| 1. |
- Blomquist, Caroline, et al.
(författare)
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Decreased lipogenesis-promoting factors in adipose tissue in postmenopausal women with overweight on a Paleolithic-type diet
- 2018
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Ingår i: European Journal of Nutrition. - : Springer. - 1436-6207 .- 1436-6215. ; 57:8, s. 2877-2886
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We studied effects of diet-induced postmenopausal weight loss on gene expression and activity of proteins involved in lipogenesis and lipolysis in adipose tissue.Methods: Fifty-eight postmenopausal women with overweight (BMI 32.5 ± 5.5) were randomized to eat an ad libitum Paleolithic-type diet (PD) aiming for a high intake of protein and unsaturated fatty acids or a prudent control diet (CD) for 24 months. Anthropometry, plasma adipokines, gene expression of proteins involved in fat metabolism in subcutaneous adipose tissue (SAT) and lipoprotein lipase (LPL) activity and mass in SAT were measured at baseline and after 6 months. LPL mass and activity were also measured after 24 months.Results: The PD led to improved insulin sensitivity (P < 0.01) and decreased circulating triglycerides (P < 0.001), lipogenesis-related factors, including LPL mRNA (P < 0.05), mass (P < 0.01), and activity (P < 0.001); as well as gene expressions of CD36 (P < 0.05), fatty acid synthase, FAS (P < 0.001) and diglyceride acyltransferase 2, DGAT2 (P < 0.001). The LPL activity (P < 0.05) and gene expression of DGAT2 (P < 0.05) and FAS (P < 0.05) were significantly lowered in the PD group versus the CD group at 6 months and the LPL activity (P < 0.05) remained significantly lowered in the PD group compared to the CD group at 24 months.Conclusions: Compared to the CD, the PD led to a more pronounced reduction of lipogenesis-promoting factors in SAT among postmenopausal women with overweight. This could have mediated the favorable metabolic effects of the PD on triglyceride levels and insulin sensitivity.
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| 2. |
- Heverin, Maura, et al.
(författare)
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On the regulatory importance of 27-hydroxycholesterol in mouse liver
- 2017
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier. - 0960-0760 .- 1879-1220. ; 169, s. 10-21
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Forskningsöversikt (refereegranskat)abstract
- 27-Hydroxycholesterol (27OH) is a strong suppressor of cholesterol synthesis and a weak activator of LXR in vitro. The regulatory importance of 27OH in vivo is controversial. Here we utilized male mice with increased levels of 27OH either due to increased production (CYP27A1 transgenic mice) or reduced metabolism (Cyp7b1-/- mice). We also used mice lacking 27OH due to a knockout of Cyp27a1. The latter mice were treated with cholic acid to compensate for reduced bile acid synthesis. The effects of the different levels of 27OH on Srebp- and other LXR-regulated genes in the liver were investigated. In the liver of CYP27tg mice we found a modest increase of the mRNA levels corresponding to the LXR target genes Cyp7b1 and Abca1. A number of other LXR-regulated genes were not affected. The effect on Abca1 mRNA was not seen in the liver of Cyp7b1-/- mice. There were little or no effects on cholesterol synthesis. In the liver of the Cyp27-/- mice treated with 0.025% cholic acid there was no significant effect of the knockout on the LXR target genes. In a previous work triple-knockout mice deficient in the biosynthesis of 24S-hydroxycholesterol, 25-hydroxycholesterol and 27OH were shown to have impaired response to dietary cholesterol, suggesting side-chain oxidized oxysterols to be mediators in cholesterol-induced effects on LXR target genes at a transcriptional level (Chen W. et al., Cell Metab. 5 (2007) 73-79). The hydroxylated oxysterol responsible for the effect was not defined. We show here that treatment of wildtype mice with dietary cholesterol under the same conditions as in the above study induced the LXR target genes Lpl, Abcg8 and Srebp1c in wild type mice but failed to activate the same genes in mice lacking 27-hydroxycholesterol due to a knockout of Cyp27. We failed to demonstrate the above effects at the protein level (Abcg8) or at the activity level (Lpl). The results suggest that 27OH is not an important regulator of Srebp- or LXR regulated genes under basal conditions in mouse liver. On the other hand 27OH appears to mediate cholesterol-induced effects on some LXR target genes at a transcriptional level under some in vivo conditions.
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| 3. |
- Mahmood, Dana, 1965-, et al.
(författare)
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Response of angiopoietin-like proteins 3 and 4 to haemodialysis
- 2014
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Ingår i: International Journal of Artificial Organs. - : SAGE Publications. - 0391-3988 .- 1724-6040. ; 37:1, s. 13-20
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: Patients on chronic hemodialysis (cHD) have decreased activity of lipoprotein lipase (LPL). Angiopoietin-like proteins (ANGPTL) 3 and 4 have been shown to inactivate LPL. The aim of this study was to investigate the levels of the ANGPTLs in plasma of cHD-patients and to evaluate if cHD may alter these levels. Material and methods: Baseline data were collected from cHD patients (n = 23), and controls (n = 23) and samples were analyzed from 17 patients during low-flux or high-flux HD, and from ultrafiltrate (n = 5). The levels of ANGPTL3 and 4, LPL and triglycerides were studied in a cross-over design on cHD with local citrate compared to tinzaparin as anticoagulant. Results: The level of ANGPTL3 was higher than ANGPTL4 in patients and controls (p<0.01); the ANGPTL3 was 2.0 and ANGPTL4 was 3.3-fold higher in cHD versus controls. The levels of ANGPTL4 increased during cHD. After 180 min of HD the values had decreased again. When the dialysis was performed with high-flux filter, the mean level of ANGPTL4 at 180 min was below the value observed before cHD (p = 0.003). There was immunoreaction for ANGPTL4 in UFs when using high-flux, but not with low-flux, filter. ANGPTL3 was not detectable in UF. On cHD with citrate, no LPL activity was released into the blood. Conclusions: ANGPTL3 and ANGPTL4 were increased in HD patients. Anticoagulation with tinzaparin during cHD causes release of ANGPTL4 from tissues into blood. cHD using high-flux filters, to some extent, removed ANGPTL4. With citrate the levels of ANGPTL4 decreased.
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| 4. |
- Makoveichuk, Elena, et al.
(författare)
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High concentrations of Angiopoietin-like Protein 4 detected in serum from patients with rheumatoid arthritis can be explained by non-specific antibody reactivity
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Angiopoietin-like protein 4 (ANGPTL4) is suggested to be a master regulator of plasma triglyceride metabolism. Our aim was to study whether the previously reported high levels of ANGPTL4 detected in serum from patients with rheumatoid arthritis (RA) by ELISA was due to any specific molecular form of this protein (oligomers, monomers or fragments). ANGPTL4 levels were first determined in serum from 68 RA patients and 43 age and sex matched control subjects and the mean values differed by a factor of 5.0. Then, ANGPTL4 was analyzed after size exclusion chromatography (SEC) of serum samples. With serum from one of the RA patients with high levels of ANGPTL4, the dominant reactivity was found in fractions corresponding to high-molecular weight proteins. In addition, a minor peak of reactivity eluting late from the column was found both in the patient and in controls. By the use of Hetero-Block r, and by careful selection of antibodies, we documented non-specific reactions for ANGPTL4 in 39% of samples from the RA patients, most likely due to cross-reactivity of the antibodies with rheumatoid factor (RF). The corresponding figure for control subjects was 6.3%. After corrections for non-specific reactions, the mean level of ANGPTL4 in serum from RA patients was still significantly higher than in control individuals (mean levels were 101 +/- 62 and 67 +/- 39 ng/ml respectively, P = 0.02). We re-analyzed samples from our previously published studies on ANGPL4 levels in patients on hemodialysis and patients with diabetes type 2. These samples did not show false positive reactions. The levels of ANGPTL4 were comparable to those detected previously.
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| 5. |
- Makoveichuk, Elena, et al.
(författare)
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Inactivation of lipoprotein lipase in 3T3-L1 adipocytes by angiopoietin-like protein 4 requires that both proteins have reached the cell surface
- 2013
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier. - 0006-291X .- 1090-2104. ; 441:4, s. 941-946
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Tidskriftsartikel (refereegranskat)abstract
- Lipoprotein lipase (LPL) and angiopoietin-like protein 4 (Angptl4) were studied in 3T3-L1 adipocytes. Transfections of the adipocytes with Angptl4 esiRNA caused reduction of the expression of Angptl4 to about one fourth of that in cells treated with vehicle only. This resulted in higher levels of LPL activity both on cell surfaces (heparin-releasable) and in the medium, while LPL activity within the cells remained unaffected. This demonstrated that even though both proteins are made in the same cell, Angptl4 does not inactivate LPL during intracellular transport. Most of the Angptl4 protein was present as covalent dimers and tetramers on cell surfaces, while within the cells there were only monomers. LPL gradually lost activity when incubated in medium, but there was no marked difference between conditioned medium from normal cells (rich in Angptl4) and medium after knockdown of Angptl4. Hence Angptl4 did not markedly accelerate inactivation of LPL in the medium. Experiments with combinations of different cells and media indicated that inactivation of LPL occurred on the surfaces of cells producing Angptl4. (C) 2013 Elsevier Inc. All rights reserved.
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| 6. |
- Makoveichuk, Elena, et al.
(författare)
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Inactivation of lipoprotein lipase occurs on the surface of THP-1 macrophages where oligomers of angiopoietin-like protein 4 are formed
- 2012
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - San Diego : Elsevier. - 0006-291X .- 1090-2104. ; 425:2, s. 138-143
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Tidskriftsartikel (refereegranskat)abstract
- Lipoprotein lipase (LPL) hydrolyzes triglycerides in plasma lipoproteins causing release of fatty acids for metabolic purposes in muscles and adipose tissue. LPL in macrophages in the artery wall may, however, promote foam cell formation and atherosclerosis. Angiopoietin-like protein (ANGPTL) 4 inactivates LPL and ANGPTL4 expression is controlled by peroxisome proliferator-activated receptors (PPAR). The mechanisms for inactivation of LPL by ANGPTL4 was studied in THP-1 macrophages where active LPL is associated with cell surfaces in a heparin-releasable form, while LPL in the culture medium is mostly inactive. The PPAR delta agonist GW501516 had no effect on LPL mRNA, but increased ANGPTL4 mRNA and caused a marked reduction of the heparin-releasable LPL activity concomitantly with accumulation of inactive, monomeric LPL in the medium. Intracellular ANGPTL4 was monomeric, while dimers and tetramers of ANGPTL4 were present in the heparin-releasable fraction and medium. GW501516 caused an increase in the amount of ANGPTL4 oligomers on the cell surface that paralleled the decrease in LPL activity. Actinomycin D blocked the effects of GW501516 on ANGPTL4 oligomer formation and prevented the inactivation of LPL Antibodies against ANGPTL4 interfered with the inactivation of LPL. We conclude that inactivation of LPL in THP-1 macrophages primarily occurs on the cell surface where oligomers of ANGPTL4 are formed. (c) 2012 Elsevier Inc. All rights reserved.
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| 7. |
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| 8. |
- Makoveichuk, Elena, et al.
(författare)
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TNF-alpha decreases lipoprotein lipase activity in 3T3-L1 adipocytes by up-regulation of angiopoietin-like protein 4
- 2017
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier. - 1388-1981 .- 1879-2618. ; 1862:5, s. 533-540
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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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| 9. |
- Neuger, Lucyna, et al.
(författare)
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Effects of the heparin-mimicking compound RG-13577 on lipoprotein lipase and on lipase mediated binding of LDL to cells
- 2001
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Ingår i: Atherosclerosis. - 0021-9150 .- 1879-1484. ; 157:1, s. 13-21
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Tidskriftsartikel (refereegranskat)abstract
- Lipoprotein lipase (LPL) has high affinity for heparin and heparin-like compounds. In vivo the enzyme is attached to heparan sulfate proteoglycans on the endothelium of capillaries and larger blood vessels. The enzyme is released from these sites after intravenous injection of heparin. One has here investigated the effects of RG-13577 on LPL, both after intravenous injection to rats and under cell culture conditions. RG-13577 is a heparin-mimicking compound known to prevent angiogenesis by interference with binding of growth factors to cells. It has therefore been considered for use in cancer therapy as well as for prevention of atherosclerosis and restenosis. It was found that intravenously injected RG-13577 released both LPL and hepatic lipase (HL) to the blood. Binding of LPL in extrahepatic tissues was prevented and clearance of radiolabeled LPL from the circulation was delayed. Furthermore, RG-13577 released LPL from extracellular matrix (ECM) produced by endothelial cells and from THP-1 monocyte-derived macrophages. Lipase-mediated binding and uptake of human LDL in these cells was also prevented by RG-13577. Thus, in the test systems RG-13577 had the same effects as heparin, but on a molar basis RG-13577 was in all cases less effective.
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| 10. |
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