure was formed by self-assembly of primary nanocrystals based on unique 3D oriented-attachment mechanism. Optical characterization exhibited a strong quantum confinement, revealing small size of primary nanocrystals. The thermal stability and UV–Vis study reveal CeO 2 mesocrystal has various potential for high temperature applications and optical apparatus applications.
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5.
  • Bonini, Tiziano, et al. (författare)
  • Radio formats and social media use in Europe : 28 case studies of public service practice
  • 2014
  • Ingår i: Radio Journal. - : Intellect Ltd.. - 1476-4504 .- 2040-1388. ; 12:1-2, s. 89-109
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this article is to report, summarize and spread the results of a largescale European research project funded by EBU Radio in 2011 to map best practices in social media and European public radio, focusing on the way successful public service radio formats have incorporated social media in their production flow. The programmes have been selected for one of the following reasons: programmes that are audience leaders in their country, use innovative radio language or are youthoriented productions. The survey has been carried out by a team of ten European researchers from seven countries on a sample of 28 public radio programmes analysed for two months between January and February 2011. The research team attempted to answer the empirical question: ‘How social media are used by public service?’. Are there some common threads and shared practices among successful programmes in different countries? The team adopted an empirical approach based on social media content analysis and interviews with radio producers. This article will present the main results of this empirical research project. It will conclude with practical guidelines for public radio production and social media innovation.
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6.
  • Zhou, Qiongyu, et al. (författare)
  • Corrosion behavior of Hf0.5 Nb0.5 Ta0.5 Ti1.5 Zr refractory high-entropy in aqueous chloride solutions
  • 2019
  • Ingår i: Electrochemistry Communications. - : Elsevier BV. - 1388-2481. ; 98, s. 63-68
  • Tidskriftsartikel (refereegranskat)abstract
    • The Hf0.5Nb0.5Ta0.5Ti1.5Zr refractory high-entropy alloy with excellent corrosion resistance in the 3.5 wt% NaCl solution is identified in this work. This refractory high-entropy alloy exhibits much better general corrosion resistance than that of the 316L stainless steel, due to its corrosion current density being about one fifth of that in the latter. Meanwhile, the pitting potential of Hf0.5Nb0.5Ta0.5Ti1.5Zr reaches an unusually high value of +8.36 V, much higher than that of reported high-entropy alloys. The superior passivity of Hf0.5Nb0.5Ta0.5Ti1.5Zr is accredited to the formation of a single-phase solid solution containing high amount of homogenously distributed passivity-promoting elements, and also the existence of metallic Ta and OH− species in the passive film, which contribute to the high immunity to passive film breakdown.
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7.
  • Araya, Zufan, et al. (författare)
  • Metabolism of 25-hydroxyvitamin D3 by microsomal and mitochondrial vitamin D3 25-hydroxylases (CYP2D25 and CYP27A1) : a novel reaction by CYP27A1
  • 2003
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - 1388-1981 .- 1879-2618. ; 1632:1-21-3, s. 40-47
  • Tidskriftsartikel (refereegranskat)abstract
    • The metabolism of 25-hydroxyvitamin D(3) was studied with a crude mitochondrial cytochrome P450 extract from pig kidney and with recombinant human CYP27A1 (mitochondrial vitamin D(3) 25-hydroxylase) and porcine CYP2D25 (microsomal vitamin D(3) 25-hydroxylase). The kidney mitochondrial cytochrome P450 catalyzed the formation of 1alpha,25-dihydroxyvitamin D(3), 24,25-dihydroxyvitamin D(3) and 25,27-dihydroxyvitamin D(3). An additional metabolite that was separated from the other hydroxylated products on HPLC was also formed. The formation of this 25-hydroxyvitamin D(3) metabolite was dependent on NADPH and the mitochondrial electron transferring protein components. A monoclonal antibody directed against purified pig liver CYP27A1 immunoprecipitated the 1alpha- and 27-hydroxylase activities towards 25-hydroxyvitamin D(3) as well as the formation of the unknown metabolite. These results together with substrate inhibition experiments indicate that CYP27A1 is responsible for the formation of the unknown 25-hydroxyvitamin D(3) metabolite in kidney. Recombinant human CYP27A1 was found to convert 25-hydroxyvitamin D(3) into 1alpha,25-dihydroxyvitamin D(3), 25,27-dihydroxyvitamin D(3) and a major metabolite with the same retention time on HPLC as that formed by kidney mitochondrial cytochrome P450. Gas chromatography-mass spectrometry (GC-MS) analysis of the unknown enzymatic product revealed it to be a triol different from other known hydroxylated 25-hydroxyvitamin D(3) metabolites such as 1alpha,25-, 23,25-, 24,25-, 25,26- or 25,27-dihydroxyvitamin D(3). The product had the mass spectrometic properties expected for 4beta,25-dihydroxyvitamin D(3). Recombinant porcine CYP2D25 converted 25-hydroxyvitamin D(3) into 1alpha,25-dihydroxyvitamin D(3) and 25,26-dihydroxyvitamin D(3). It can be concluded that both CYP27A1 and CYP2D25 are able to carry out multiple hydroxylations of 25-hydroxyvitamin D(3).
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8.
  • Rotticci, D., et al. (författare)
  • An active-site titration method for lipases
  • 2000
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - 1388-1981 .- 1879-2618. ; 1483:1, s. 132-140
  • Tidskriftsartikel (refereegranskat)abstract
    • A method for active-site titration of lipases has been developed based on irreversible inhibition by methyl p-nitrophenyl n-hexylphosphonate. This method was applied to five lipases displaying from minor to pronounced interfacial activation. Soluble and immobilized lipases were successfully titrated in aqueous media. A low concentration of sodium dodecyl sulfate was needed for lipases displaying pronounced interfacial activation. The carrier of some of the immobilized preparations adsorbed part of the produced p-nitrophenolate, This problem could be solved by extracting the p-nitrophenolate after inhibition. The method was extended to apolar organic solvents in the case of immobilized lipase preparations.
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9.
  • Svartz, Jesper, 1972-, et al. (författare)
  • Leukotriene C4 synthase homo-oligomers detected in living cells by bioluminescence resonance energy transfer
  • 2003
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier. - 1388-1981 .- 1879-2618. ; 1633:2, s. 90-95
  • Tidskriftsartikel (refereegranskat)abstract
    • Leukotrienes (LTs) are biologically active compounds derived from arachidonic acid which have important pathophysiological roles in asthma and inflammation. The cysteinyl leukotriene LTC4 and its metabolites LTD4 and LTE4 stimulate bronchoconstriction, airway mucous formation and generalized edema formation. LTC4 is formed by addition of glutathione to LTA4, catalyzed by the integral membrane protein, LTC4 synthase (LTCS). We now report the use of bioluminescence resonance energy transfer (BRET) to demonstrate that LTCS forms homo-oligomers in living cells. Fusion proteins of LTCS and Renilla luciferase (Rluc) and a variant of green fluorescent protein (GFP), respectively, were prepared. High BRET signals were recorded in transiently transfected human embryonic kidney (HEK 293) cells co-expressing Rluc/LTCS and GFP/LTCS. Homo-oligomer formation in living cells was verified by co-transfection of a plasmid expressing non-chimeric LTCS. This resulted in dose-dependent attenuation of the BRET signal. Additional evidence for oligomer formation was obtained in cell-free assays using glutathione S-transferase (GST) pull-down assay. To map interaction domains for oligomerization, GFP/LTCS fusion proteins were prepared with truncated variants of LTCS. The results obtained identified a C-terminal domain (amino acids 114–150) sufficient for oligomerization of LTCS. Another, centrally located, interaction domain appeared to exist between amino acids 57–88. The functional significance of LTCS homo-oligomer formation is currently being investigated.
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10.
  • Alves, Marina Amaral, et al. (författare)
  • Systems biology approaches to study lipidomes in health and disease
  • 2021
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier. - 1388-1981 .- 1879-2618. ; 1866:2
  • Forskningsöversikt (refereegranskat)abstract
    • Lipids have many important biological roles, such as energy storage sources, structural components of plasma membranes and as intermediates in metabolic and signaling pathways. Lipid metabolism is under tight homeostatic control, exhibiting spatial and dynamic complexity at multiple levels. Consequently, lipid-related disturbances play important roles in the pathogenesis of most of the common diseases. Lipidomics, defined as the study of lipidomes in biological systems, has emerged as a rapidly-growing field. Due to the chemical and functional diversity of lipids, the application of a systems biology approach is essential if one is to address lipid functionality at different physiological levels. In parallel with analytical advances to measure lipids in biological matrices, the field of computational lipidomics has been rapidly advancing, enabling modeling of lipidomes in their pathway, spatial and dynamic contexts. This review focuses on recent progress in systems biology approaches to study lipids in health and disease, with specific emphasis on methodological advances and biomedical applications.
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11.
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12.
  • Bentinger, Magnus, et al. (författare)
  • Effects of various squalene epoxides on coenzyme Q and cholesterol synthesis
  • 2014
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1841:7, s. 977-986
  • Tidskriftsartikel (refereegranskat)abstract
    • 2,3-Oxidosqualene is an intermediate in cholesterol biosynthesis and 2,3:22,23-dioxidosqualene act as the substrate for an alternative pathway that produces 24(S),25-epoxycholesterol which effects cholesterol homeostasis. In light of our previous findings concerning the biological effects of certain epoxidated all-trans-polyisoprenes, the effects of squalene carrying epoxy moieties on the second and third isoprene residues were investigated here. In cultures of HepG2 cells both monoepoxides of squalene and one of their hydrolytic products inhibited cholesterol synthesis and stimulated the synthesis of coenzyme Q (CoQ). Upon prolonged treatment the cholesterol content of these cells and its labeling with [H-3]mevalonate were reduced, while the amount and labeling of CoQ increased. Injection of the squalene monoepoxides into mice once daily for 6 days elevated the level of CoQ in their blood, but did not change the cholesterol level. The same effects were observed upon treatment of apoE-deficient mice and diabetic GK-rats. This treatment increased the hepatic level of CoQ10 in mice, but the amount of CoQ9, which is the major form, was unaffected. The presence of the active compounds in the blood was supported by the finding that cholesterol synthesis in the white blood cells was inhibited. Since the ratio of CoQ9/CoQ10 varies depending on the experimental conditions, the cells were titrated with substrate and inhibitors, leading to the conclusion that the intracellular isopentenyl-PP pool is a regulator of this ratio. Our present findings indicate that oxidosqualenes may be useful for stimulating both the synthesis and level of CoQ both in vitro and in vivo.
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13.
  • Caddeo, Andrea, et al. (författare)
  • LPIAT1/MBOAT7 contains a catalytic dyad transferring polyunsaturated fatty acids to lysophosphatidylinositol.
  • 2021
  • Ingår i: Biochimica et biophysica acta. Molecular and cell biology of lipids. - : Elsevier BV. - 1879-2618 .- 1388-1981. ; 1866:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Human membrane bound O-acyltransferase domain-containing 7 (MBOAT7), also known as lysophosphatidylinositol acyltransferase 1 (LPIAT1), is an enzyme involved in the acyl-chain remodeling of phospholipids via the Lands' cycle. The MBOAT7 rs641738 variant has been associated with the entire spectrum of fatty liver disease (FLD) and neurodevelopmental disorders, but the exact enzymatic activity and the catalytic site of the protein are still unestablished. Human wild type MBOAT7 and three MBOAT7 mutants missing in the putative catalytic residues (N321A, H356A, N321A+H356A) were produced into Pichia pastoris, and purified using Ni-affinity chromatography. The enzymatic activity of MBOAT7 wild type and mutants was assessed measuring the incorporation of radiolabeled fatty acids into lipid acceptors. MBOAT7 preferentially transferred 20:4 and 20:5 polyunsaturated fatty acids (PUFAs) to lysophosphatidylinositol (LPI). On the contrary, MBOAT7 showed weak enzymatic activity for transferring saturated and unsaturated fatty acids, regardless the lipid substrate. Missense mutations in the putative catalytic residues (N321A, H356A, N321A+H356A) result in a loss of O-acyltransferase activity. Thus, MBOAT7 catalyzes the transfer of PUFAs to lipid acceptors. MBOAT7 shows the highest affinity for LPI, and missense mutations at the MBOAT7 putative catalytic dyad inhibit the O-acyltransferase activity of the protein. Our findings support the hypothesis that the association between the MBOAT7 rs641738 variant and the increased risk of NAFLD is mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling. Taken together, the increased understanding of the enzymatic activity of MBOAT7 give insights into the understanding on the basis of FLD.
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14.
  • Cai, Demin, et al. (författare)
  • Gestational dietary betaine supplementation suppresses hepatic expression of lipogenic genes in neonatal piglets through epigenetic and glucocorticoid receptor-dependent mechanisms
  • 2016
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1861:1, s. 41-50
  • Tidskriftsartikel (refereegranskat)abstract
    • Methyl donors play critical roles in nutritional programming through epigenetic regulation of gene expression. Here we fed gestational sows with control or betaine-supplemented diets (3 g/kg) throughout the pregnancy to explore the effects of maternal methyl-donor nutrient on neonatal expression of hepatic lipogenic genes. Betaine-exposed piglets demonstrated significantly lower liver triglyceride content associated with down-regulated hepatic expression of lipogenic genes acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD) and sterol regulatory element-binding protein-1c. Moreover, s-adenosyl methionine to s-adenosyl homocysteine ratio was elevated in the liver of betaine-exposed piglets, which was accompanied by DNA hypermethylation on FAS and SCD gene promoters and more enriched repression histone mark H31K27me3 on SCD gene promoter. Furthermore, glucocorticoid receptor (GR) binding to SCD gene promoter was diminished along with reduced serum cortisol and liver GR protein content in betaine-exposed piglets. GR-mediated SCD gene regulation was confirmed in HepG2 cells in vitro. Dexamethasone (Dex) drastically increased the luciferase activity of porcine SCD promoter, while the deletion of GR response element on SCD promoter significantly attenuated Dex-mediated SCD transactivation. In addition, miR-let-7e, miR-1285 and miR-124a, which respectively target porcine SCD, ACC and GR, were significantly up-regulated in the liver of betaine-exposed piglets, being in accordance with decreased protein content of these three genes. Taken together, our results suggest that maternal dietary betaine supplementation during gestation attenuates hepatic lipogenesis in neonatal piglets via epigenetic and GR-mediated mechanisms.
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15.
  • Fowler, Christopher J., et al. (författare)
  • Tumour epithelial expression levels of endocannabinoid markers modulate the value of endoglin-positive vascular density as a prognostic marker in prostate cancer
  • 2013
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1831:10, s. 1579-1587
  • Tidskriftsartikel (refereegranskat)abstract
    • Fatty acid amide hydrolase (FAAH) is responsible for the hydrolysis of the endogenous cannabinoid (CB) receptor ligand anandamide. Here we have investigated whether the expression levels of FAAH and CB1 receptors influence the prognostic value of markers of angiogenesis in prostate cancer. Data from a cohort of 419 patients who were diagnosed with prostate cancer at transurethral resection for lower urinary tract symptoms, of whom approximately 2/3 had been followed by expectancy, were used. Scores for the angiogenesis markers endoglin and von Willebrand factor (vWf), the endocannabinoid markers fatty acid amide hydrolase (FAAH) and cannabinoid CB1 receptors and the cell proliferation marker Ki-67 were available in the database. For the cases followed by expectancy, the prognostic value of endoglin was dependent upon the tumour epithelial FAAH immunoreactivity (FAAH-IR) and CB1IR scores, and the non-malignant epithelial FAAH-IR scores, but not the non-malignant CB1IR scores or the tumour blood vessel FAAH-IR scores. This dependency upon the tumour epithelial FAAH-IR or CB1IR scores was less apparent for vWf, and was not seen for Ki-67. Using an endoglin cut-off value of 10 positively stained vessels per core and a median split of tumour FAAH-IR, four groups could be generated, with 15 year of disease-specific survival (%) of 68 +/- 7 (low endoglin, low FAAH), 45 +/- 11 (high endoglin, low FAAH), 77 +/- 6 (low endoglin, high FAAH) and 21 +/- 10 (high endoglin, high FAAH). Thus, the cases with high endoglin and high FAAH scores have the poorest rate of disease-specific survival. At diagnosis, the number of cases with tumour stages 1a-1b relative to stages 2-4 was sensitive to the endoglin score in a manner dependent upon the tumour FAAH-IR. It is concluded that the prognostic value of endoglin as a marker of neovascularisation in prostate cancer can be influenced by the expression level of markers of the endocannabinoid system. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.
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18.
  • Hansen, Ida R., et al. (författare)
  • Contrasting effects of cold acclimation versus obesogenic diets on chemerin gene expression in brown and brite adipose tissues
  • 2014
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1841:12, s. 1691-1699
  • Tidskriftsartikel (refereegranskat)abstract
    • Based on results from a signal sequence trap, we investigated chemerin gene expression in brown adipose tissue. Male NMRI mice were exposed to 30, 22 or 4 degrees C for 3 weeks, or were fed control (chow) diet, cafeteria diet or high-fat diet at thermoneutrality for the same time. In brown adipose tissue, cold acclimation strongly diminished chemerin gene expression, whereas obesogenic diets augmented expression. Qualitatively, changes in expression were paralleled in brite/beige adipose tissues (e.g. inguinal), whereas white adipose tissue (epididymal) and muscle did not react to these cues. Changes in tissue expression were not directly paralleled by alterations in plasma levels. Both these intact animal studies and brown adipocyte cell culture studies indicated that the gene expression regulation was not congruent with a sympathetic/adrenergic control. The data are discussed in relation to suggested endocrine, paracrine and autocrine effects of chemerin.
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21.
  • Hoffmann, Inga, 1984-, et al. (författare)
  • Novel insights into cyclooxygenases, linoleate diol synthases, and lipoxygenases from deuterium kinetic isotope effects and oxidation of substrate analogs
  • 2012
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1821:12, s. 1508-1517
  • Tidskriftsartikel (refereegranskat)abstract
    • Cyclooxygenases (COX) and 8R-dioxygenase (8R-DOX) activities of linoleate diol synthases (LDS) are homologous heme-dependent enzymes that oxygenate fatty acids by a tyrosyl radical-mediated hydrogen abstraction and antarafacial insertion of O2. Soybean lipoxygenase-1 (sLOX-1) contains non-heme iron and oxidizes 18:2n-6 with a large deuterium kinetic isotope effect (D-KIE). The aim of the present work was to obtain further mechanistic insight into the action of these enzymes by using a series of n-6 and n-9 fatty acids and by analysis of D-KIE. COX-1 oxidized C20 and C18 fatty acids in the following order of rates: 20:2n-6 > 20:1n-6 > 20:3n-9 > 20:1n-9 and 18:3n-3 ≥ 18:2n-6 > 18:1n-6. 18:2n-6 and its geometrical isomer (9E,12Z)18:2 were both mainly oxygenated at C-9 by COX-1, but the 9Z,12E isomer was mostly oxygenated at C-13. A cis-configured double bond in the n-6 position therefore seems important for substrate positioning. 8R-DOX oxidized (9Z,12E)18:2 at C-8 in analogy with 18:2n-6, but the 9E,12Z isomer was only subject to hydrogen abstraction at C-11 and oxygen insertion at C-9 by 8R-DOX of 5,8-LDS. sLOX-1 and 13R-MnLOX oxidized [11S-2H]18:2n-6 with similar D-KIE (~53), which implies that the catalytic metals did not alter the D-KIE. Oxygenation of 18:2n-6 by COX-1 and COX-2 took place with a D-KIE of 3-5 as probed by incubations of [11,11-2H2]- and [11S-2H]18:2n-6. In contrast, the more energetically demanding hydrogen abstractions of the allylic carbons of 20:1n-6 by COX-1 and 18:1n-9 by 8R-DOX were both accompanied by large D-KIE (>20).
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22.
  • Idevall-Hagren, Olof, et al. (författare)
  • Detection and manipulation of phosphoinositides
  • 2015
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1851:6, s. 736-745
  • Forskningsöversikt (refereegranskat)abstract
    • Phosphoinositides (PIs) are minor components of cell membranes, but play key roles in cell function. Recent refinements in techniques for their detection, together with imaging methods to study their distribution and changes, have greatly facilitated the study of these lipids. Such methods have been complemented by the parallel development of techniques for the acute manipulation of their levels, which in turn allow bypassing the long-term adaptive changes implicit in genetic perturbations. Collectively, these advancements have helped elucidate the role of Pis in physiology and the impact of the dysfunction of their metabolism in disease. Combining methods for detection and manipulation enables the identification of specific roles played by each of the Pis and may eventually lead to the complete deconstruction of the PI signaling network. Here, we review current techniques used for the study and manipulation of cellular Pis and also discuss advantages and disadvantages associated with the various methods. This article is part of a Special Issue entitled Phosphoinositides.
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23.
  • Johnsson, Anna-Karin, et al. (författare)
  • COX-1 dependent biosynthesis of 15-hydroxyeicosatetraenoic acid in human mast cells
  • 2021
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier. - 1388-1981 .- 1879-2618. ; 1866:5
  • Tidskriftsartikel (refereegranskat)abstract
    • 15-hydroxyeicosatetraenoic acid (15-HETE) is an arachidonic acid derived lipid mediator which can originate both from 15-lipoxygenase (15-LOX) activity and cyclooxygenase (COX) activity. The enzymatic source determines the enantiomeric profile of the 15-HETE formed. 15-HETE is the most abundant arachidonic acid metabolite in the human lung and has been suggested to influence the pathophysiology of asthma. Mast cells are central effectors in asthma, but there are contradictory reports on whether 15-HETE originates from 15-LOX or COX in human mast cells. This prompted the current study where the pathway of 15-HETE biosynthesis was examined in three human mast cell models; the cell line LAD2, cord blood derived mast cells (CBMC) and tissue isolated human lung mast cells (HLMC). Levels and enantiomeric profiles of 15-HETE and levels of the downstream metabolite 15-KETE, were analyzed by UPLC-MS/MS after stimulation with anti-IgE or calcium ionophore A23187 in the presence and absence of inhibitors of COX isoenzymes. We found that 15-HETE was produced by COX-1 in human mast cells under these experimental conditions. Unexpectedly, chiral analysis showed that the 15(R) isomer was predominant and gradually accumulated, whereas the 15(S) isomer was metabolized by the 15hydroxyprostaglandin dehydrogenase. We conclude that during physiological conditions, i.e., without addition of exogenous arachidonic acid, both enantiomers of 15-HETE are produced by COX-1 in human mast cells but that the 15(S) isomer is selectively depleted by undergoing further metabolism. The study highlights that 15-HETE cannot be used as an indicator of 15-LOX activity for cellular studies, unless chirality and sensitivity to pharmacologic inhibition is determined.
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24.
  • Kågedal, Katarina, et al. (författare)
  • Increased expression of the lysosomal cholesterol transporter NPC1 in Alzheimers disease
  • 2010
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : ELSEVIER SCIENCE BV. - 1388-1981 .- 1879-2618. ; 1801:8, s. 831-838
  • Tidskriftsartikel (refereegranskat)abstract
    • The Niemann-Pick type Cl (NPC1) protein mediates the trafficking of cholesterol from lysosomes to other organelles. Mutations in the NPC1 gene lead to the retention of cholesterol and other lipids in the lysosomal compartment, and such defects are the basis of NPC disease. Several parallels exist between NPC disease and Alzheimers disease (AD), including altered cholesterol homeostasis, changes in the lysosomal system, neurofibrillary tangles, and increased amyloid-beta generation. How the expression of NPC1 in the human brain is affected in AD has not been investigated so far. In the present study, we measured NPC1 mRNA and protein expression in three distinct regions of the human brain, and we revealed that NPC1 expression is upregulated at both mRNA and protein levels in the hippocampus and frontal cortex of AD patients compared to control individuals. In the cerebellum, a brain region that is relatively spared in AD, no difference in NPC1 expression was detected. Similarly, murine NPC1 mRNA levels were increased in the hippocampus of 12-month-old transgenic mice expressing a familial AD form of human amyloid-beta precursor protein (APP) and presenilin-1 (APP/PS1tg) compared to 12-month-old wild type mice, whereas no change in NPC1 was detected in mouse cerebellum. Immunohistochemical analysis of human hippocampus indicated that NPC1 expression was strongest in neurons. However, in vitro studies revealed that NPC1 expression was not induced by transfecting SK-N-SH neurons with human APP or by treating them with oligomeric amyloid-beta peptide. Total cholesterol levels were reduced in hippocampus from AD patients compared to control individuals, and it is therefore possible that the increased expression of NPC1 is linked to perturbed cholesterol homeostasis in AD.
  •  
25.
  • Ljunggren, Stefan A, et al. (författare)
  • Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.
  • 2015
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier. - 1388-1981 .- 1879-2618. ; 1851:12, s. 1587-1595
  • Tidskriftsartikel (refereegranskat)abstract
    • The scavenger receptor class B type 1 (SR-B1) is an important HDL receptor involved in cholesterol uptake and efflux, but its physiological role in human lipoprotein metabolism is not fully understood. Heterozygous carriers of the SR-B1P297S mutation are characterized by increased HDL cholesterol levels, impaired cholesterol efflux from macrophages and attenuated adrenal function. Here, the composition and function of lipoproteins were studied in SR-B1P297S heterozygotes.Lipoproteins from six SR-B1P297S carriers and six family controls were investigated. HDL and LDL/VLDL were isolated by ultracentrifugation and proteins were separated by two-dimensional gel electrophoresis and identified by mass spectrometry. HDL antioxidant properties, paraoxonase 1 activities, apoA-I methionine oxidations and HDL cholesterol efflux capacity were assessed.Multivariate modeling separated carriers from controls based on lipoprotein composition. Protein analyses showed a significant enrichment of apoE in LDL/VLDL and of apoL-1 in HDL from heterozygotes compared to controls. The relative distribution of plasma apoE was increased in LDL and in lipid-free form. There were no significant differences in paraoxonase 1 activities, HDL antioxidant properties or HDL cholesterol efflux capacity but heterozygotes showed a significant increase of oxidized methionines in apoA-I.The SR-B1P297S mutation affects both HDL and LDL/VLDL protein compositions. The increase of apoE in carriers suggests a compensatory mechanism for attenuated SR-B1 mediated cholesterol uptake by HDL. Increased methionine oxidation may affect HDL function by reducing apoA-I binding to its targets. The results illustrate the complexity of lipoprotein metabolism that has to be taken into account in future therapeutic strategies aiming at targeting SR-B1.
  •  
26.
  • Lundell, Kerstin, et al. (författare)
  • Gene structure of pig sterol 12alpha-hydroxylase (CYP8B1) and expression in fetal liver : comparison with expression of taurochenodeoxycholic acid 6alpha-hydroxylase (CYP4A21)
  • 2003
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1634:3, s. 86-96
  • Tidskriftsartikel (refereegranskat)abstract
    • Cholic acid is the major trihydroxy bile acid formed in most mammals. The domestic pig (Sus scrofa) is an exception. The bile of adult pig is devoid of cholic acid whereas hyocholic acid is found in amounts equal to that of cholic acid in humans. The pathway leading to formation of hyocholic acid is believed to be species-specific and to have evolved in the pig to compensate for a nonexistent or deficient cholic acid biosynthesis. However, a high level of cholic acid has recently been found in the bile of fetal pig. Here we describe that a gene encoding the key enzyme in cholic acid biosynthesis, the sterol 12alpha-hydroxylase (CYP8B1), is in fact present in the pig genome. The deduced amino acid sequence shows 81% identity to the human and rabbit orthologues. CYP8B1 mRNA is expressed at significant levels in fetal pig liver. Both CYP8B1 and the key enzyme in hyocholic acid formation, taurochenodeoxycholic acid 6alpha-hydroxylase (CYP4A21), were found to be expressed in pig liver in a developmental-dependent but opposite fashion.
  •  
27.
  • Lundqvist, Johan, et al. (författare)
  • 1α,25-Dihydroxyvitamin D3 affects hormone production and expression of steroidogenic enzymes in human adrenocortical NCI-H295R cells
  • 2010
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1801:9, s. 1056-1062
  • Tidskriftsartikel (refereegranskat)abstract
    • The current study presents data indicating that 1 alpha,25-dihydroxyvitamin D-3 affects the production of hormones and expression of crucial steroidogenic enzymes in the human adrenocortical cell line NCI-H295R. This cell line is widely used as a model for adrenal steroidogenesis. Treatment of the cells with 1 alpha,25-dihydroxyvitamin D-3 suppressed the levels of corticosterone, aldosterone, DHEA, DHEA-sulfate and androstenedione in the culture medium. In order to study the mechanisms behind this suppression of hormone production, we investigated the effects of 1 alpha,25-dihydroxyvitamin D-3 on important genes and enzymes controlling the biosynthesis of adrenal hormones. The mRNA levels were decreased for CYP21A2 while they were increased for CYP11A1 and CYP17A1. No significant changes were observed in mRNA for CYP11B1, CYP11B2 or 3 beta-hydroxysteroid dehydrogenase (3 beta HSD). In similarity with the effects on mRNA levels, also the endogenous enzyme activity of CYP21A2 decreased after treatment with 1 alpha,25-dihydroxyvitamin D3. Interestingly, the two CYP17A1-mediated activities were influenced reciprocally the 17 alpha-hydroxylase activity increased whereas the 17,20-lyase activity decreased. The current data indicate that the 1 alpha,25-dihydroxyvitamin D-3-mediated decrease in corticosterone and androgen production is due to suppression of the 21-hydroxylase activity by CYP21A2 and the 17,20-lyase activity by CYP17A1, respectively. In conclusion, the current study reports novel findings on 1 alpha,25-dihydroxyvitamin D-3-mediated effects on hormone production and regulation of genes and enzymes involved in steroidogenesis in the adrenocortical NCI-H295R cell line, a model for human adrenal cortex.
  •  
28.
  • Lundqvist, Johan, et al. (författare)
  • 1α,25-Dihydroxyvitamin D3 exerts tissue-specific effects on estrogen and androgen metabolism
  • 2011
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1811:4, s. 263-270
  • Tidskriftsartikel (refereegranskat)abstract
    • It is well-known that 1α,25-dihydroxyvitamin D(3) and analogs exert anti-proliferative and pro-differentiating effects and these compounds have therefore been proposed to be of potential use as anti-cancer agents. Due to its effects on aromatase gene expression and enzyme activity, 1α,25-dihydroxyvitamin D(3) has been proposed as an interesting substance in breast cancer treatment and prevention. In the present study, we have examined the effects of 1α,25-dihydroxyvitamin D(3) on estrogen and androgen metabolism in adrenocortical NCI-H295R cells, breast cancer MCF-7 cells and prostate cancer LNCaP cells. The NCI-H295R cell line has been proposed as a screening tool to study endocrine disruptors. We therefore studied whether this cell line reacted to 1α,25-dihydroxyvitamin D(3) treatment in the same way as cells from important endocrine target tissues. 1α,25-Dihydroxyvitamin D(3) exerted cell line-specific effects on estrogen and androgen metabolism. In breast cancer MCF-7 cells, aromatase gene expression and estradiol production were decreased, while production of androgens was markedly increased. In NCI-H295R cells, 1α,25-dihydroxyvitamin D(3) stimulated aromatase expression and decreased dihydrotestosterone production. In prostate cancer LNCaP cells, aromatase expression increased after the same treatment, as did production of testosterone and dihydrotestosterone. In summary, our data show that 1α,25-dihydroxyvitamin D(3) exerts tissue-specific effects on estrogen and androgen production and metabolism. This is important knowledge about 1α,25-dihydroxyvitamin D(3) as an interesting substance for further research in the field of breast cancer prevention and treatment. Furthermore, the observed cell line-specific effects are of importance in the discussion about NCI-H295R cells as a model for effects on estrogen and androgen metabolism.
  •  
29.
  • Lundqvist, Johan, et al. (författare)
  • Effects of CYP7B1-related steroids on androgen receptor activation in different cell lines
  • 2012
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1821:7, s. 973-979
  • Tidskriftsartikel (refereegranskat)abstract
    • The widely expressed steroid hydroxylase CYP7B1 is involved in metabolism of a number of steroids reported to influence estrogen and androgen signaling. Several studies by us and other investigators have linked this enzyme to effects on estrogen receptor activation. In a previous report we examined the effect of CYP7B1-mediated hormone metabolism for estrogen-mediated response in kidney-derived HEK293 cells. In the current study we used an androgen response element (ARE) reporter system to examine androgen-dependent response of some CYP7B1 substrates and CYP7B1-formed metabolites in several cell lines derived from different tissues. The results indicate significantly lower androgen receptor activation by CYP7B1-formed steroid metabolites than by the corresponding steroid substrates, suggesting that CYP7B1-mediated catalysis may decrease some androgenic responses. Thus, CYP7B1-dependent metabolism may be of importance not only for estrogenic signaling but also for androgenic. This finding, that CYP7B1 activity may be a regulator of androgenic signaling by converting AR ligands into less active metabolites, is also supported by real-time RT-PCR experiment where a CYP7B1 substrate, but not the corresponding product, was able to stimulate known androgen-sensitive genes. Furthermore, our data indicate that the effects of some steroids on hormone response element reporter systems are cell line-specific. For instance, despite transfection of the same reporter systems, 5-androstene-3β,17β-diol strongly activates an androgen-dependent response element in prostate cancer cells whereas it elicits only ER-dependent responses in kidney HEK293 cells. Potential roles of cell-specific metabolism or comodulator expression for the observed differences are discussed.
  •  
30.
  • Mahammad, Saleemulla, et al. (författare)
  • Limited cholesterol depletion causes aggregation of plasma membrane lipid raftsinducing T cell activation
  • 2010
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1801:6, s. 625-634
  • Tidskriftsartikel (refereegranskat)abstract
    • Acute cholesterol depletion is generally associated with decreased or abolished T cell signalling but it can also cause T cell activation. This anomaly has been addressed in Jurkat T cells using progressive cholesterol depletion with methyl-beta-cyclodextrin (MBCD). At depletion levels higher than 50% there is substantial cell death, which explains reports of signalling inhibition. At 10–20% depletion levels, tyrosine phosphorylation is increased, ERK is activated and there is a small increase in cytoplasmic Ca2+. Peripheral actin polymerisation is also triggered by limited cholesterol depletion. Strikingly, the lipid raft marker GM1 aggregates upon cholesterol depletion and these aggregated domains concentrate the signalling proteins Lck and LAT, whereas the opposite is true for the non lipid raft marker the transferrin receptor. Using PP2, an inhibitor of Src family kinase activation, it is demonstrated that the lipid raft aggregation occurs independently of and thus upstream of the signalling response. Upon cholesterol depletion there is an increase in overall plasma membrane order, indicative of more ordered domains forming at the expense of disordered domains. That cholesterol depletion and not unspecific effects of MBCD was behind the reported results was confirmed by performing all experiments with MBCD–cholesterol, when no net cholesterol extraction took place. We conclude that non-lethal cholesterol depletion causes the aggregation of lipid rafts which then induces T cell signalling.
  •  
31.
  • Makoveichuk, Elena, et al. (författare)
  • TNF-alpha decreases lipoprotein lipase activity in 3T3-L1 adipocytes by up-regulation of angiopoietin-like protein 4
  • 2017
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier. - 1388-1981 .- 1879-2618. ; 1862:5, s. 533-540
  • Tidskriftsartikel (refereegranskat)abstract
    • Lipoprotein lipase (LPL) hydrolyzes lipids in plasma lipoproteins so that the fatty acids can be taken up and used by cells. The activity of LPL changes rapidly in response to changes in nutrition, physical activity and other conditions. Angiopoietin-like protein 4 (ANGPTL4) is an important controller of LPL activity. Both LPL and ANGPTL4 are produced and secreted by adipocytes. When the transcription blocker Actinomycin D was added to cultures of 3T3-L1 adipocytes, LPL activity in the medium increased several-fold. LPL mRNA decreased moderately during 5 h, while ANGPTL4 mRNA and protein declined rapidly, explaining that LPL activity was increased. TNF-alpha is known to reduce LPL activity in adipose tissue. We have shown that TNF-a increased ANGPTL4 both at the mRNA and protein level. Expression of ANGPTL4 is known to be under control of Foxol. Use of the Foxol-specific inhibitor AS1842856, or knockdown of ANGPTL4 by RNAi, resulted in increased LPL activity in the medium. Both with ActD and with the Foxol inhibitor the cells became unresponsive to TNF-a. This study shows that TNF-a, by a Foxol dependent pathway, increases the transcription of ANGPTL4 which is secreted by the cells and causes inactivation of LPL.
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32.
  •  
33.
  • Mwinyi, Jessica, et al. (författare)
  • NAFLD is associated with methylation shifts with relevance for the expression of genes involved in lipoprotein particle composition
  • 2017
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1862:3, s. 314-323
  • Tidskriftsartikel (refereegranskat)abstract
    • Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides, cholesterol and toxic free fatty acids and is related to low vitamin D levels. In an analysis of specific gene sets we elucidate to what extent NAFLD associates to epigenetic and related transcriptional changes in gene networks regulating lipid, energy and vitamin D balance. Two gene clusters responsible for lipid homeostasis (74 genes) and vitamin D and energy balance (31 genes) were investigated with regard to average epigenetic shifts within the first 1500 bp next to the transcriptional start site. Three cohorts from two published genome wide driven studies that used a microarray approach were investigated including altogether 103 NAFLD and 75 liver healthy subjects. In the first two steps associations between NAFLD abundance, strength of fibrosis and methylation were investigated in two cohorts by multiple linear regression analyses, correcting for important clinical and demographic parameters. Methylation associated strength of transcription in genes showing significant NAFLD related methylation changes were studied in a third step using a third cohort and applying Pearson's correlation and robust linear regression analyses. 41 genes in gene cluster 1 and 14 genes in cluster 2 were significantly differentially methylated in dependency of NAFLD and hepatic fibrosis. We detect new genes significantly changed in methylation, including APO family members (lipid transport), NPC1L1, STARD (cholesterol transport) and GRHL (energy homeostasis). Our results allow novel insights into the hepatic epigenetic regulation of genes important for lipid and vitamin D balance in NAFLD.
  •  
34.
  • Nedergaard, Jan, et al. (författare)
  • Cell proliferation and apoptosis inhibition : essential processes for recruitment of the full thermogenic capacity-of-brown-adipose-tissue
  • 2019
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1864:1, s. 51-58
  • Forskningsöversikt (refereegranskat)abstract
    • In mice living under normal animal house conditions, the brown adipocytes in classical brown adipose tissue depots are already essentially fully differentiated: UCP1 mRNA and UCP1 protein levels are practically saturated. This means that any further recruitment in response to cold exposure or any other browning agent - does not result in significant augmentation of these parameters. This may easily be construed to indicate that classical brown adipose tissue cannot be further recruited. However, this is far from the case: the capacity for further recruitment instead lies in the ability of the tissue to increase the number of brown-fat cells, a remarkable and highly controlled physiological recruitment process. We have compiled here the available data concerning the unique ability of norepinephrine to increase cell proliferation and inhibit apoptosis in brown adipocytes. Adrenergically stimulated cell proliferation is fully mediated via beta(1)-adrenoceptors and occurs through activation of stem cells in the tissue; intracellular mediation of the signal involves CAMP and protein kinase A activation, but activation of Erk1/2 is not part of the pathway. Apoptosis inhibition in brown adipocytes is induced by both beta- and alpha(1)-adrenergic receptors and here the intracellular pathway includes Erk1/2 activation. This unique ability of norepinephrine to increase cell number in an apparently mitogenically dormant tissue provides possibilities to augment the metabolic capacity of brown adipose tissue, also for therapeutic purposes.
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35.
  • Nedergaard, Jan, et al. (författare)
  • UCP1 mRNA does not produce heat
  • 2013
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1831:5, s. 943-949
  • Tidskriftsartikel (refereegranskat)abstract
    • Because of the possible role of brown adipose tissue and UCP1 in metabolic regulation, even in adult humans, there is presently considerable interest in quantifying, from in-vitro data, the thermogenic capacities of brown and brite/beige adipose tissues. An important issue is therefore to establish which parameters are the most adequate for this. A particularly important issue is the relevance of UCP1 mRNA levels as estimates of the degree of recruitment and of the thermogenic capacity resulting from differences in physiological conditions and from experimental manipulations. By solely following UCP1 mRNA levels in brown adipose tissue, the conclusion would be made that the tissue's highest activation occurs after only 6 h in the cold and then successively decreases to being only some 50% elevated after 1 month in the cold. However, measurement of total UCP1 protein levels per depot (mouse) reveals that the maximal thermogenic capacity estimated in this way is reached first after 1 month but represents an approx. 10-fold increase in thermogenic capacity. Since this in-vitro measure correlates quantitatively and temporally with the acquisition of nonshivering thermogenesis, this must be considered the most physiologically relevant parameter. Similarly, observations that cold acclimation barely increases UCP1 mRNA levels in classical brown adipose tissue but leads to a 200-fold increase in UCP1 mRNA levels in brite/beige adipose tissue depots may overemphasise the physiological significance of these depots, as the high fold-increases are due to very low initial levels, and the UCP1 mRNA levels reached are at least an order of magnitude lower than in brown adipose tissue; furthermore, based on total UCP1 protein amounts, the brite/beige depots attain only about 10% of the thermogenic capacity of the classical brown adipose tissue depots. Consequently, inadequate conclusions may be reached if UCP1 mRNA levels are used as a proxy for the metabolic significance of recruited versus non-recruited brown adipose tissue and for estimating the metabolic significance of brown versus brite/beige adipose tissues. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease.
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36.
  • Nilsson, Anders K., 1982, et al. (författare)
  • Sphingolipidomics of serum in extremely preterm infants : Association between low sphingosine-1-phosphate levels and severe retinopathy of prematurity
  • 2021
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier. - 1388-1981 .- 1879-2618. ; 1866:7
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Extremely preterm infants are at risk of developing retinopathy of prematurity (ROP) that can cause impaired vision or blindness. Changes in blood lipids have been associated with ROP. This study aimed to monitor longitudinal changes in the serum sphingolipidome of extremely preterm infants and investigate the relationship to severe ROP development.METHODS: This is a prospective study that included 47 infants born <28 gestational weeks. Serum samples were collected from cord blood and at postnatal days 1, 7, 14, and 28, and at postmenstrual weeks (PMW) 32, 36, and 40. Serum sphingolipids and phosphatidylcholines were extracted and analyzed by LC-MS/MS. Associations between sphingolipid species and ROP were assessed using mixed models for repeated measures.RESULTS: The serum concentration of all investigated lipid classes, including ceramide, mono- di- and trihexosylceramide, sphingomyelin, and phosphatidylcholine displayed distinct temporal patterns between birth and PMW40. There were also substantial changes in the lipid species composition within each class. Among the analyzed sphingolipid species, sphingosine-1-phosphate showed the strongest association with severe ROP, and this association was independent of gestational age at birth and weight standard deviation score change.CONCLUSIONS: The serum phospho- and sphingolipidome undergoes significant remodeling during the first weeks of the preterm infant's life. Low postnatal levels of the signaling lipid sphingosine-1-phosphate are associated with the development of severe ROP.
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37.
  • Nilsson, Stefan, et al. (författare)
  • Triacylglycerol-rich lipoproteins protect lipoprotein lipase from inactivation by ANGPTL3 and ANGPTL4
  • 2012
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - Amsterdam : Elsevier. - 1388-1981 .- 1879-2618. ; 1821:10, s. 1370-1378
  • Tidskriftsartikel (refereegranskat)abstract
    • Lipoprotein lipase (LPL) is important for clearance of triacylglycerols (TG) from plasma both as an enzyme and as a bridging factor between lipoproteins and receptors for endocytosis. The amount of LPL at the luminal side of the capillary endothelium determines to what extent lipids are taken up. Mechanisms to control both the activity of LPL and its transport to the endothelial sites are regulated, but poorly understood. Angiopoietin-like proteins (ANGPTLs) 3 and 4 are potential control proteins for LPL, but plasma concentrations of ANGPTLs do not correlate with plasma TG levels. We investigated the effects of recombinant human N-terminal (NT) ANGPTLs3 and 4 on LPL-mediated bridging of TG-rich lipoproteins to primary mouse hepatocytes and found that the NT-ANGPTLs, in concentrations sufficient to cause inactivation of LPL in vitro, were unable to prevent LPL-mediated lipoprotein uptake. We therefore investigated the effects of lipoproteins (chylomicrons, VLDL and LDL) on the inactivation of LPL in vitro by NT-ANGPTLs3 and 4 and found that LPL activity was protected by TG-rich lipoproteins. In vivo, postprandial TG protected LPL from inactivation by recombinant NT-ANGPTL4 injected to mice. We conclude that lipoprotein-bound LPL is stabilized against inactivation by ANGPTLs. The levels of ANGPTLs found in blood may not be sufficient to overcome this stabilization. Therefore it is likely that the prime site of action of ANGPTLs on LPL is in subendothelial compartments where TG-rich lipoprotein concentration is lower than in blood. This could explain why the plasma levels of TG and ANGPTLs do not correlate.
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38.
  • Oliw, Ernst H., 1948-, et al. (författare)
  • Manganese lipoxygenase oxidizes bis-allylic hydroperoxides and octadecenoic acids by different mechanisms
  • 2011
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1811:3, s. 138-147
  • Tidskriftsartikel (refereegranskat)abstract
    • Manganese lipoxygenase (MnLOX) oxidizes (11R)-hydroperoxylinolenic acid (11R-HpOTrE) to a peroxyl radical. Our aim was to compare the enzymatic oxidation of 11R-HpOTrE and octadecenoic acids with LOO-H and allylic C-H bond dissociation enthalpies of ~88 and ~87kcal/mol. Mn(III)LOX oxidized (11Z)-, (12Z)-, and (13Z)-18:1 to hydroperoxides with R configuration, but this occurred at insignificant rates (<1%) compared to 11R-HpOTrE. We next examined whether transitional metals could mimic this oxidation. Ce(4+) and Mn(3+) transformed 11R-HpOTrE to hydroperoxides at C-9 and C-13 via oxidation to a peroxyl radical at C-11, whereas Fe(3+) was a poor catalyst. Our results suggest that MnLOX oxidizes bis-allylic hydroperoxides to peroxyl radicals in analogy with Ce(4+) and Mn(3+). The enzymatic oxidation likely occurs by proton-coupled electron transfer of the electron from the hydroperoxide anion to Mn(III) and H(+) to the catalytic base, Mn(III)OH(-). Hydroperoxides abolish the kinetic lag times of MnLOX and FeLOX by oxidation of their metal centers, but 11R-HpOTrE was isomerized by MnLOX to (13R)-hydroperoxy-(9Z,11E,15Z)-octadecatrienoic acid (13R-HpOTrE) with a kinetic lag time. This lag time could be explained by two competing transformations, dehydration of 11R-HpOTrE to 11-ketolinolenic acid and oxidation of 11R-HpOTrE to peroxyl radical; the reaction rate then increases as 13R-HpOTrE oxidizes MnLOX with subsequent formation of two epoxyalcohols. We conclude that oxidation of octadecenoic acids and bis-allylic hydroperoxides occurs by different mechanisms, which likely reflect the nature of the hydrogen bonds, steric factors, and the redox potential of the Mn(III) center.
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39.
  • Oliw, E, 1948- (författare)
  • Polyunsaturated C-18 fatty acids derivatized with Gly and Ile as an additional tool for studies of the catalytic evolution of fungal 8-and 9-dioxygenases
  • 2018
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : ELSEVIER SCIENCE BV. - 1388-1981 .- 1879-2618. ; 1863:11, s. 1378-1387
  • Tidskriftsartikel (refereegranskat)abstract
    • The fungal linoleate diol synthase (LDS) family contains over twenty characterized 8-, 9-, and 10-dioxygenases (DOX), usually fused to catalytically competent cytochromes P450. Crystal structures are not available, but indirect evidence suggests that linoleic acid enters the active site of 8R-DOX-LDS headfirst and enters 9S-DOX-allene oxide synthase (AOS) with the omega-end (tail) first. Fatty acids derivatized with amino acids can conceivably be used to study oxidation in tail first position by enzymes, which bind natural fatty acids headfirst. The results might reveal catalytic similarities of homologous enzymes. 8R-DOX-5,8-LDS oxidize 18:2n-6-Ile and 18:2n-6-Gly in tail first position to 9S-hydroperoxy metabolites, albeit with less position and stereo specificity than 9S-DOX-AOS. The oxygenation mechanism of 9S-DOX-AOS with antarafacial hydrogen abstraction at C-11 and oxygen insertion at C-9 was also retained. Two homologues, 8R-DOX-7,8-LDS and 8R-DOX-AOS, oxidized 18:2n-6-Ile and 18:2n-6-Gly at C-9, suggesting a conserved feature of 8R-DOX domains. 9R-DOX-AOS, with 54% sequence identity to 9S-DOX-AOS, did not oxidize the derivatized C-18 fatty acids. 9Z,12Z-16:2, two carbon shorter than 18:n-6 from the omega-end, was rapidly metabolized to an alpha-ketol, but 7Z,10Z-16:2 was not a substrate. An unsaturated carbon chain from C-1 to C-8 was apparently more important than the configuration at the omega-end. 8R-DOX-LDS and 9R-DOX-AOS may thus bind 18:2n-6 in the same orientation. The oxidation of 18:2n-6 in straight or reverse head-to-tail positions illustrates evolutionary traits between 8- and 9-DOX domains. Fatty acids derivatized with amino acids provide a complementary tool for the analysis of evolution of enzymes.
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40.
  • Patanapirunhakit, Patamat, et al. (författare)
  • Sphingolipids in HDL - Potential markers for adaptation to pregnancy?
  • 2021
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier. - 1388-1981 .- 1879-2618. ; 1866:8
  • Forskningsöversikt (refereegranskat)abstract
    • Plasma high density lipoprotein (HDL) exhibits many functions that render it an effective endothelial protective agent and may underlie its potential role in protecting the maternal vascular endothelium during pregnancy. In non-pregnant individuals, the HDL lipidome is altered in metabolic disease compared to healthy individuals and is linked to reduced cholesterol efflux, an effect that can be reversed by lifestyle management. Specific sphingolipids such as sphingosine-1-phosphate (S1P) have been shown to mediate the vaso-dilatory effects of plasma HDL via interaction with the endothelial nitric oxide synthase pathway. This review describes the relationship between plasma HDL and vascular function during healthy pregnancy and details how this is lost in preeclampsia, a disorder of pregnancy associated with widespread endothelial dysfunction. Evidence of a role for HDL sphingolipids, in particular S1P and ceramide, in cardiovascular disease and in healthy pregnancy and pre-eclampsia is discussed. Available data suggest that HDL-S1P and HDL-ceramide can mediate vascular protection in healthy pregnancy but not in preeclampsia. HDL sphingolipids thus are of potential importance in the healthy maternal adaptation to pregnancy.
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41.
  • Pettersson, Hanna, et al. (författare)
  • CYP7B1-mediated metabolism of 5 alfa-androstane-3 alfa,17 beta-diol (3 alfa-Adiol) : A novel pathway for potential regulation of the cellular levels of androgens and neurosteroids
  • 2009
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1791:12, s. 1206-1215
  • Tidskriftsartikel (refereegranskat)abstract
    • The current study presents data indicating that 5alfa-androstane-3alfa,17beta-diol (3alfa-Adiol) undergoes a previously unknown metabolism into hydroxymetabolites, catalyzed by CYP7B1. 3alfa-Adiol is an androgenic steroid which serves as a source for the potent androgen dihydrotestosterone and also can modulate gamma-amino butyric acid A (GABAA) receptor function in the brain. The steroid hydroxylase CYP7B1 is known to metabolize cholesterol derivatives, sex hormone precursors and certain estrogens, but has previously not been thought to act on androgens or 3a-hydroxylated steroids. 3alfa-Adiol was found to undergo NADPH-dependent metabolism into 6- and 7-hydroxymetabolites in incubations with porcine microsomes and human kidney-derived HEK293 cells, which are high in CYP7B1 content. This metabolism was suppressed by addition of steroids known to be metabolized by CYP7B1. Also, recombinant expression of human CYP7B1 in HEK293 cells significantly increased the rate of 3alfa-Adiol hydroxylation. In addition, 3alfa-Adiol significantly suppressed CYP7B1-mediated catalytic reactions, in a way as would be expected for substrates that compete for the same enzyme. The present results indicate that CYP7B1-mediated catalysis may play a role for control of the cellular levels of androgens, not only of estrogens. These findings suggest a previously unknown mechanism for metabolic elimination of 3alfa-Adiol which may impact intracellular levels of dihydrotestosterone and GABAA-modulating steroids.
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42.
  • Pettersson, Hanna, et al. (författare)
  • Effects of CYP7B1-mediated catalysis on estrogen receptor activation.
  • 2010
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1801:9, s. 1090-1097
  • Tidskriftsartikel (refereegranskat)abstract
    • Most of the many biological effects of estrogens are mediated via the estrogen receptors ER alpha and beta. The current study examines the role of CYP7B1-mediated catalysis for activation of ER. Several reports suggest that CYP7B1 may be important for hormonal action but previously published studies are contradictory concerning the manner in which CYP7B1 affects ER beta-mediated response. In the current study, we examined effects of several CYP7B1-related steroids on ER activation, using an estrogen response element (ERE) reporter system. Our studies showed significant stimulation of ER by 5-androstene-3 beta,17 beta-diol (Aene-diol) and 5 alpha-androstane-3 beta,17 beta-diol (3 beta-Adiol). In contrast, the CYP7B1-formed metabolites from these steroids did not activate the receptor, indicating that CYP7B1-mediated metabolism abolishes the ER-stimulating effect of these compounds. The mRNA level of HEM45, a gene known to be stimulated by estrogens, was strongly up-regulated by Aene-diol but not by its CYP7B1-formed metabolite, further supporting this concept. We did not observe stimulation by dehydroepiandrosterone (DHEA) or 7 alpha-hydroxy-DHEA, previously suggested to affect ER beta-mediated response. As part of these studies we examined metabolism of Aene-diol in pig liver which is high in CYP7B1 content These experiments indicate that CYP7B1-mediated metabolism of Aene-diol is of a similar rate as the metabolism of the well-known CYP7B1 substrates DHEA and 3 beta-Adiol. CYP7B1-mediated metabolism of 3 beta-Adiol has been proposed to influence ER beta-mediated growth suppression. Our results indicate that Aene-diol also might be important for ER-related pathways. Our data indicate that low concentrations of Aene-diol can trigger ER-mediated response equally well for both ER alpha and beta and that CYP7B1-mediated conversion of Aene-diol into a 7 alpha-hydroxymetabolite will result in loss of action.
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43.
  • Pettersson, Hanna, et al. (författare)
  • Metabolism of a novel side chain modified Delta 8(14)-15-ketosterol, a potential cholesterol lowering drug : 28-hydroxylation by CYP27A1
  • 2008
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1781:8, s. 383-390
  • Tidskriftsartikel (refereegranskat)abstract
    • The synthetic inhibitors of sterol biosynthesis, 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one and 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one, are of interest as potential cholesterol lowering drugs. Rapid metabolism of synthetic 15-ketosterols may lead to a decrease, or loss, of their potency to affect lipid metabolism. 3beta-Hydroxy-5alpha-cholest-8(14)-en-15-one is reported to be rapidly side chain oxygenated by rat liver mitochondria. In an attempt to reduce this metabolism, the novel side chain modified 15-ketosterol 3beta-Hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one was synthesized. We have examined the metabolism by recombinant human CYP27A1 of this novel side chain modified 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one and compared the rate of metabolism with that of the previously described 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one. Both sterols were found to be efficiently metabolized by recombinant human CYP27A1. None of the two 15-ketosterols was significantly metabolized by microsomal 7alpha-hydroxylation. Interestingly, CYP27A1-mediated product formation was much lower with the side chain modified 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one than with the previously described 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one. A surprising finding was that this novel side chain modified sterol was metabolized mainly in the C-28 position by CYP27A1. The data on 28-hydroxylation by human CYP27A1 provide new insights on the catalytic properties and substrate specificity of this enzyme. The finding that 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one with a modified side chain is metabolized at a dramatically slower rate than the previously described 15-ketosterol with unmodified side chain may be important for future development of synthetic cholesterol lowering sterols.
  •  
44.
  •  
45.
  • Sargsyan, Ernest, et al. (författare)
  • Oleate protects beta-cells from the toxic effect of palmitate by activating pro-survival pathways of the ER stress response
  • 2016
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1861:9, s. 1151-1160
  • Tidskriftsartikel (refereegranskat)abstract
    • Long-term exposure of beta cells to saturated fatty acids impairs insulin secretion and increases apoptosis. In contrast, unsaturated fatty acids protect beta-cells from the long-term negative effects of saturated fatty acids. We aimed to identify the mechanisms underlying this protective action of unsaturated fatty acids. To address the aim, insulin-secreting MINE cells were exposed to palmitate in the absence or presence of oleate and analyzed by using nano-LC MS/MS based proteomic approach. Important findings were validated by using alternative approaches. Proteomic analysis identified 34 proteins differentially expressed in the presence of palmitate compared to control samples. These proteins play a role in insulin processing, mitochondrial function, metabolism of biomolecules, calcium homeostasis, exocytosis, receptor signaling, ER protein folding, antioxidant activity and anti-apoptotic function. When oleate was also present during culture, expression of 15 proteins was different from the expression in the presence of palmitate alone. Most of the proteins affected by oleate are targets of the ER stress response and play a pro-survival role in beta cells such as protein folding and antioxidative defence. We conclude that restoration of pro-survival pathways of the ER stress response is a major mechanism underlying the protective effect of unsaturated fatty acids in beta-cells treated with saturated fatty acids.
  •  
46.
  • Surmacz, Liliana, et al. (författare)
  • Short-chain polyisoprenoids in the yeast Saccharomyces cerevisiae - New companions of the old guys
  • 2015
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1851:10, s. 1296-1303
  • Tidskriftsartikel (refereegranskat)abstract
    • Dolichols are, among others, obligatory cofactors of protein glycosylation in eukaryotic cells. It is well known that yeast cells accumulate a family of dolichols with Dol-15/16 dominating while upon certain physiological conditions a second family with Dol-21 dominating is noted. In this report we identified the presence of additional short-chain length polyprenols - all-trans Pren-7 in three yeast strains (SS328, BY4741 and L5366), Pren-7 was accompanied by traces of putative Pren-6 and -8. Moreover, in two of these strains a single polyprenol mainly-cis-Pren-11 was synthesized at the stationary phase of growth. Identity of polyprenols was confirmed by HR-HPLC/MS, NMR and metabolic labeling. Additionally, simvastatin inhibited their biosynthesis.
  •  
47.
  • Tang, Wanjin, et al. (författare)
  • Glucocorticoid receptor-mediated upregulation of human CYP27A1, a potential anti-atherogenic enzyme
  • 2008
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1781:11-12, s. 718-723
  • Tidskriftsartikel (refereegranskat)abstract
    • Sterol 27-hydroxylase (CYP27A1) is required for the hepatic conversion of cholesterol into bile acids and for production of 27-hydroxycholesterol which affects cholesterol homeostasis in several ways. Dexamethasone increases hepatic bile acid biosynthesis and CYP27A1-mediated enzyme activity in HepG2 cells. This study examines the mechanism of the dexamethasone-induced effect on the human CYP27A1 promoter. Dexamethasone treatment of HepG2 cells overexpressed with glucocorticoid receptor alpha (GRalpha) increased the CYP27A1 promoter activity more than four-fold as compared with untreated cells. The GR-antagonist mifepristone almost completely abolished the dexamethasone-induced effect on the promoter activity. Progressive deletion analysis of the CYP27A1 promoter indicated that sequences involved in GR-mediated induction by dexamethasone are present in a region between -1094 and -792. Several putative GRE sites could be found in this region and EMSA experiments revealed that two of these could bind GR. Site-directed mutagenesis of GR-binding sequences in the CYP27A1 promoter identified a GRE at -824/-819 important for GR-mediated regulation of the transcriptional activity. Endogenous and pharmacological glucocorticoids may have a strong impact on several aspects of cholesterol homeostasis and other processes related to CYP27A1-mediated metabolism. The glucocorticoid-mediated induction of human CYP27A1 transcription is of particular interest due to the anti-atherogenic properties ascribed to this enzyme.
  •  
48.
  • Turunen, Mikael, et al. (författare)
  • Defect in fatty acid esterification of dolichol in Niemann-Pick type C1 mouse livers in vivo
  • 2007
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1771:4, s. 506-513
  • Tidskriftsartikel (refereegranskat)abstract
    • Fatty acid esterification of dolichol and cholesterol in Niemann-Pick type C 1 mouse (Balb/c NIH npcl(-/-)) livers was investigated in response to treatment with peroxisomal proliferators. These inducers have hypolipidemic properties and influence the mevalonate pathway and the intracellular transport of the final products of this biosynthetic route. Such inducers are consequently interesting to use in a disease model with defective intracellular transport of lipids. In wild-type mice, the levels of dolichol and cholesterol found as free alcohols were not changed to any great extent upon treatment with the peroxisomal inducers dehydroepiandrosterone, clofibrate and diethylhexylphtalate. In contrast, the amounts of dolichyl esters increased whereas cholesteryl esters decreased by the same treatments. The rate of enzymatic esterification of dolichol in isolated microsomes was accordingly elevated after 5- to 7-day treatments with the efficient peroxisomal proliferators DEHP and PFOA, while the corresponding esterification of cholesterol was decreased. Upon peroxisomal induction in npcl(-/-) mice, the enzymatic dolichol esterification in vitro increased whereas the low concentration of dolichyl esters remained unchanged. The results thus demonstrate that the induction of fatty acid esterification of dolichol in vivo is impaired in npcl(-/-) mouse liver. It is therefore proposed that the intracellular lipid transport defect in npcl(-/-) mouse liver disables either dolichol and/or the fatty acid from reaching the site of esterification in vivo. This proposal was strengthened by the finding that the amount of dolichol was decreased in an isolated Golgi fraction from npcl(-/-) mice.
  •  
49.
  • Waldie, Sarah, et al. (författare)
  • Lipoprotein ability to exchange and remove lipids from model membranes as a function of fatty acid saturation and presence of cholesterol.
  • 2020
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier. - 1388-1981 .- 1879-2618. ; 1865:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Lipoproteins play a central role in the development of atherosclerosis. High and low-density lipoproteins (HDL and LDL), known as 'good' and 'bad' cholesterol, respectively, remove and/or deposit lipids into the artery wall. Hence, insight into lipid exchange processes between lipoproteins and cell membranes is of particular importance in understanding the onset and development of cardiovascular disease. In order to elucidate the impact of phospholipid tail saturation and the presence of cholesterol in cell membranes on these processes, neutron reflection was employed in the present investigation to follow lipid exchange with both HDL and LDL against model membranes. Mirroring clinical risk factors for the development of atherosclerosis, lower exchange was observed in the presence of cholesterol, as well as for an unsaturated phospholipid, compared to faster exchange when using a fully saturated phospholipid. These results highlight the importance of membrane composition on the interaction with lipoproteins, chiefly the saturation level of the lipids and presence of cholesterol, and provide novel insight into factors of importance for build-up and reversibility of atherosclerotic plaque. In addition, the correlation between the results and well-established clinical risk factors suggests that the approach taken can be employed also for understanding a broader set of risk factors including, e.g., effects of triglycerides and oxidative stress, as well as local effects of drugs on atherosclerotic plaque formation.
  •  
50.
  • Ekblad, Lars, et al. (författare)
  • Localization of phosphatidylinositol 4-kinase isoenzymes in rat liver plasma membrane domains
  • 2001
  • Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - 1388-1981. ; 1531:3, s. 209-221
  • Tidskriftsartikel (refereegranskat)abstract
    • The presence of different isoenzymes of phosphatidylinositol 4-kinase in isolated rat liver plasma membranes and their further distribution in plasma membrane domains was examined. Both wortmannin-sensitive and -insensitive PtdIns 4-kinase activities were detected in highly purified plasma membranes obtained by aqueous two-phase affinity partitioning. The wortmannin-sensitive enzyme was identified as the 230 kDa isoform by Western blotting, whereas the 92 kDa isoform was not detected in plasma membranes. The apparent molecular weights of these isoforms were 205 and 105 kDa on SDS polyacrylamide gel electrophoresis, but approximately 500 and 230 kDa respectively on gel filtration, suggesting that both enzymes either are dimers or composed of heterologous subunits. Approximately 25% of the total 230 kDa isoenzyme present in liver, and only ca 5% of the wortmannin-insensitive one, was associated with the plasma membrane fraction. Plasma membrane domains were isolated by a combination of sucrose and Nycodenz gradient centrifugations. The 230 kDa isoform was identified in the blood sinusoidal domain, but not in the bile canalicular one, and was also found in lateral plasma membranes. The wortmannin-insensitive isoenzyme was present only in this latter material. The functional implications of this distribution of PtdIns 4-kinase isoenzymes in plasma membrane regions are discussed.
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