Increased diet-induced fatty streak formation in female mice with deficiency of liver-derived insulin-like growth factor
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ORIGINAL ARTICLE
Increased diet-induced fatty streak formation in female mice with deficiency of liver-derived insulin-like growth factor-I ˚ sa Tivesten2 Johan Svensson1,3 • Klara Sjo¨gren1 • Malin Levin2 • Jan Bore´n2 • A 1 Claes Ohlsson
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Received: 3 July 2015 / Accepted: 17 November 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com
Abstract The role of endocrine IGF-I for atherosclerosis is unclear. We determined the importance of circulating, liverderived IGF-I for fatty streak formation in mice. Mice with adult, liver-specific IGF-I inactivation (LI-IGF-I-/- mice, serum IGF-I reduced by approximately 80 %) and control mice received an atherogenic (modified Paigen) diet between 6 and 12 months of age. At study end, Oil Red O staining of aortic root cryosections showed increased fatty streak area and lipid deposition in female but not in male LIIGF-I-/- mice compared to controls. Mac-2 staining of aortic root and measurements of CD68 mRNA level in femoral artery revealed increased macrophage accumulation in proportion to the increased fatty streak area in female LIIGF-I-/- mice. Moreover, female LI-IGF-I-/- mice displayed increased serum cholesterol and interleukin-6 as well as increased vascular cell-adhesion molecule 1 (VCAM1) mRNA levels in the femoral artery and elevated VCAM1 protein expression in the aortic root. Thus, increased dietinduced fatty streak formation in female LI-IGF-I-/- mice was associated with increased serum cholesterol and signs of systemic inflammation, endothelial activation, lipid deposition, and macrophage infiltration in the vascular wall. ˚ sa Tivesten and Claes Ohlsson have contributed equally. A & Johan Svensson [email protected] 1
Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 45 Go¨teborg, Sweden
2
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 45 Go¨teborg, Sweden
3
Department of Internal Medicine, Sahlgrenska University Hospital, Gro¨na Stra˚ket 8, 413 45 Go¨teborg, Sweden
Keywords IGF-I Liver derived Fatty streak Paigen diet Inflammation Endothelial dysfunction
Introduction Insulin-like growth factor-I (IGF-I) is important for cell growth and proliferation [1]. Circulating IGF-I, which is mainly liver-derived [1–3], gradually declines with increasing age and is dependent on growth hormone (GH) secretion, food intake, and exercise [1]. Experimental studies suggest that in addition to regulating postnatal longitudinal growth, IGF-I maintains brain function, cortical bone mass, cardiovascular performance, and metabolic indices during adulthood [1]. There is increasing clinical evidence that low IGF-I is a risk factor for cardiovascular disease (CVD) morbidity. Studies of polymorphisms in the IGF-I gene demonstrate a link between low serum IGF-I levels and impaired measures of early atherosclerosis such as increased carotid intima-media thickness [4,
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