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Olivecrona, Gunilla
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Publications (10 of 115) Show all publications
Oteng, A.-B., Ruppert, P. M. M., Boutens, L., Dijk, W., van Dierendonck, X. A. M., Olivecrona, G., . . . Kersten, S. (2019). Characterization of ANGPTL4 function in macrophages and adipocytes using Angptl4-knockout and Angptl4-hypomorphic mice[S]. Journal of Lipid Research, 60(10), 1741-1754
Open this publication in new window or tab >>Characterization of ANGPTL4 function in macrophages and adipocytes using Angptl4-knockout and Angptl4-hypomorphic mice[S]
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2019 (English)In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 60, no 10, p. 1741-1754Article in journal (Refereed) Published
Abstract [en]

Angiopoietin-like protein (ANGPTL)4 regulates plasma lipids, making it an attractive target for correcting dyslipidemia. However, ANGPTL4 inactivation in mice fed a high fat diet causes chylous ascites, an acute-phase response, and mesenteric lymphadenopathy. Here, we studied the role of ANGPTL4 in lipid uptake in macrophages and in the above-mentioned pathologies using Angptl4-hypomorphic and Angptl4(-/-) mice. Angptl4 expression in peritoneal and bone marrow-derived macrophages was highly induced by lipids. Recombinant ANGPTL4 decreased lipid uptake in macrophages, whereas deficiency of ANGPTL4 increased lipid uptake, upregulated lipid-induced genes, and increased respiration. ANGPTL4 deficiency did not alter LPL protein levels in macrophages. Angptl4-hypomorphic mice with partial expression of a truncated N-terminal ANGPTL4 exhibited reduced fasting plasma triglyceride, cholesterol, and NEFAs, strongly resembling Angptl4(-/-) mice. However, during high fat feeding, Angptl4-hypomorphic mice showed markedly delayed and attenuated elevation in plasma serum amyloid A and much milder chylous ascites than Angptl4(-/-) mice, despite similar abundance of lipid-laden giant cells in mesenteric lymph nodes. In conclusion, ANGPTL4 deficiency increases lipid uptake and respiration in macrophages without affecting LPL protein levels. Compared with the absence of ANGPTL4, low levels of N-terminal ANGPTL4 mitigate the development of chylous ascites and an acute-phase response in mice.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2019
Keywords
angiopoietin-like protein 4, lipoprotein lipase, dyslipidemia, macrophage foam cells, inflammation, ucose homeostasis
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-164449 (URN)10.1194/jlr.M094128 (DOI)000488795300008 ()31409739 (PubMedID)
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved
Nyrén, R., Makoveichuk, E., Malla, S., Kersten, S., Nilsson, S. K., Ericsson, M. & Olivecrona, G. (2019). Lipoprotein lipase in mouse kidney: effects of nutritional status and high-fat diet. American Journal of Physiology - Renal Physiology, 316(3), F558-F571
Open this publication in new window or tab >>Lipoprotein lipase in mouse kidney: effects of nutritional status and high-fat diet
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2019 (English)In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 316, no 3, p. F558-F571Article in journal (Refereed) Published
Abstract [en]

Activity of lipoprotein lipase (LPL) is high in mouse kidney, but the reason is poorly understood. The aim was to characterize localization, regulation, and function of LPL in kidney of C57BL/6J mice. We found LPL mainly in proximal tubules, localized inside the tubular epithelial cells, under all conditions studied. In fed mice, some LPL, colocalized with the endothelial markers CD31 and GPIHBP1 and could be removed by perfusion with heparin. indicating a vascular location. The role of angiopoietin-like protein 4 (ANGPTL4) for nutritional modulation of LPL activity was studied in wild-type and Angptl4(-/-) mice. In Angptl4(-/-) mice, kidney LPL activity remained high in fasted animals, indicating that ANGPTL4 is involved in suppression of LPL activity on fasting, like in adipose tissue. The amount of ANGPTL4 protein in kidney was low, and the protein appeared smaller in size, compared with ANGPTL4 in heart and adipose tissue. To study the influence of obesity, mice were challenged with high-fat diet for 22 wk, and LPL was studied after an overnight fast compared with fasted mice given food for 3 h. High-fat diet caused blunting of the normal adaptation of LPL activity to feeding/fasting in adipose tissue, but in kidneys this adaptation was lost only in male mice. LPL activity increases to high levels in mouse kidney after feeding, but as no difference in uptake of chylomicron triglycerides in kidneys is found between fasted and fed states, our data confinn that LPL appears to have a minor role for lipid uptake in this organ.

Place, publisher, year, edition, pages
American Physiological Society, 2019
Keywords
angiopoietin-like protein 4, high-fat diet, lipoprotein lipase, mouse, triglyceride uptake
National Category
Physiology
Identifiers
urn:nbn:se:umu:diva-158108 (URN)10.1152/ajprenal.00474.2018 (DOI)000462008700015 ()30698048 (PubMedID)
Funder
Swedish Research Council, 2015-02942Swedish Heart Lung Foundation, 2016-245-32M
Available from: 2019-04-12 Created: 2019-04-12 Last updated: 2019-04-12Bibliographically approved
Kovrov, O., Kristensen, K. K., Larsson, E., Ploug, M. & Olivecrona, G. (2019). On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity. Journal of Lipid Research, 60(4), 783-793
Open this publication in new window or tab >>On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity
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2019 (English)In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 60, no 4, p. 783-793Article in journal (Refereed) Published
Abstract [en]

Angiopoietin-like (ANGPTL) 8 is a secreted inhibitor of LPL, a key enzyme in plasma triglyceride metabolism. It was previously reported that ANGPTL8 requires another member of the ANGPTL family, ANGPTL3, to act on LPL. ANGPTL3, much like ANGPTL4, is a physiologically relevant regulator of LPL activity, which causes irreversible inactivation of the enzyme. Here, we show that ANGPTL8 can form complexes with either ANGPTL3 or ANGPTL4 when the proteins are refolded together from their denatured states. In contrast to the augmented inhibitory effect of the ANGPTL3/ANGPTL8 complex on LPL activity, the ANGPTL4/ANGPTL8 complex is less active compared with ANGPTL4 alone. In our experiments, all three members of the ANGPTL family use the same mechanism to inactivate LPL, which involves dissociation of active dimeric LPL to monomers. This inactivation can be counteracted by the presence of glycosylphosphatidylinositol-anchored HDL binding protein 1, the endothelial LPL transport protein previously known to protect LPL from spontaneous and ANGPTL4-catalyzed inactivation. Our data demonstrate that ANGPTL8 may function as an important metabolic switch, by forming complexes with ANGPTL3, or with ANGPTL4, in order to direct the flow of energy from triglycerides in blood according to the needs of the body.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2019
Keywords
angiopoietin-like 8, angiopoietin-like 3, angiopoietin-like 4, glycosylphosphatidylinositol-anchored HDL binding protein 1, lipoprotein metabolism, enzymology, enzyme regulation, triglycerides
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-159138 (URN)10.1194/jlr.M088807 (DOI)000466567300011 ()30686789 (PubMedID)2-s2.0-85064197839 (Scopus ID)
Available from: 2019-05-20 Created: 2019-05-20 Last updated: 2019-06-18Bibliographically approved
Kristensen, K. K., Midtgaard, S. R., Mysling, S., Kovrov, O., Hansen, L. B., Skar-Gislinge, N., . . . Ploug, M. (2018). A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase. Proceedings of the National Academy of Sciences of the United States of America, 115(26), E6020-E6029
Open this publication in new window or tab >>A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 26, p. E6020-E6029Article in journal (Refereed) Published
Abstract [en]

The intravascular processing of triglyceride-rich lipoproteins depends on lipoprotein lipase (LPL) and GPIHBP1, a membrane protein of endothelial cells that binds LPL within the subendothelial spaces and shuttles it to the capillary lumen. In the absence of GPIHBP1, LPL remains mislocalized within the subendothelial spaces, causing severe hypertriglyceridemia (chylomicronemia). The N-terminal domain of GPIHBP1, an intrinsically disordered region (IDR) rich in acidic residues, is important for stabilizing LPL's catalytic domain against spontaneous and ANGPTL4-catalyzed unfolding. Here, we define several important properties of GPIHBP1's IDR. First, a conserved tyrosine in the middle of the IDR is posttranslationally modified by O-sulfation; this modification increases both the affinity of GPIHBP1-LPL interactions and the ability of GPIHBP1 to protect LPL against. ANGPTL4-catalyzed unfolding. Second, the acidic IDR of GPIHBP1 increases the probability of a GPIHBP1-LPL encounter via electrostatic steering, increasing the association rate constant (k(on)) for LPL binding by >250-fold. Third, we show that LPL accumulates near capillary endothelial cells even in the absence of GPIHBP1. In wild-type mice, we expect that the accumulation of LPL in close proximity to capillaries would increase interactions with GPIHBP1. Fourth, we found that GPIHBP1's IDR is not a key factor in the pathogenicity of chylomicronemia in patients with the GPIHBP1 autoimmune syndrome. Finally, based on biophysical studies, we propose that the negatively charged IDR of GPIHBP1 traverses a vast space, facilitating capture of LPL by capillary endothelial cells and simultaneously contributing to GPIHBP1's ability to preserve LPL structure and activity.

Place, publisher, year, edition, pages
National Academy of Sciences, 2018
Keywords
hypertriglyceridemia, electrostatic steering, intrinsically disordered region, intravascular lipolysis, autoimmune disease
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-150771 (URN)10.1073/pnas.1806774115 (DOI)000436245000024 ()29899144 (PubMedID)
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2018-08-31Bibliographically approved
Blomquist, C., Chorell, E., Ryberg, M., Mellberg, C., Worrsjö, E., Makoveichuk, E., . . . Olsson, T. (2018). Decreased lipogenesis-promoting factors in adipose tissue in postmenopausal women with overweight on a Paleolithic-type diet. European Journal of Nutrition, 57(8), 2877-2886
Open this publication in new window or tab >>Decreased lipogenesis-promoting factors in adipose tissue in postmenopausal women with overweight on a Paleolithic-type diet
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2018 (English)In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 57, no 8, p. 2877-2886Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
diet, fat metabolism, lipoprotein lipase, obesity, postmenopausal women
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:umu:diva-141559 (URN)10.1007/s00394-017-1558-0 (DOI)000450829600020 ()29075849 (PubMedID)
Available from: 2017-11-08 Created: 2017-11-08 Last updated: 2019-05-10Bibliographically approved
Chang, C. L., Garcia-Arcos, I., Nyrén, R., Olivecrona, G., Kim, J. Y., Hu, Y., . . . Deckelbaum, R. J. (2018). Lipoprotein Lipase Deficiency Impairs Bone Marrow Myelopoiesis and Reduces Circulating Monocyte Levels. Arteriosclerosis, Thrombosis and Vascular Biology, 38(3), 509-519
Open this publication in new window or tab >>Lipoprotein Lipase Deficiency Impairs Bone Marrow Myelopoiesis and Reduces Circulating Monocyte Levels
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2018 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 38, no 3, p. 509-519Article in journal (Refereed) Published
Abstract [en]

Objective: Tissue macrophages induce and perpetuate proinflammatory responses, thereby promoting metabolic and cardiovascular disease. Lipoprotein lipase (LpL), the rate-limiting enzyme in blood triglyceride catabolism, is expressed by macrophages in atherosclerotic plaques. We questioned whether LpL, which is also expressed in the bone marrow (BM), affects circulating white blood cells and BM proliferation and modulates macrophage retention within the artery.

Approach and Results: We characterized blood and tissue leukocytes and inflammatory molecules in transgenic LpL knockout mice rescued from lethal hypertriglyceridemia within 18 hours of life by muscle-specific LpL expression (MCKL0 mice). LpL-deficient mice had ≈40% reduction in blood white blood cell, neutrophils, and total and inflammatory monocytes (Ly6C/Ghi). LpL deficiency also significantly decreased expression of BM macrophage-associated markers (F4/80 and TNF-α [tumor necrosis factor α]), master transcription factors (PU.1 and C/EBPα), and colony-stimulating factors (CSFs) and their receptors, which are required for monocyte and monocyte precursor proliferation and differentiation. As a result, differentiation of macrophages from BM-derived monocyte progenitors and monocytes was decreased in MCKL0 mice. Furthermore, although LpL deficiency was associated with reduced BM uptake and accumulation of triglyceride-rich particles and macrophage CSF–macrophage CSF receptor binding, triglyceride lipolysis products (eg, linoleic acid) stimulated expression of macrophage CSF and macrophage CSF receptor in BM-derived macrophage precursor cells. Arterial macrophage numbers decreased after heparin-mediated LpL cell dissociation and by genetic knockout of arterial LpL. Reconstitution of LpL-expressing BM replenished aortic macrophage density.

Conclusions: LpL regulates peripheral leukocyte levels and affects BM monocyte progenitor differentiation and aortic macrophage accumulation.

Keywords
bone marrow, colony-stimulating factors, hematopoiesis, leukocytosis, lipoprotein lipase, crophages, monocytes
National Category
Cardiac and Cardiovascular Systems Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-145575 (URN)10.1161/ATVBAHA.117.310607 (DOI)000425754700008 ()29371243 (PubMedID)
Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-06-09Bibliographically approved
Meyers, N. L., Larsson, M., Vorrsjo, E., Olivecrona, G. & Small, D. M. (2017). Aromatic residues in the C terminus of apolipoprotein C-III mediate lipid binding and LPL inhibition. JOURNAL OF LIPID RESEARCH, 58(5), 840-852
Open this publication in new window or tab >>Aromatic residues in the C terminus of apolipoprotein C-III mediate lipid binding and LPL inhibition
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2017 (English)In: JOURNAL OF LIPID RESEARCH, Vol. 58, no 5, p. 840-852Article in journal (Refereed) Published
Abstract [en]

Plasma apoC-III levels correlate with triglyceride (TG) levels and are a strong predictor of CVD outcomes. ApoC-III elevates TG in part by inhibiting LPL. ApoC-III likely inhibits LPL by competing for lipid binding. To probe this, we used oil-drop tensiometry to characterize binding of six apoC-III variants to lipid/water interfaces. This technique monitors the dependence of lipid binding on surface pressure, which increases during TG hydrolysis by LPL. ApoC-III adsorption increased surface pressure by upward of 18 mN/m at phospholipid/TG/water interfaces. ApoC-III was retained to high pressures at these interfaces, desorbing at 21-25 mN/m. Point mutants, which substituted alanine for aromatic residues, impaired the lipid binding of apoC-III. Adsorption and retention pressures decreased by 1-6 mN/m in point mutants, with the magnitude determined by the location of alanine substitutions. Trp42 was most critical to mediating lipid binding. These results strongly correlate with our previous results, linking apoC-III point mutants to increased LPL binding and activity at lipid surfaces.(jlr) We propose that aromatic residues in the C-terminal half of apoC-III mediate binding to TG-rich lipoproteins. Increased apoC-III expression in the hypertriglyceridemic state allows apoC-III to accumulate on lipoproteins and inhibit LPL by preventing binding and/or access to sub-strate.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2017
Keywords
lipoprotein lipase, lipid and lipoprotein metabolism, LDL/metabolism, lipid/emulsions, protein-lipid teraction, surface pressure, drop tensiometry
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-136199 (URN)10.1194/jlr.M071126 (DOI)000400479800004 ()28159869 (PubMedID)
Available from: 2017-07-07 Created: 2017-07-07 Last updated: 2018-06-09Bibliographically approved
Makoveichuk, E., Ruge, T., Nilsson, S., Södergren, A. & Olivecrona, G. (2017). High concentrations of Angiopoietin-like Protein 4 detected in serum from patients with rheumatoid arthritis can be explained by non-specific antibody reactivity. PLoS ONE, 12(1), Article ID e0168922.
Open this publication in new window or tab >>High concentrations of Angiopoietin-like Protein 4 detected in serum from patients with rheumatoid arthritis can be explained by non-specific antibody reactivity
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0168922Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Rheumatology and Autoimmunity Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-131869 (URN)10.1371/journal.pone.0168922 (DOI)000392405300017 ()28107351 (PubMedID)
Available from: 2017-02-27 Created: 2017-02-27 Last updated: 2019-05-23Bibliographically approved
Reimund, M., Kovrov, O., Olivecrona, G. & Lookene, A. (2017). Lipoprotein lipase activity and interactions studied in human plasma by isothermal titration calorimetry. Journal of Lipid Research, 58(1), 279-288
Open this publication in new window or tab >>Lipoprotein lipase activity and interactions studied in human plasma by isothermal titration calorimetry
2017 (English)In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 58, no 1, p. 279-288Article in journal (Refereed) Published
Abstract [en]

LPL hydrolyzes triglycerides in plasma lipoproteins. Due to the complex regulation mechanism, it has been difficult to mimic the physiological conditions under which LPL acts in vitro. We demonstrate that isothermal titration calorimetry (ITC), using human plasma as substrate, overcomes several limitations of previously used techniques. The high sensitivity of ITC allows continuous recording of the heat released during hydrolysis. Both initial rates and kinetics for complete hydrolysis of plasma lipids can be studied. The heat rate was shown to correspond to the release of fatty acids and was linearly related to the amount of added enzyme, either purified LPL or postheparin plasma. Addition of apoC-III reduced the initial rate of hydrolysis by LPL, but the inhibition became less prominent with time when the lipoproteins were triglyceride poor. Addition of angiopoietinlike protein (ANGPTL) 3 or ANGPTL4 caused reduction of the activity of LPL via a two-step mechanism.(Jlr) We conclude that ITC can be used for quantitative measurements of LPL activity and interactions under in vivo-like conditions, for comparisons of the properties of plasma samples from patients and control subjects as substrates for LPL, as well as for testing of drug candidates developed with the aim to affect the LPL system.

Keywords
lipolysis, apolipoproteins, angiopoietin-like proteins, triglycerides, very low density lipoprotein, enzymology
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-131652 (URN)10.1194/jlr.D071787 (DOI)000392408700024 ()27845686 (PubMedID)2-s2.0-85009962352 (Scopus ID)
Available from: 2017-02-27 Created: 2017-02-27 Last updated: 2019-05-21Bibliographically approved
Heverin, M., Ali, Z., Olin, M., Tillander, V., Joibari, M. M., Makoveichuk, E., . . . Björkhem, I. (2017). On the regulatory importance of 27-hydroxycholesterol in mouse liver. Journal of Steroid Biochemistry and Molecular Biology, 169, 10-21
Open this publication in new window or tab >>On the regulatory importance of 27-hydroxycholesterol in mouse liver
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2017 (English)In: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 169, p. 10-21Article, review/survey (Refereed) Published
Abstract [en]

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. 

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Cholesterol metabolism, Gene expression, Nuclear receptor, OXysterols, Cytochrome P-450, Cyp27-/- mice, Lipoprotein lipase, Abcg8, Srebp1c, Lxr
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-136070 (URN)10.1016/j.jsbmb.2016.02.001 (DOI)000401391300003 ()26851362 (PubMedID)
Note

Special Issue: SI

Available from: 2017-06-16 Created: 2017-06-16 Last updated: 2018-06-09Bibliographically approved
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