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01.05.2014 | Article

Fetuin-A influences vascular cell growth and production of proinflammatory and angiogenic proteins by human perivascular fat cells

verfasst von: Dorothea I. Siegel-Axel, Susanne Ullrich, Norbert Stefan, Kilian Rittig, Felicia Gerst, Christian Klingler, Ulrike Schmidt, Birgit Schreiner, Elko Randrianarisoa, Hans-Eberhard Schaller, Ulrich A. Stock, Cora Weigert, Alfred Königsrainer, Hans-Ulrich Häring

Erschienen in: Diabetologia | Ausgabe 5/2014

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Abstract

Aims/hypothesis

Fetuin-A (alpha2-Heremans-Schmid glycoprotein), a liver-derived circulating glycoprotein, contributes to lipid disorders, diabetes and cardiovascular diseases. In a previous study we found that perivascular fat cells (PVFCs) have a higher angiogenic potential than other fat cell types. The aim was to examine whether fetuin-A influences PVFC and vascular cell growth and the expression and secretion of proinflammatory and angiogenic proteins, and whether TLR4-independent pathways are involved.

Methods

Mono- and co-cultures of human PVFCs and endothelial cells were treated with fetuin-A and/or palmitate for 6–72 h. Proteins were quantified by ELISA and Luminex, mRNA expression by real-time PCR, and cell growth by BrDU-ELISA. Some PVFCs were preincubated with a nuclear factor κB NFκBp65 inhibitor, or the toll-like receptor 4 (TLR4) inhibitor CLI-095, or phosphoinositide 3-kinase (PI3K)/Akt inhibitors and/or stimulated with insulin. Intracellular forkhead box protein O1 (FoxO1), NFκBp65 and inhibitor of κB kinase β (IKKβ) localisation was visualised by immunostaining.

Results

PVFCs expressed and secreted IL-6, IL-8, plasminogen activator inhibitor 1 (PAI-1), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF)-BB, monocyte chemotactic protein-1 (MCP-1), vascular endothelial growth factor (VEGF), placental growth factor (PLGF) and hepatocyte growth factor (HGF). Fetuin-A upregulated IL-6 and IL-8, and this was potentiated by palmitate and blocked by CLI-095. Immunostaining and electrophoretic mobility shift assay (EMSA) showed partial NFκBp65 activation. MCP-1 was upregulated and blocked by CLI-095, but not by palmitate. However, HGF was downregulated, which was slightly potentiated by palmitate. This effect persisted after TLR4 pathway blockade. Stimulation of insulin–PI3K–Akt signalling by insulin resulted in nuclear FoxO1 extrusion and HGF upregulation. Fetuin-A counteracted these insulin effects.

Conclusions/interpretation

Fetuin-A and/or palmitate influence the expression of proinflammatory and angiogenic proteins only partially via TLR4 signalling. HGF downregulation seems to be mediated by interference with the insulin-dependent receptor tyrosine kinase pathway. Fetuin-A may also influence angiogenic and proinflammatory proteins involved in atherosclerosis.

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Mori K, Emoto M, Inaba M (2012) Fetuin-A and the cardiovascular system. Adv Clin Chem 56:175–195PubMedCrossRef

Dziegielewska KM, Andersen NA, Lovell D, Nicol SC, Muller-Esterl W, Saunders NR (1992) Fetuin—a new acute phase protein in the adult and in the fetus. Folia Histochem Cytobiol 30:187–189PubMed

Stefan N, Haring HU (2012) The role of hepatokines in metabolism. Nat Rev Endocrinol 9:144–152CrossRef

Stefan N, Hennige AM, Staiger H et al (2006) Alpha2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care 29:853–857PubMedCrossRef

Mori K, Emoto M, Inaba M (2011) Fetuin-A: a multifunctional protein. Recent Pat Endocr Metab Immune Drug Discov 5:124–146PubMedCrossRef

Mathews ST, Chellam N, Srinivas PR et al (2000) Alpha2-HSG, a specific inhibitor of insulin receptor autophosphorylation, interacts with the insulin receptor. Mol Cell Endocrinol 164:87–98PubMedCrossRef

Rauth G, Pöschke O, Fink E et al (1992) The nucleotide and partial amino acid sequences of rat fetuin. Identity with the natural tyrosine kinase inhibitor of the rat insulin receptor. Eur J Biochem 204:523–529PubMedCrossRef

Ohnishi T, Nakamura O, Arakaki N, Daikuhara Y (1997) Effect of phosphorylated rat fetuin on the growth of hepatocytes in primary culture in the presence of human hepatocyte-growth factor. Evidence that phosphorylated fetuin is a natural modulator of hepatocyte-growth factor. Eur J Biochem 243:753–761PubMedCrossRef

Ohnishi T, Nakamura O, Arakaki N, Miyazaki H, Daikuhara Y (1994) Effects of cytokines and growth factors on phosphorylated fetuin biosynthesis by adult rat hepatocytes in primary culture. Biochem Biophys Res Commun 200:598–605PubMedCrossRef

10.

Hennige AM, Staiger H, Wicke C et al (2008) Fetuin-A induces cytokine expression and suppresses adiponectin production. PLoS One 12:e1765CrossRef

11.

Kim F, Pham M, Luttrell I et al (2007) Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 100:1589–1596PubMedCrossRef

12.

Fessler MB, Rudel LL, Brown JM (2009) Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome. Curr Opin Lipidol 20:379–385PubMedCrossRefPubMedCentral

13.

Pal D, Dasgupta S, Kundu R et al (2012) Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 18:1279–1285PubMedCrossRef

14.

Stefan N, Haring HU (2013) Circulating fetuin-A and free fatty acids interact to predict insulin resistance in humans. Nat Med 19:394–395PubMedCrossRef

15.

Stefan N, Fritsche A, Weikert C (2008) Plasma fetuin-A levels and the risk of type 2 diabetes. Diabetes 57:2762–2767PubMedCrossRefPubMedCentral

16.

Kaess BM, Enserro DM, McManus DD et al (2012) Cardiometabolic correlates and heritability of fetuin-A, retinol-binding protein 4, and fatty-acid binding protein 4 in the Framingham Heart Study. J Clin Endocrinol Metab 97:E1943–E1947PubMedCrossRefPubMedCentral

17.

Heinrichsdorff J, Olefsky JM (2012) Fetuin-A: the missing link in lipid-induced inflammation. Nat Med 18:1182–1183PubMedCrossRef

18.

Weikert C, Stefan N, Schulze MB et al (2008) Plasma fetuin-a levels and the risk of myocardial infarction and ischemic stroke. Circulation 118:2555–2562PubMedCrossRef

19.

Rittig K, Thamer C, Haupt A et al (2009) High plasma fetuin-A is associated with increased carotid intima-media thickness in a middle-aged population. Atherosclerosis 207:341–342PubMedCrossRef

20.

Fisher E, Stefan N, Saar K et al (2009) Association of AHSG gene polymorphisms with fetuin-A plasma levels and cardiovascular diseases in the EPIC-Potsdam study. Circ Cardiovasc Genet 2:607–613PubMedCrossRef

21.

Voros K, Graf L, Prohaszka Z et al (2011) Serum fetuin-A in metabolic and inflammatory pathways in patients with myocardial infarction. Eur J Clin Invest 41:703–709PubMedCrossRef

22.

Rittig K, Dolderer JH, Balletshofer B et al (2012) The secretion pattern of perivascular fat cells is different from that of subcutaneous and visceral fat cells. Diabetologia 55:1514–1525PubMedCrossRef

23.

Rittig K, Staib K, Machann J et al (2008) Perivascular fatty tissue at the brachial artery is linked to insulin resistance but not to local endothelial dysfunction. Diabetologia 51:2093–2099PubMedCrossRef

24.

Weigert C, Brodbeck K, Staiger H et al (2004) Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor-κB. J Biol Chem 279:23942–23952PubMedCrossRef

25.

Libby P, Ridker PM, Hansson GK (2011) Progress and challenges in translating the biology of atherosclerosis. Nature 473:317–325PubMedCrossRef

26.

Moulton KS, Vakili K, Zurakowski D et al (2003) Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci 100:4736–4741PubMedCrossRefPubMedCentral

27.

Sullivan GW, Sarembock IJ, Linden J (2000) The role of inflammation in vascular diseases. J Leukoc Biol 67:591–602PubMed

28.

Verhagen SN, Visseren FL (2011) Perivascular adipose tissue as a cause of atherosclerosis. Atherosclerosis 214:3–10PubMedCrossRef

29.

Ix JH, Wassel CL, Kanaya AM et al (2008) Fetuin-A and incident diabetes mellitus in older persons. JAMA 300:182–188PubMedCrossRefPubMedCentral

30.

Moreno PR, Purushothaman M, Purushothaman KR (2012) Plaque neovascularization: defense mechanisms, betrayal, or a war in progress. Ann N Y Acad Sci 1254:7–17PubMedCrossRef

31.

Chowdhury M, Ghosh J, Slevin M, Smyth JV, Alexander MY, Serracino-Inglott F (2010) A comparative study of carotid atherosclerotic plaque microvessel density and angiogenic growth factor expression in symptomatic versus asymptomatic patients. Eur J Vasc Endovasc Surg 39:388–395PubMedCrossRef

32.

Liu Y, Wilkinson FL, Kirton JP et al (2007) Hepatocyte growth factor and c-Met expression in pericytes: implications for atherosclerotic plaque development. J Pathol 212:12–19PubMedCrossRef

33.

Kaga T, Kawano H, Sakaguchi M, Nakazawa T, Taniyama Y, Morishita R (2012) Hepatocyte growth factor stimulated angiogenesis without inflammation: differential actions between hepatocyte growth factor, vascular endothelial growth factor and basic fibroblast growth factor. Vasc Pharmacol 57:3–9CrossRef

34.

Min JK, Lee YM, Kim JH et al (2005) Hepatocyte growth factor suppresses vascular endothelial growth factor-induced expression of endothelial ICAM-1 and VCAM-1 by inhibiting the nuclear factor-κB pathway. Circ Res 96:300–307PubMedCrossRef

35.

Bacharach E, Itin A, Keshet E (1992) In vivo patterns of expression of urokinase and its inhibitor PAI-1 suggest a concerted role in regulating physiological angiogenesis. Proc Natl Acad Sci 89:10686–10690PubMedCrossRefPubMedCentral

36.

Simonini A, Moscucci M, Muller DW et al (2000) IL-8 is an angiogenic factor in human coronary atherectomy tissue. Circulation 101:1519–1526PubMedCrossRef

37.

Song A, Xu M, Bi Y et al (2011) Serum fetuin-A associates with type 2 diabetes and insulin resistance in Chinese adults. PLoS One 6:e19228PubMedCrossRefPubMedCentral

38.

Araujo TG, Oliveira AG, Carvalho BM et al (2012) Hepatocyte growth factor plays a key role in insulin resistance-associated compensatory mechanisms. Endocrinology 153:5760–5769PubMedCrossRef

39.

Hennige AM, Ranta F, Heinzelmann I et al (2010) Overexpression of kinase-negative protein kinase Cδ in pancreatic beta-cells protects mice from diet-induced glucose intolerance and beta-cell dysfunction. Diabetes 59:119–127PubMedCrossRefPubMedCentral

40.

Dasgupta S, Bhattacharya S, Biswas A et al (2010) NF-κB mediates lipid-induced fetuin-A expression in hepatocytes that impairs adipocyte function effecting insulin resistance. Biochem J 429:451–462PubMedCrossRef

41.

Takata H, Ikeda Y, Suehiro T et al (2009) High glucose induces transactivation of the alpha2-HS glycoprotein gene through the ERK1/2 signaling pathway. J Atheroscler Thromb 16:448–456PubMedCrossRef

42.

Mori K, Ikari Y, Jono S et al (2010) Fetuin-A is associated with calcified coronary artery disease. Coron Artery Dis 21:281–285PubMedCrossRef

43.

Jensen MK, Bartz TM, Mukamal KJ et al (2013) Fetuin-A, type 2 diabetes, and risk of cardiovascular disease in older adults: the cardiovascular health study. Diabetes Care 36(5):1222–1228PubMedCrossRef

Titel: Fetuin-A influences vascular cell growth and production of proinflammatory and angiogenic proteins by human perivascular fat cells
verfasst von: Dorothea I. Siegel-Axel
Susanne Ullrich
Norbert Stefan
Kilian Rittig
Felicia Gerst
Christian Klingler
Ulrike Schmidt
Birgit Schreiner
Elko Randrianarisoa
Hans-Eberhard Schaller
Ulrich A. Stock
Cora Weigert
Alfred Königsrainer
Hans-Ulrich Häring
Publikationsdatum: 01.05.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 5/2014
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-014-3177-0

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