Study identifying an Insulin-like growth factor binding protein-5 as a biomarker for detection of early liver disease presented at the annual congress of the british toxicology societ

Anne Pryde

David J. Flint

Emma M. Large

Filippi

John N. Plevris

M. Helen Grant

Nakamura

Sokolovic

Yasuoka

English

Large, Emma

Pryde, Anne

Plevris, John

Flint, David

Grant, Mary

University of Strathclyde Institutional Repository

Strathprints Institutional RepositoryLarge, Emma and Pryde, Anne and Plevris, John and Flint, David and Grant, Mary (2011) Insulin-like growth factor binding protein-5 as a biomarker for detection of early liver disease. [ProceedingsPaper]Strathprints is designed to allow users to access the research output of the University of Strathclyde.Copyright c© and Moral Rights for the papers on this site are retained by the individual authorsand/or other copyright owners. You may not engage in further distribution of the material for anyprofitmaking activities or any commercial gain. You may freely distribute both the url (http://strathprints.strath.ac.uk/) and the content of this paper for research or study, educational, ornot-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to Strathprints administrator:mailto:strathprints@strath.ac.ukhttp://strathprints.strath.ac.uk/22 Abstracts / Toxicology 290 (2011) 1–46that the treatmentwith aspirin and5-FUdidnot cause toxicity after48h exposurewhichmay explain the lack of SSAT response to thesedrugs.ReferencesWallace,H.M., Fraser, A.V.,Hughes, A., 2003.Aperspectiveof polyaminemetabolism.Biochem. J. 15, 1–14.Wallace, H.M., 2007. Targeting polyamine metabolism: a viable therapeu-tic/preventative solution for cancer? Expert Opin. Pharmacother. 8, 2109–2116.doi:10.1016/j.tox.2011.09.041P034Insulin-like growth factor binding protein-5 as a biomarker forthe detection of early liver diseaseEmma M. Large1,∗, Anne Pryde3, John N. Plevris3, David J. Flint2,M. Helen Grant11 Bioengineering Unit, University of Strathclyde, Glasgow G4 0NW,United Kingdom2 SIPBS, University of Strathclyde, Glasgow G4 0NW, United Kingdom3 Department of Hepatology, University of Edinburgh, United KingdomE-mail address: e.large@strath.ac.uk (E.M. Large).A steady upward trend in the mortality rates from cirrhosis inthe UK has been observed in recent years and in particular in Scot-land. The liver has a huge regenerative capacity but early diagnosisis essential. Non-alcoholic fatty liver disease (NAFLD) is the mostcommon cause of liver disease in the developed world mirroringthe global epidemic of Type 2 diabetes and obesity.This work aims to determine if Insulin-like growth factor bind-ing protein-5 (IGFBP-5) would be a suitable biomarker for thedetection of NAFLD. It has already been shown to be upregulatedin skin ﬁbrosis (Yasuoka et al., 2006a) and in ﬁbrosis of the lung(Yasuoka et al., 2006b). Also, its expression enhances the survivalof hepatic stellate cells and myoﬁbroblasts and the expression ofproﬁbrotic genes (Sokolovic et al., 2010)The University of Edinburgh have developed a model of NAFLDin vitro using C3A cells (Filippi et al., 2004), a clonal derivativeof the human hepatoblastoma-based HepG2 cell line. The modelutilised two methods to induce lipid accumulation in cell lines. Inthe ﬁrst, cells were treated with lactate, pyruvate, octanoate andNH4Cl (LPON) for up to 7 days in culture, and this has been shownto increase intracellular reactive oxygen species (ROS). Alterna-tively, lipid accumulation can be induced, without ROS formation,by the presence of oleate. The lack of ROS formation has beensuggested to be due to the inability of oleate to induce carnitinepalmitoyltransferase-1 (CPT-1) which is essential for the transportof long chain fatty acids across the mitochondrial membrane foroxidation (Nakamura et al., 2009). In our experiments, intracel-lular lipid accumulation was observed by staining cultures withhaematoxylin/oil red O, and IGFBP-5 release into the medium wasmeasured using an ELISA.Intracellular accumulation of lipids was observed to increaseover time in culturewith the presence of LPONor oleate in compar-ison with the controls. In the presence of LPON, IGFBP-5 increasedto 0.3±0.1ng/ml at 7 days, whereas, in the presence of oleate,IGFBP-5 secreted increased to approximately 0.1ng/ml at 5 and 7days (Fig. 1). Control levels were below the levels of detection ofthe ELISA. The difference in levels of IGFBP-5 may be attributed tothe lack of ROS formation with the presence of oleate. This sug-gests that IGFBP-5 may be a suitable biomarker for the detectionof NAFLD.Fig. 1. IGFBP-5 release from C3a cells exposed to LPON or oleate (results aremean± SEM, n=3).Acknowledgements: EML is an EPSRC funded student.ReferencesFilippi, C., Keatch, S.A., Rangar, D., Nelson, L.J., Hayes, P.C., Plevris, J.N., 2004. Journalof Hepatology 41, 599–605.Nakamura, S., Takamura, T., Matsuzawa-Nagata, N., Takayama, H., Misu, H., Noda,H., Nabemoto, S., Kurita, S., Ota, T., Ando, H., Miyamoto, K.-I., Kaneko, S., 2009.Journal of Biological Chemistry 284, 14809–14818.Sokolovic, A., Sokolovic, M., Boers, W., Elferink, R., Bosma, P., 2010. Fibrogenesis andTissue Repair, 3.Yasuoka,H., Jukic,D.M., Zhou, Z., Choi, A.M.K., Feghali-Bostwick, C.A., 2006a.Arthritis& Rheumatism 54, 3001–3010.Yasuoka, H., Zhou, Z., Pilewski, J.M., Oury, T.D., Choi, A.M.K., Feghali-Bostwick, C.A.,2006b. American Journal of Pathology 169, 1633–1642.doi:10.1016/j.tox.2011.09.042P035Acute depletion of the prion proteinmay abrogate A oligomertoxicityHelois E. Radford ∗, Nick C. Verity, Maria Guerra Martin, GiovannaR. MallucciMRC Toxicology Unit, Leicester LE1 9HN, UKE-mail address: her11@le.ac.uk (H.E. Radford).Amyloid-beta1-42 (A) oligomers bind to the prion protein (PrP)with very high afﬁnity (Balducci et al., 2010; Lauren et al., 2009).This interaction has been shown to mediate the toxic effects of Aon LTP and synaptic function in vitro (Lauren et al., 2009), and oncertain tests ofmemory in vivo (Gimbel et al., 2010). However, con-ﬂicting reports exist, where the effects of A have been found to beindependentof PrP (Balducci et al., 2010;Calella et al., 2010;Kesselset al., 2010). If PrP does mediate A toxicity, it becomes an attrac-tive new target for therapy in AD. The reasons for the contradictoryﬁndings are unclear, but in each case, despite somemethodologicaldifferences, the role of PrP has been assessed by comparing A tox-icity in wild-type and embryonic PrP-null (PrP0/0) mice. The aim ofthis study was to examine the role of PrP in mediating A effectsusing two experimental paradigms. First, in PrP0/0 mice as above,and second, using RNAi for acute knockdown of PrP, to model theeffects of a PrP-targeted treatment.We measured dendritic spine loss induced by injection ofsynthetic A oligomers (1M) into the hippocampus, as this isassociated with both memory deﬁcits and loss of LTP. In wild-type(WT) and PrP0/0 mice, we found that A-mediated spine loss wasindependent of PrP in hippocampal slices, and also in vivo, afterinjection of A. Spine densitywas equally reduced byA treatmentin WT (n=70 dendrites from 3 separate mice± SEM) and PrP0/0(n=70 dendrites from 3 separate mice± SEM) mice, in each system(Fig. 1). However, when PrP was acutely depleted in adult WT miceusing lentivirally-mediated RNAi in the hippocampus, we foundsigniﬁcantly less spine loss post A treatment (n=150 dendritesfrom 6 separate mice± SEM) than in animals given control virusand A (n=100 dendrites from 4 separate mice± SEM) (Fig. 1).

doi:10.1016/j.tox.2011.09.042 P035 Acute depletion of the prion protein may abrogate A oligomer toxicity Helois

This interaction has been shown to mediate the toxic effects of A on LTP and synaptic function in

Insulin-like growth factor binding protein-5 as a biomarker for detection of early liver disease

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Toxicology

Insulin-like growth factor binding protein-5 as a biomarker for the detection of early liver disease

http://dx.doi.org/10.1016/j.tox.2011.09.042

Insulin-like growth factor binding protein-5 as a biomarker for detection of early liver disease

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