| 1. |
- Shao, Yangzhen, 1981, et al.
(författare)
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A mouse model reveals an important role for catecholamine-induced lipotoxicity in the pathogenesis of stress-induced cardiomyopathy.
- 2013
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Ingår i: European journal of heart failure. - : Wiley. - 1879-0844 .- 1388-9842. ; 15:1, s. 9-22
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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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| 2. |
- Wang, Xiaodi, 1981-, et al.
(författare)
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Synthesis of uniform quasi-octahedral CeO2 mesocrystals via a surfactant-free route
- 2011
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Ingår i: Journal of nanoparticle research. - : Springer Science and Business Media LLC. - 1388-0764 .- 1572-896X. ; 13:11, s. 5879-5885
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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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| 3. |
- Bonini, Tiziano, et al.
(författare)
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Radio formats and social media use in Europe : 28 case studies of public service practice
- 2014
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Ingår i: Radio Journal. - : Intellect Ltd.. - 1476-4504 .- 2040-1388. ; 12:1-2, s. 89-109
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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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| 4. |
- Bentinger, Magnus, et al.
(författare)
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Effects of various squalene epoxides on coenzyme Q and cholesterol synthesis
- 2014
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1841:7, s. 977-986
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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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| 5. |
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| 6. |
- Bäckhed, Fredrik, 1973, et al.
(författare)
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Coordinated regulation of the metabolome and lipidome at the host-microbial interface
- 2010
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981. ; 1801:3, s. 240-245
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Forskningsöversikt (refereegranskat)abstract
- The creative use of gnotobiotic animals, coupled with the development of modern metagenomic sequencing platforms and metabolomic profiling of biospecimens, has bestowed new insight into the remarkably intricate interface between the host mammal and its resident microbiota. As mutual benefactors, each partner exhibits evidence of adaptation: the host provides a hospitable habitat, giving consideration to its own species of origin, diet, genotype, geographical location, presence or absence of disease, and use of medications; the microbiota, in turn, configures its constituency, collective genome (microbiome), transcriptome, and metabolome to optimally suit its ecological niche. In this review, we discuss the mechanisms through which the gut microbiota and its host collaborate to regulate lipid metabolism, thereby influencing the metabolic response to nutrient intake and ultimately, the development of obesity and associated diseases such as lipotoxicity. These studies therefore demonstrate that the gut microbiota is an 'environmental' influence whose synergistic interdependence with its host strongly suggests that we are in fact 'supraorganisms'.
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| 7. |
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| 8. |
- Fowler, Christopher J., et al.
(författare)
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Tumour epithelial expression levels of endocannabinoid markers modulate the value of endoglin-positive vascular density as a prognostic marker in prostate cancer
- 2013
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1831:10, s. 1579-1587
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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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| 9. |
- Hansen, Ida R., et al.
(författare)
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Contrasting effects of cold acclimation versus obesogenic diets on chemerin gene expression in brown and brite adipose tissues
- 2014
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1841:12, s. 1691-1699
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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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| 10. |
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| 11. |
- Hoffmann, Inga, 1984-, et al.
(författare)
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Novel insights into cyclooxygenases, linoleate diol synthases, and lipoxygenases from deuterium kinetic isotope effects and oxidation of substrate analogs
- 2012
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1821:12, s. 1508-1517
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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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| 12. |
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| 13. |
- Jernerén, Fredrik, et al.
(författare)
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Reaction mechanism of 5,8-linoleate diol synthase, 10R-dioxygenase, and 8,11-hydroperoxide isomerase of Aspergillus clavatus
- 2010
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Ingår i: Biochimica et Biophysica Acta. - : Elsevier BV. - 0006-3002 .- 1878-2434. ; 1801:4, s. 503-507
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Tidskriftsartikel (refereegranskat)abstract
- Aspergilli express fusion proteins of an animal haem peroxidase domain with fatty acid dioxygenase (DOX) activity ( approximately 600 amino acids) and a functional or non-functional hydroperoxide isomerase/cytochrome P450 domain ( approximately 500 amino acids with EXXR and GPHXCLG motifs). 5,8-Linoleate diol synthases (LDS; ppoA) and 10R-DOX (ppoC) of Aspergillusnidulans and A. fumigatus belong to this group. Our objective was to determine the oxylipins formed from linoleic acid by A. clavatus and their mechanism of biosynthesis. A. clavatus oxidized linoleic acid to (8R)-hydroperoxylinoleic acid (8R-HPODE), (10R)-hydroperoxy-8(E),12(Z)-octadecadienoic acid (10R-HPODE), and to (5S,8R)-dihydroxy- and (8R,11S)-dihydroxylinoleic acids (DiHODE) as major products. This occurred by abstraction of the pro-S hydrogen at C-8 and antarafacial dioxygenation at C-8 or at C-10 with double bond migration. 8R-HPODE was then isomerized to 5S,8R-DiHODE and to 8R,11S-DiHODE by abstraction of the pro-S hydrogens at C-5 and C-11 of 8R-HPODE, respectively, followed by suprafacial oxygenation. The genome of A. clavatus codes for two enzymes, which can be aligned with >65% amino acid identity to 10R-DOX and 5,8-LDS, respectively. The 5,8-LDS homologue likely forms and isomerizes 8R-HPODE to 5S,8R-DiHODE. A third gene (ppoB) codes for a protein which carries a serine residue at the cysteine position of the P450 motif. This Cys to Ser replacement is known to abolish P450 2B4 catalysis and the hydroperoxide isomerase activity of 5,8-LDS, suggesting that ppoB of A. clavatus may not be involved in the biosynthesis of 8R,11S-DiHODE.
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| 14. |
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| 15. |
- Kågedal, Katarina, et al.
(författare)
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Increased expression of the lysosomal cholesterol transporter NPC1 in Alzheimers disease
- 2010
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : ELSEVIER SCIENCE BV. - 1388-1981 .- 1879-2618. ; 1801:8, s. 831-838
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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.
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| 16. |
- Lagerstedt, Jens, et al.
(författare)
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The "beta-clasp" model of apolipoprotein A-I - A lipid-free solution structure determined by electron paramagnetic resonance spectroscopy.
- 2012
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Ingår i: Biochimica et Biophysica Acta. - : Elsevier BV. - 0006-3002. ; 1821:3, s. 448-455
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein A-I (apoA-I) is the major protein component of high density lipoproteins (HDL) and plays a central role in cholesterol metabolism. The lipid-free/lipid-poor form of apoA-I is the preferred substrate for the ATP-binding cassette transporter A1 (ABCA1). The interaction of apoA-I with ABCA1 leads to the formation of cholesterol laden high density lipoprotein (HDL) particles, a key step in reverse cholesterol transport and the maintenance of cholesterol homeostasis. Knowledge of the structure of lipid-free apoA-I is essential to understanding its critical interaction with ABCA1 and the molecular mechanisms underlying HDL biogenesis. We therefore examined the structure of lipid-free apoA-I by electron paramagnetic resonance spectroscopy (EPR). Through site directed spin label EPR, we mapped the secondary structure of apoA-I and identified sites of spin coupling as residues 26, 44, 64, 167, 217 and 226. We capitalize on the fact that lipid-free apoA-I self-associates in an anti-parallel manner in solution. We employed these sites of spin coupling to define the central plane in the dimeric apoA-I complex. Applying both the constraints of dipolar coupling with the EPR-derived pattern of solvent accessibility, we assembled the secondary structure into a tertiary context, providing a solution structure for lipid-free apoA-I. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
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| 17. |
- Li, Jie, et al.
(författare)
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Minimally modified LDL upregulates endothelin type B receptors in rat coronary artery via ERK1/2 MAPK and NF-kappa B pathways
- 2012
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981. ; 1821:4, s. 582-589
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Tidskriftsartikel (refereegranskat)abstract
- Minimally modified low density lipoprotein (mmLDL) is a well-known risk factor for coronary artery disease. Upregulation of vascular endothelin type B (ETB) receptors on the vascular smooth muscle cells is predicted to be the molecular mechanism that leads to cardiovascular pathogenesis. The objective of the present study was to examine the hypothesis that mmLDL upregulates ETB receptors in rat coronary artery. The contractile responses to sarafotoxin 6c (ETB receptor agonist) were studied using a sensitive myograph. ETB receptor mRNA and protein expression was determined using real-time PCR and Western blot analysis. The results showed that organ culture increased the contractile responses induced by sarafotoxin 6c and the levels of ETB receptor mRNA and protein. This increase was further enhanced by the addition of mmLDL (10 mu g/mL). Specific ERK1/2 inhibitors (SB386023 and U0126) and an NF-kappa B inhibitor (wedelolactone) attenuated the mmLDL-increased ETB receptor-mediated contraction and ETB receptor mRNA and protein levels. Wedelolactone significantly attenuated the mmLDL-decreased I kappa B-alpha protein expression. Consistent with this result, I kappa B-alpha protein expression was significantly decreased by culture with mmLDL compared to the level of expression in the organ culture group. However, the JNK inhibitor, SP600125 or p38 pathway inhibitor, SB203580 did not inhibit mmLDL-enhanced effects. The PKC inhibitor, staurosporine attenuated only culture-alone-increased effects. In conclusion, mmLDL upregulates the ETB receptors in rat coronary arterial smooth muscle cells, mainly via activation of the ERK1/2 MAPK and the downstream transcriptional factor NF-kappa B. (C) 2011 Elsevier B.V. All rights reserved.
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| 18. |
- Lundqvist, Johan, et al.
(författare)
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1α,25-Dihydroxyvitamin D3 affects hormone production and expression of steroidogenic enzymes in human adrenocortical NCI-H295R cells
- 2010
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1801:9, s. 1056-1062
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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.
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| 19. |
- Lundqvist, Johan, et al.
(författare)
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1α,25-Dihydroxyvitamin D3 exerts tissue-specific effects on estrogen and androgen metabolism
- 2011
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1811:4, s. 263-270
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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.
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| 20. |
- Lundqvist, Johan, et al.
(författare)
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Effects of CYP7B1-related steroids on androgen receptor activation in different cell lines
- 2012
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1821:7, s. 973-979
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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.
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| 21. |
- Mahammad, Saleemulla, et al.
(författare)
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Limited cholesterol depletion causes aggregation of plasma membrane lipid raftsinducing T cell activation
- 2010
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1801:6, s. 625-634
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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.
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| 22. |
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| 23. |
- Nedergaard, Jan, et al.
(författare)
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UCP1 mRNA does not produce heat
- 2013
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1831:5, s. 943-949
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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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| 24. |
- Nilsson, Stefan, et al.
(författare)
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Triacylglycerol-rich lipoproteins protect lipoprotein lipase from inactivation by ANGPTL3 and ANGPTL4
- 2012
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - Amsterdam : Elsevier. - 1388-1981 .- 1879-2618. ; 1821:10, s. 1370-1378
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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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| 25. |
- Oliw, Ernst H., 1948-, et al.
(författare)
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Manganese lipoxygenase oxidizes bis-allylic hydroperoxides and octadecenoic acids by different mechanisms
- 2011
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1811:3, s. 138-147
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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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| 26. |
- Oresic, Matej, 1967-
(författare)
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Informatics and computational strategies for the study of lipids
- 2011
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Ingår i: Biochimica et Biophysica Acta. - : Elsevier. - 0006-3002 .- 1878-2434. ; 1811:11, s. 991-999
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Forskningsöversikt (refereegranskat)abstract
- The ability to translate vast amounts of information, as obtained from lipidomic analysis, into the knowledge and understanding of biological phenomena is an important challenge faced by the lipidomics community. While many of the informatics and computational tools from other domains such as bioinformatics and metabolomics are also applicable to lipidomics data processing and analysis, new solutions and strategies are needed for the studies of lipidomes at the systems level. This is due to enormous functional and structural diversity of lipids as well as because of their complex regulation at multiple spatial and temporal scales. In order to better understand the lipidomes at the physiological level, lipids need to be modeled not only at the level of biological pathways but also at the level of the biophysical systems they are part of, such as cellular membranes or lipoprotein particles. Herein the current state, recent advances and new opportunities in the field of lipid bioinformatics are reviewed.
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| 27. |
- Oresic, Matej, 1967-
(författare)
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Systems biology strategy to study lipotoxicity and the metabolic syndrome
- 2010
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Ingår i: Biochimica et Biophysica Acta. - : Elsevier. - 0006-3002 .- 1878-2434. ; 1801:3, s. 235-239
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Tidskriftsartikel (refereegranskat)abstract
- Systems biology views and studies the biological systems in the context of complex interactions between their building blocks and processes. Given its multi-level complexity, metabolic syndrome (MetS) makes a strong case for adopting the systems biology approach. Despite many MetS traits being highly heritable, it is becoming evident that the genetic contribution to these traits is mediated via gene-gene and gene-environment interactions across several spatial and temporal scales, and that some of these traits such as lipotoxicity may even be a product of long-term dynamic changes of the underlying genetic and molecular networks. This presents several conceptual as well as methodological challenges and may demand a paradigm shift in how we study the undeniably strong genetic component of complex diseases such as MetS. The argument is made here that for adopting systems biology approaches to MetS an integrative framework is needed which glues the biological processes of MetS with specific physiological mechanisms and principles and that lipotoxicity is one such framework. The metabolic phenotypes, molecular and genetic networks can be modeled within the context of such integrative framework and the underlying physiology.
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| 28. |
- Pettersson, Hanna, et al.
(författare)
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Effects of CYP7B1-mediated catalysis on estrogen receptor activation.
- 2010
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1801:9, s. 1090-1097
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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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| 29. |
- Pingitore, Piero, 1986, et al.
(författare)
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Recombinant PNPLA3 protein shows triglyceride hydrolase activity and its I148M mutation results in loss of function.
- 2014
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Ingår i: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981. ; 1841:4, s. 574-580
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Tidskriftsartikel (refereegranskat)abstract
- The patatin-like phospholipase domain containing 3 (PNPLA3, also called adiponutrin, ADPN) is a membrane-bound protein highly expressed in the liver. The genetic variant I148M (rs738409) was found to be associated with progression of chronic liver disease. We aimed to establish a protein purification protocol in a yeast system (Pichia pastoris) and to examine the human PNPLA3 enzymatic activity, substrate specificity and the I148M mutation effect. hPNPLA3 148I wild type and 148M mutant cDNA were cloned into P. pastoris expression vectors. Yeast cells were grown in 3L fermentors. PNPLA3 protein was purified from membrane fractions by Ni-affinity chromatography. Enzymatic activity was assessed using radiolabeled substrates. Both 148I wild type and 148M mutant proteins are localized to the membrane. The wild type protein shows a predominant lipase activity with mild lysophosphatidic acid acyl transferase activity (LPAAT) and the I148M mutation results in a loss of function of both these activities. Our data show that PNPLA3 has a predominant lipase activity and I148M mutation results in a loss of function.
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| 30. |
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| 31. |
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| 32. |
- Smith, Ulf, 1943, et al.
(författare)
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Antagonistic effects of thiazolidinediones and cytokines in lipotoxicity.
- 2010
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Ingår i: BBA - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 0006-3002 .- 1388-1981. ; 1801, s. 377-380
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Tidskriftsartikel (refereegranskat)abstract
- Ectopic lipid accumulation is promoted by obesity and an impaired ability to accumulate triglycerides in the subcutaneous depots. The adipose tissue is dysregulated in hypertrophic obesity, i.e., when the adipose cells have become enlarged. In some individuals, however, obesity is a consequence of a recruitment of new adipocytes, i.e., a hyperplastic obesity. This form of obesity is usually not associated with the metabolic complications and is termed "obese but metabolically normal". We here review recent findings showing that hypertrophic obesity is associated with an impaired differentiation of committed preadipocytes. This may be a primary (genetic?) event, thus leading to hypertrophic fat cells and the associated inflammation. However, it is also possible that the inflammation is a primary event allowing, in particular, TNFalpha to inhibit preadipocyte differentiation. TNFalpha, instead, promotes a partial transdifferentiation of the preadipocytes to assume a macrophage-like phenotype. PPARgamma activation promotes adipogenesis but can apparently not overcome the impaired preadipocyte differentiation seen in hypertrophic obesity.
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| 33. |
- Ståhlman, Marcus, 1975, et al.
(författare)
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Dyslipidemia, but not hyperglycemia and insulin resistance, is associated with marked alterations in the HDL lipidome in type 2 diabetic subjects in the DIWA cohort: Impact on small HDL particles
- 2013
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Ingår i: Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981. ; 1831:11, s. 1609-1617
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Tidskriftsartikel (refereegranskat)abstract
- In this study we have used mass spectrometry in order to characterize the HDL lipidome in three groups of women from the DIWA cohort; one control group, plus two groups with type 2 diabetes with insulin resistance; one dyslipidemic and one normolipidemic. The aim was to investigate whether dyslipidemia is required in addition to insulin resistance for the occurrence of an altered HDL lipidome, which in turn might impact HDL functionality. The dyslipidemic type 2 diabetic subjects were distinguished by obesity, hypertriglyceridemia with elevated apoC3, low HDL-cholesterol and chronic low grade inflammation. In a stepwise multivariate linear regression analysis, including biomarkers of dyslipidemia and insulin resistance as independent variables, only dyslipidemia showed a significant correlation with HDL lipid classes. Small HDL-particles predominated in dyslipidemic subjects in contrast to the normolipidemic diabetic and control groups, and were enriched in lysophosphatidylcholine (+13%), a product of proinflammatory phospholipases, and equally in two core lipids, palmitate-rich triacylglycerols and diacylglycerols (+77 %), thereby reflecting elevated CETP activity. Dyslipidemic small HDL particles were further distinguished not only as the primary carrier of ceramides, which promote inflammation and insulin resistance, but also by a subnormal plasmalogen/apoAI ratio, consistent with elevated oxidative stress typical of type 2 diabetes. From these data we conclude that in type 2 diabetes, dyslipidemia predominates relative to hyperglycemia for the occurrence of an altered HDL lipidome. Furthermore, dyslipidemia alters the cargo of bioactive lipids, with implications for HDL function. (C) 2013 Published by Elsevier B.V.
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| 34. |
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| 35. |
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| 36. |
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| 37. |
- Wei, Jiang, et al.
(författare)
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Estrogen upregulates hepatic apolipoprotein M expression via the estrogen receptor
- 2011
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981. ; 1811:12, s. 1146-1151
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein M (apoM) is present predominantly in high-density lipoprotein (HDL) in human plasma, thus possibly involved in the regulation of HDL metabolism and the process of atherosclerosis. Although estrogen replacement therapy increases serum levels of apoAl and HDL, it does not seem to reduce the cardiovascular risk in postmenopausal women. Therefore, we investigated the effects of estrogen on apoM expression in vitro and in vivo. HepG2 cells were incubated with different concentrations of estrogen with or without the estrogen receptor antagonist, fulvestrant, and apoM expression in the cells was determined. Hepatic apoM expression and serum levels of apoM were also determined in normal and in ovariectomized rats treated with either placebo or estradiol benzoate, using sham operated rats as controls. Estrogen significantly increased mRNA levels of apoM and apoAl in HepG2 cell cultures in a dose- and time-dependent manner; the upregulation of both apolipoproteins was fully abolished by addition of estrogen receptor antagonist In normal rats, estrogen treatment led to an increase in plasma lipid levels including HDL cholesterol, a marked upregulation of apoM mRNA and a significant increase in serum levels of apoM. The same pattern of regulation was found in ovariectomized rats treated with estrogen. Thus, estrogen upregulates apoM expression both in vivo and in vitro by mechanism(s) involving the estrogen receptor. (C) 2011 Elsevier B.V. All rights reserved.
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