| 1. |
- Sjögren, Klara, 1970, et al.
(författare)
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Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice.
- 1999
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424. ; 96:12, s. 7088-92
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Tidskriftsartikel (refereegranskat)abstract
- The body growth of animals is regulated by growth hormone and IGF-I. The classical theory of this regulation is that most IGF-I in the blood originates in the liver and that body growth is controlled by the concentration of IGF-I in the blood. We have abolished IGF-I production in the livers of mice by using the Cre/loxP recombination system. These mice demonstrated complete inactivation of the IGF-I gene in the hepatocytes. Although the liver accounts for less than 5% of body mass, the concentration of IGF-I in the serum was reduced by 75%. This finding confirms that the liver is the principal source of IGF-I in the blood. However, the reduction in serum IGF-I concentration had no discernible effect on postnatal body growth. We conclude that postnatal body growth is preserved despite complete absence of IGF-I production by the hepatocytes.
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| 2. |
- Bohlooly-Yeganeh, Mohammad, 1966, et al.
(författare)
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Growth hormone overexpression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia.
- 2005
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Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 54:1, s. 51-62
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Tidskriftsartikel (refereegranskat)abstract
- It is well known that peripherally administered growth hormone (GH) results in decreased body fat mass. However, GH-deficient patients increase their food intake when substituted with GH, suggesting that GH also has an appetite stimulating effect. Transgenic mice with an overexpression of bovine GH in the central nervous system (CNS) were created to investigate the role of GH in CNS. This study shows that overexpression of GH in the CNS differentiates the effect of GH on body fat mass from that on appetite. The transgenic mice were not GH-deficient but were obese and showed increased food intake as well as increased hypothalamic expression of agouti-related protein and neuropeptide Y. GH also had an acute effect on food intake following intracerebroventricular injection of C57BL/6 mice. The transgenic mice were severely hyperinsulinemic and showed a marked hyperplasia of the islets of Langerhans. In addition, the transgenic mice displayed alterations in serum lipid and lipoprotein levels and hepatic gene expression. In conclusion, GH overexpression in the CNS results in hyperphagia-induced obesity indicating a dual effect of GH with a central stimulation of appetite and a peripheral lipolytic effect.
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| 3. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 4. |
- Isaksson, Olle, 1943, et al.
(författare)
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Metabolic functions of liver-derived (endocrine) insulin-like growth factor I.
- 2001
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Ingår i: Hormone research. - 0301-0163. ; 55 Suppl 2, s. 18-21
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Tidskriftsartikel (refereegranskat)abstract
- Until now it has been difficult to determine the relative importance of locally produced (autocrine/paracrine) versus systemically derived (endocrine) insulin-like growth factor I (IGF-I) in the intact organism. We recently eliminated IGF-I production in the livers of mice using the Cre/loxP recombination system. These mice displayed a reduction in serum IGF-I levels of more than 80%, but demonstrated normal body growth, suggesting that autocrine/paracrine-acting IGF-I, but not endocrine-acting IGF-I, regulates body growth. Long-term metabolic studies of mice in which IGF-I production had been inactivated in the liver, have shown that the mice have decreased fat mass, but increased serum levels of insulin and cholesterol. Despite the marked increase in plasma insulin following glucose administration, the glucose elimination was not altered in these animals. Thus, the mice showed an adequately compensated insulin resistance. In conclusion, liver-derived or endocrine IGF-I is not required for post-natal statural growth, but seems to be of vital importance for normal carbohydrate and lipid metabolism.
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| 5. |
- Isaksson, Olle, 1943, et al.
(författare)
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The somatomedin hypothesis revisited in a transgenic model.
- 2001
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Ingår i: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. - 1096-6374. ; 11 Suppl A
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Tidskriftsartikel (refereegranskat)abstract
- Studies of insulin-like growth factor I (IGF-I) gene knockout mice models have clearly shown that IGF-I is necessary for prenatal as well as postnatal body growth in mice. Clinical studies of a patient with an IGF-I gene defect which caused complete absence of IGF-I, verified that it is important for intrauterine and postnatal growth. Recent studies of mice with liver-specific and inducible IGF-I gene knockout indicated that liver-derived IGF-I is not necessary for postnatal body growth, although serum IGF-I levels are decreased by more than 80% in these mice. Therefore, extrahepatic IGF-I is sufficient for maintenance of postnatal body growth in mice. Further investigations are needed to assess whether liver-derived circulating IGF-I is essential for other biological functions.
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| 6. |
- Ohlsson, Claes, 1965, et al.
(författare)
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The relative importance of endocrine versus autocrine/paracrine insulin-like growth factor-I in the regulation of body growth.
- 2000
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Ingår i: Pediatric nephrology (Berlin, Germany). - 0931-041X. ; 14:7, s. 541-3
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Tidskriftsartikel (refereegranskat)abstract
- Body growth is regulated by growth hormone (GH) and insulin-like growth factor-I (IGF-I). The classical somatomedin hypothesis of this regulation is that most IGF-I in the blood originates in the liver and that body growth is controlled by the concentration of IGF-I in the blood. We have recently abolished IGF-I production in the livers of mice by using the Cre/loxP recombination system. These mice displayed a more than 75% reduction in serum IGF-I associated with increased serum levels of GH. In contrast, they demonstrated a normal postnatal growth, indicating that extrahepatic, autocrine/paracrine-acting IGF-I is the main determinant of postnatal growth. Thus, the "classical" somatomedin hypothesis needs revision. We propose the "dual somatomedin hypothesis" according to which: (1) autocrine/paracrine IGF-I is the main determinant of postnatal body growth and (2) liver-derived, endocrine-acting, IGF-I exerts negative feedback on GH secretion and possibly also exerts other effects on carbohydrate and lipid metabolism.
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| 7. |
- Ohlsson, Claes, 1965, et al.
(författare)
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The role of liver-derived insulin-like growth factor-I.
- 2009
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Ingår i: Endocrine reviews. - : The Endocrine Society. - 1945-7189 .- 0163-769X. ; 30:5, s. 494-535
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Forskningsöversikt (refereegranskat)abstract
- IGF-I is expressed in virtually every tissue of the body, but with much higher expression in the liver than in any other tissue. Studies using mice with liver-specific IGF-I knockout have demonstrated that liver-derived IGF-I, constituting a major part of circulating IGF-I, is an important endocrine factor involved in a variety of physiological and pathological processes. Detailed studies comparing the impact of liver-derived IGF-I and local bone-derived IGF-I demonstrate that both sources of IGF-I can stimulate longitudinal bone growth. We propose here that liver-derived circulating IGF-I and local bone-derived IGF-I to some extent have overlapping growth-promoting effects and might have the capacity to replace each other (= redundancy) in the maintenance of normal longitudinal bone growth. Importantly, and in contrast to the regulation of longitudinal bone growth, locally derived IGF-I cannot replace (= lack of redundancy) liver-derived IGF-I for the regulation of a large number of other parameters including GH secretion, cortical bone mass, kidney size, prostate size, peripheral vascular resistance, spatial memory, sodium retention, insulin sensitivity, liver size, sexually dimorphic liver functions, and progression of some tumors. It is clear that a major role of liver-derived IGF-I is to regulate GH secretion and that some, but not all, of the phenotypes in the liver-specific IGF-I knockout mice are indirect, mediated via the elevated GH levels. All of the described multiple endocrine effects of liver-derived IGF-I should be considered in the development of possible novel treatment strategies aimed at increasing or reducing endocrine IGF-I activity.
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| 8. |
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| 9. |
- Sjögren, Klara, 1970, et al.
(författare)
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A model for tissue-specific inducible insulin-like growth factor-I (IGF-I) inactivation to determine the physiological role of liver-derived IGF-I.
- 2002
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Ingår i: Endocrine. - 0969-711X. ; 19:3, s. 249-56
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor-I (IGF-I) has important growthpromoting and metabolic effects and is expressed in virtually every tissue of the body. The highest expression is found in the liver, but the physiological role of liver-derived IGF-I is unknown. It has been difficult to separate the endocrine effects of liver-derived IGF-I from the autocrine/paracrine effects of locally produced IGF-I in peripheral tissues. Therefore, we have developed a mouse model with a liver-specific inducible deletion of the IGF-I gene (LI-IGF-I-/- mouse). The LI-IGF-I-/- mouse has dramatically reduced (>80%) serum IGF-I levels, demonstrating that the major part of serum IGF-I is liver-derived. Surprisingly, LI-IGFI -/- mice demonstrate a normal appendicular skeletal growth up to at least 12 mo of age despite the dramatic decrease in circulating IGF-I levels, indicating that liver-derived IGF-I is not required for appendicular skeletal growth. However, the adult axial skeletal growth is reduced in the LI-IGF-I-/- mice. Furthermore, the amount of cortical bone is reduced due to decreased radial growth of the cortical bone, while the trabecular bone mineral density is unchanged in the LI-IGFI -/- mice. The decreased levels of circulating IGF-I are associated with increased serum levels of growth hormone (GH), indicating a role for liver-derived IGFI in the negative-feedback regulation of GH secretion. Measurements of factors regulating GH secretion in the pituitary and in the hypothalamus revealed an increased expression of GH-releasing-hormone (GHRH) and GHsecretagogue (GHS) receptors in the pituitary of LI-IGFI -/- mice. This in turn results in an increased sensitivity to systemically administered GHRH and GHS, demonstrating that the regulatory action of liver-derived IGF-I on GH secretion is at the pituitary rather than at the hypothalamic level. The liver is an important metabolic organ and LI-IGF-I-/- mice are markedly hyperinsulinemic and yet normoglycemic, consistent with an adequately compensated insulin resistance. Interestingly, LI-IGF-I-/- mice display a reduced age-dependent fat mass accumulation compared with control mice. Furthermore, LI-IGF-I-/- mice have increased blood pressure attributable to increased peripheral resistance indicating a role for liver-derived IGF-I in the regulation of blood pressure. In conclusion, liver-derived IGF-I is important for carbohydrate and lipid metabolism and for the regulation of GH secretion at the pituitary level. Furthermore, it regulates adult axial skeletal growth and cortical radial growth while it is not required for appendicular skeletal growth.
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| 10. |
- Sjögren, Klara, 1970, et al.
(författare)
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A transgenic model to determine the physiological role of liver-derived insulin-like growth factor I.
- 2002
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Ingår i: Minerva endocrinologica. - 0391-1977. ; 27:4, s. 299-311
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor-I (IGF-I) has important growth promoting and metabolic effects and is expressed in virtually every tissue of the body. The highest expression is found in the liver but the physiological role of liver-derived IGF-I is unknown. It has been difficult to separate the endocrine effects of liver-derived IGF-I from the autocrine/paracrine effects of locally produced IGF-I in peripheral tissues. Therefore, we have developed a mouse model with a liver-specific inducible deletion of the IGF-I gene. The liver-IGF-I deficient mouse have dramatically reduced (>80%) serum IGF-I levels, demonstrating that the major part of serum IGF-I is liver-derived. Surprisingly, liver-IGF-I deficient mice demonstrate a normal appendicular skeletal growth up to at least 12 months of age despite the dramatic decrease in circulating IGF-I levels, indicating that liver-derived IGF-I is not required for appendicular skeletal growth. However, the adult axial skeletal growth is clearly reduced in the liver-IGF-I deficient mice. Furthermore, the amount of cortical bone is reduced due to decreased radial growth of the cortical bone while the amount of trabecular bone is unchanged in the liver-IGF-I deficient mice. The decreased levels of circulating IGF-I are associated with increased serum levels of growth hormone (GH), indicating a role for liver-derived IGF-I in the negative feedback regulation of GH secretion. Measurements of factors regulating GH-secretion in the pituitary and in the hypothalamus revealed an increased expression of growth hormone releasing hormone (GHRH) and growth hormone secretagogue (GHS) receptors in the pituitary of liver-IGF-I deficient mice. This in turn results in an increased sensitivity to systemically administered GHRH and GHS, demonstrating that the regulatory action of liver-derived IGF-I on GH secretion is at the pituitary rather than at the hypothalamic level. The liver is an important metabolic organ and liver-IGF-I deficient mice are markedly hyperinsulinemic and yet normoglycemic, consistent with an adequately compensated insulin resistance. Interestingly, liver-IGF-I deficient mice display a reduced age-dependent fat mass accumulation compared with control mice. In conclusion, liver-derived IGF-I is important for carbohydrate- and lipid-metabolism and for the regulation of GH-secretion at the pituitary level. Furthermore, it regulates adult axial skeletal growth and cortical radial growth while it is not required for appendicular skeletal growth.
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| 11. |
- Sjögren, Klara, 1970, et al.
(författare)
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Disproportional skeletal growth and markedly decreased bone mineral content in growth hormone receptor -/- mice.
- 2000
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Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 0006-291X. ; 267:2, s. 603-8
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Tidskriftsartikel (refereegranskat)abstract
- Growth hormone (GH) is important for skeletal growth as well as for a normal bone metabolism in adults. The skeletal growth and adult bone metabolism was studied in mice with an inactivated growth hormone receptor (GHR) gene. The lengths of femur, tibia, and crown-rump were, as expected, decreased in GHR-/- mice. Unexpectedly, GHR-/- mice displayed disproportional skeletal growth reflected by decreased femur/crown-rump and femur/tibia ratios. GHR-/- mice demonstrated decreased width of the growth plates in the long bones and disturbed ossification of the proximal tibial epiphysis. Furthermore, the area bone mineral density (BMD) as well as the bone mineral content (BMC)/body weight were markedly decreased in GHR-/- mice. The decrease in BMC in GHR-/- mice was not due to decreased trabecular volumetric BMD but to a decreased cross-sectional cortical bone area In conclusion, GHR-/- mice demonstrate disproportional skeletal growth and markedly decreased bone mineral content.
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| 12. |
- Sjögren, Klara, 1970, et al.
(författare)
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Effects of liver-derived insulin-like growth factor I on bone metabolism in mice.
- 2002
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Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - 0884-0431. ; 17:11, s. 1977-87
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor (IGF) I is an important regulator of both skeletal growth and adult bone metabolism. To better understand the relative importance of systemic IGF-I versus locally expressed IGF-I we have developed a transgenic mouse model with inducible specific IGF-I gene inactivation in the liver (LI-IGF-I-/-). These mice are growing normally up to 12 weeks of age but have a disturbed carbohydrate and lipid metabolism. In this study, the long-term effects of liver-specific IGF-I inactivation on skeletal growth and adult bone metabolism were investigated. The adult (week 8-55) axial skeletal growth was decreased by 24% in the LI-IGF-I-/- mice whereas no major reduction of the adult appendicular skeletal growth was seen. The cortical cross-sectional bone area, as measured in the middiaphyseal region of the long bones, was decreased in old LI-IGF-I-/- mice. This reduction in the amount of cortical bone was caused mainly by decreased periosteal circumference and was associated with a weaker bone determined by a decrease in ultimate load. In contrast, the amount of trabecular bone was not decreased in the LI-IGF-I-/- mice. DNA microarray analysis of 30-week-old LI-IGF-I-/- and control mice indicated that only four genes were regulated in bone whereas approximately 40 genes were regulated in the liver, supporting the hypothesis that liver-derived IGF-I is of minor importance for adult bone metabolism. In summary, liver-derived IGF-I exerts a small but significant effect on cortical periosteal bone growth and on adult axial skeletal growth while it is not required for the maintenance of the trabecular bone in adult mice.
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| 13. |
- Sjögren, Klara, 1970, et al.
(författare)
-
Liver-derived IGF-I is of importance for normal carbohydrate and lipid metabolism.
- 2001
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Ingår i: Diabetes. - 0012-1797. ; 50:7, s. 1539-45
-
Tidskriftsartikel (refereegranskat)abstract
- IGF-I is important for postnatal body growth and exhibits insulin-like effects on carbohydrate metabolism. The function of liver-derived IGF-I is still not established, although we previously demonstrated that liver-derived IGF-I is not required for postnatal body growth. Mice whose IGF-I gene in the liver was inactivated at 24 days of age were used to investigate the long-term role of liver-derived IGF-I for carbohydrate and lipid metabolism. Serum levels of leptin in these mice were increased by >100% at 3 months of age, whereas the fat mass of the mice was decreased by 25% at 13 months of age. The mice became markedly hyperinsulinemic and yet normoglycemic, indicating an adequately compensated insulin resistance. Furthermore, they had increased serum levels of cholesterol. We conclude that liver-derived IGF-I is of importance for carbohydrate and lipid metabolism.
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| 14. |
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| 15. |
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| 16. |
- Sjögren, Olle, 1943
(författare)
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Ecological Wunderkind and heroic trollhunter: the celebrity saga of Greta Thunberg
- 2023
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Ingår i: Celebrity Studies. - : Informa UK Limited. - 1939-2397 .- 1939-2400. ; 14:4, s. 472-484
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Tidskriftsartikel (refereegranskat)abstract
- In December 2019, a Swedish climate activist was appointed Person of the Year by Time Magazine. Greta Thunberg was only 15 when she inspired a wave of school strikes and protest marches. She stole the media attention at a series of global summits, until public gatherings and international travels were interrupted by the pandemic. The aim of this article is to highlight a short but intense celebritisation process with culture-bound responses. First, I will establish Thunberg's deep roots in a Nordic children's culture, which defends bio-diversity with 'superhoney' and science. Then, I will compare the strong impact of an ecological Wunderkind in the EU with the polarised reactions in the US. In the conclusion, I will relate Thunberg's activist strategy and persona to other types of eco-celebrities and discuss the significance of diverging time horizons.
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| 17. |
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| 18. |
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| 19. |
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| 20. |
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| 21. |
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| 22. |
- Sjögren, Olle, 1943
(författare)
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Revy och buskis
- 2007
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Ingår i: Heed, S-Å & Forser, T (red) - Ny svensk teaterhistoria vol 3. 1900-talets teater. - Stockholm : Gidlunds förlag. - 9789178447411
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 23. |
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| 24. |
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| 25. |
- Skrtic, Stanko, 1970, et al.
(författare)
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Possible roles of insulin-like growth factor in regulation of physiological and pathophysiological liver growth.
- 2001
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Ingår i: Hormone research. - 0301-0163. ; 55 Suppl 1, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIMS: Almost all circulating insulin-like growth factor-1 (IGF-1) is produced and secreted from the liver. However, the possible role of IGF-1 in local regulation of liver functions including liver growth is unclear. In the present study, we investigated the role of IGF-1 on liver growth in vivo and in hepatic stellate cell function in vitro. RESULTS: Liver-specific knock-out of the IGF-1 gene by use of the cre-loxP system caused enhanced liver growth, possibly reflecting increased growth hormone (GH) secretion due to decreased negative feedback by IGF-1. Studies on cultured rat hepatic stellate cells (HSC) showed that IGF-1 and hepatocyte-conditioned medium (PCcM) time- and dose-dependently increased hepatocyte growth factor (HGF) mRNA and HGF immunoreactivity. IGF-1 and PCcM also enhanced DNA synthesis in the HSC cultures. The PCcM did not contain bioactive IGF-1 and was also able to stimulate proliferation when prepared under serum- and hormone-free conditions. CONCLUSION: In vivo results show that IGF-1 is not essential for normal growth of the intact liver. The in vitro results indicate that both IGF-1 and IGF- 1-independent factor(s) from hepatocytes can stimulate HGF production by HSC. It remains to be investigated whether these effects are of importance for liver regeneration or pathological conditions.
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| 26. |
- Svensson, Johan, 1964, et al.
(författare)
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Liver-derived IGF-I regulates kidney size, sodium reabsorption, and renal IGF-II expression.
- 2007
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Ingår i: The Journal of endocrinology. - 0022-0795. ; 193:3, s. 359-66
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Tidskriftsartikel (refereegranskat)abstract
- The GH/-IGF-I axis is important for kidney size and function and may also be involved in the development of renal failure. In this study, the role of liver-derived endocrine IGF-I for kidney size and function was investigated in mice with adult liver-specific IGF-I inactivation (LI-IGF-I(-/-) mice). These mice have an 80-85% reduction of serum IGF-I level and compensatory increased GH secretion. Seven-month-old as well as 24-month-old LI-IGF-I(-/-) mice had decreased kidney weight. Glomerular filtration rate, assessed using creatinine clearance as well as creatinine clearance corrected for body weight, was unchanged. The 24-h urine excretion of sodium and potassium was increased in the LI-IGF-I(-/-) mice. In the 24-month-old mice, there was no between-group difference in kidney morphology. Microarray and real-time PCR (RT-PCR) analyses showed a high renal expression of IGF-II in the control mice, whereas in the LI-IGF-I(-/-) mice, there was a tissue-specific decrease in the renal IGF-II mRNA levels (-79%, P < 0.001 vs controls using RT-PCR). In conclusion, deficiency of circulating liver-derived IGF-I in mice results, despite an increase in GH secretion, in a global symmetrical decrease in kidney size, increased urinary sodium and potassium excretion, and a clear down regulation of renal IGF-II expression. However, the LI-IGF-I(-/-) mice did not develop kidney failure or nephrosclerosis. One may speculate that liver-derived endocrine IGF-I induces renal IGF-II expression, resulting in symmetrical renal growth.
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| 27. |
- Svensson, Johan, 1964, et al.
(författare)
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Liver-derived igf-I regulates mean life span in mice
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- Transgenic mice with low levels of global insulin-like growth factor-I (IGF-I) throughout their life span, including pre- and postnatal development, have increased longevity. This study investigated whether specific deficiency of liver-derived, endocrine IGF-I is of importance for life span.
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| 28. |
- Svensson, Johan, 1964, et al.
(författare)
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Liver-derived IGF1 enhances the androgenic response in prostate.
- 2008
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Ingår i: The Journal of endocrinology. - 1479-6805. ; 199:3, s. 489-97
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Tidskriftsartikel (refereegranskat)abstract
- Both IGF1 and androgens are major enhancers of prostate growth and are implicated in the development of prostate hyperplasia and cancer. The aim of the present study was to investigate whether liver-derived endocrine IGF1 modulates the androgenic response in prostate. Mice with adult, liver-specific inactivation of IGF1 (LI-IGF1(-/-) mice) displayed an approximately 80% reduction in serum IGF1 levels associated with decreased prostate weight compared with control mice (anterior prostate lobe -19%, P<0.05; dorsolateral prostate (DLP) lobe -35%, P<0.01; ventral prostate (VP) lobe -47%, P<0.01). Reduced androgen receptor (Ar) mRNA and protein levels were observed in the VP lobe (-34% and -30% respectively, both P<0.05 versus control mice). Analysis of prostate morphology showed reductions in both the glandular and fibromuscular compartments of the VP and DLP lobes that were proportional to the reductions in the weights of these lobes. Immunohistochemistry revealed reduced intracellular AR immunoreactivity in the VP and DLP lobes. The non-aromatizable androgen dihydrotestosterone increased VP weight to a lesser extent in orchidectomized (ORX) LI-IGF1(-/-) mice than in ORX controls (-40%, P<0.05 versus control mice). In conclusion, deficiency of liver-derived IGF1 reduces both the glandular and fibromuscular compartments of the prostate, decreases AR expression in prostate, and reduces the stimulatory effect of androgens on VP weight. These findings may explain, at least in part, the well-known clinical association between serum IGF1 levels and conditions with abnormal prostate growth.
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| 29. |
- Tivesten, Åsa, 1969, et al.
(författare)
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Liver-derived insulin-like growth factor-I is involved in the regulation of blood pressure in mice.
- 2002
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Ingår i: Endocrinology. - 0013-7227. ; 143:11, s. 4235-42
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Tidskriftsartikel (refereegranskat)abstract
- IGF-I has been suggested to be of importance for cardiovascular structure and function, but the relative role of locally produced and liver-derived endocrine IGF-I remains unclear. Using the Cre-LoxP recombination system, we have previously created transgenic mice with a liver-specific, inducible IGF-I knockout (LI-IGF-I-/-). To examine the role of liver-derived IGF-I in cardiovascular physiology, liver-derived IGF-I was inactivated at 4 wk of age, resulting in a 79% reduction of serum IGF-I levels. At 4 months of age, systolic blood pressure (BP) was increased in LI-IGF-I-/- mice. Echocardiography showed increased posterior wall thickness in combination with decreased stroke volume and cardiac output, whereas other systolic variables were unchanged, suggesting that these cardiac effects were secondary to increased peripheral resistance. Acute nitric oxide-synthase inhibition increased systolic BP more in LI-IGF-I-/- mice than in control mice. LI-IGF-I-/- mice showed impaired acetylcholine-induced vasorelaxation in mesenteric resistance vessels and increased levels of endothelin-1 mRNA in aorta. Thus, the increased peripheral resistance in LI-IGF-I-/- mice might be attributable to endothelial dysfunction associated with increased expression of endothelin-1 and impaired vasorelaxation of resistance vessels. In conclusion, our findings suggest that liver-derived IGF-I is involved in the regulation of BP in mice.
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| 30. |
- Wallenius, Kristina, 1973, et al.
(författare)
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Liver-derived IGF-I regulates GH secretion at the pituitary level in mice.
- 2001
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Ingår i: Endocrinology. - 0013-7227. ; 142:11, s. 4762-70
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Tidskriftsartikel (refereegranskat)abstract
- We have reported that liver-specific deletion of IGF-I in mice (LI-IGF-I-/-) results in decreased circulating IGF-I and increased GH levels. In the present study, we determined how elimination of hepatic IGF-I modifies the hypothalamic-pituitary GH axis to enhance GH secretion. The pituitary mRNA levels of GH releasing factor (GHRF) receptor and GH secretagogue (GHS) receptor were increased in LI-IGF-I-/- mice, and in line with this, their GH response to ip injections of GHRF and GHS was increased. Expression of mRNA for pituitary somatostatin receptors, hypothalamic GHRF, somatostatin, and neuropeptide Y was not altered in LI-IGF-I-/- mice, whereas hypothalamic IGF-I expression was increased. Changes in hepatic expression of major urinary protein and the PRL receptor in male LI-IGF-I-/- mice indicated an altered GH release pattern most consistent with enhanced GH trough levels. Liver weight was enhanced in LI-IGF-I-/- mice of both genders. In conclusion, loss of liver-derived IGF-I enhances GH release by increasing expression of pituitary GHRF and GHS receptors. The enhanced GH release in turn affects several liver parameters, in line with the existence of a pituitary-liver axis.
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| 31. |
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