Causes and prevention of tamoxifen-induced accumulation. of triacylglycerol in rat liver

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1 1 Cuses nd prevention of tmoxifen-induced ccumultion of tricylglycerol in rt liver Oddrun Anit Gudrndsen 1*, Therese Hlvorsen Rost 1, Rolf Kristin Berge Institute of Medicine, Section of Medicl Biochemistry, University of Bergen, Hukelnd University Hospitl, N-5021 Bergen, Norwy 1 These uthors contriuted eqully to this work. Short title: Lipid metolism in tmoxifen treted rts * Corresponding uthor: Oddrun Anit Gudrndsen, Institute of Medicine, Section of Medicl Biochemistry, University of Bergen, Hukelnd University Hospitl, Bergen, Norwy. Telephone numer: Fx numer: Emil: nkjgu@ui.no Arevitions: AADA, rylcetmide decetylse; ACAT, cyl-coa:cholesterol cyltrnsferse; ACC, cetyl-coa croxylse; ACO, cyl-coa oxidse; CPT, crnitine plmitoyltrnsferse; DGAT, dicylglycerol cyltrnsferse, FAS, ftty cid synthse; FAT/CD36, ftty cid trnslocse; GPAT, glycerol-3-phosphte cyltrnsferse; L-FABP, liver ftty cid inding protein;, tetrdecylthiocetic cid; PPAR, peroxisome prolifertor-ctivted receptors; SCD-1, steroyl-coa desturse

2 2 Astrct Tmoxifen cn induce stetosis in women. In the present study we wnted to elucidte the mechnism ehind tmoxifen-induced ccumultion of tricylglycerol in liver in femle rts, nd we hoped to prevent this development y comintion tretment with the modified ftty cid tetrdecylthiocetic cid (). The incresed heptic tricylglycerol level fter tmoxifen tretment ws ccompnied with decresed cetyl-coa croxylse (ACC) nd ftty cid synthse (FAS) ctivities, incresed glycerol-3-phosphte cyltrnsferse (GPAT) ctivity, nd tendency to incresed dicylglycerol cyltrnsferse (DGAT) ctivity. The ctivities nd mrna levels of enzymes involved in β-oxidtion, ketogenesis nd uptke of lipids from liver were unffected y tmoxifen, wheres the uptke of lipoproteins ws unchnged nd the uptke of ftty cids ws decresed. Comintion tretment with tmoxifen nd (Tm+) normlized the heptic tricylglycerol level nd incresed the ctivities of ACC, FAS, GPAT nd DGAT when compred to tmoxifen treted rts. The ctivities nd mrna levels of enzymes involved in β-oxidtion, ketogenesis nd uptke of lipids were incresed fter Tm+ tretment. Conclusions: Tmoxifen incresed the heptic tricylglycerol level, proly due to incresed tricylglycerol iosynthesis comined with unchnged β-oxidtion. The tmoxifen-induced ccumultion of tricylglycerol ws prevented y co-tretment with, through mechnisms of incresed mitochondril nd peroxisoml β-oxidtion. Keywords: stetosis, lipids, ftty cid ctolism, VLDL, peroxisome prolifertor-ctivted receptor

3 3 Introduction The nti-oestrogen tmoxifen hs een used s n effective tretment for oestrogen receptorpositive rest cncers for severl yers (1). However, tmoxifen tretment is ssocited with n incresed risk of developing ftty liver (stetosis) (2-4), nd it is reported tht s mny s 43% of women with rest cncer treted with tmoxifen my develop stetosis within the first two yers of tretment (4). It hs een hypothesized tht n impired ftty cid β- oxidtion could e the cuse of ftty liver fter tmoxifen tretment (5,6) The modified ftty cid tetrdecylthiocetic cid () is lignd for ll peroxisome prolifertor-ctivted receptors (PPARs) (7), nd hs shown promising potentil in the prevention nd tretment of common lipid disorders nd insulin resistnce (8). increse oth mitochondril nd peroxisoml β-oxidtion in liver (9), nd my therefore e vlule tool for tretment of ftty liver. In the present study, femle rts with 7,12-dimethylenz[]nthrcene-induced mmmry tumours were treted with tmoxifen, or comintion of tmoxifen nd for 14 dys fter plple tumours hd developed. We hd two ims in this study: first we wnted to elucidte the mechnism ehind the ccumultion of tricylglycerol in liver fter tmoxifen tretment in this rt model, nd secondly we wnted to investigte whether co-tretment with could olish this undesirle side-effect of tmoxifen. To clrify the mechnisms involved, we mesured the ctivities nd gene expressions of enzymes controlling the heptic iosynthesis, β-oxidtion, secretion nd uptke of lipids, nd quntified severl products of these pthwys.

4 4 Mterils nd Methods Animls nd diets Thirty-two femle Sprgue-Dwley rts t the ge of three weeks were treted with single dose of 20 mg 7,12-dimethylenz[]nthrcene (D-3254; Sigm-Aldrich Norwy AS, Oslo, Norwy) from Tconic M&B A/S, Ry, Denmrk. The rts were divided into four experimentl groups of 8 rts, ech with comprle men ody weight ( g). The rts were housed in room mintined t 12h light-drk cycle nd constnt temperture of 20±3 C with free ccess to tp wter nd pellet feed (Rt nd mice stndrd diet no. 2, B&K Universl, Nittedl, Norwy). (Z)-1-(p-Dimethylminoethoxyphenyl)-1,2-diphenyl-1-utene (Tmoxifen, T-9262, Sigm-Aldrich Norwy AS) nd (synthesized s descried in (10)) were dded to commercil penut oil nd dministered y orogstric intution dily for 14 dys t doses of 40 mg tmoxifen, 300 mg, or comintion of 40 mg tmoxifen nd 300 mg per kilo ody weight (Tm+ group). The control rts received corresponding mounts of penut oil (2.8 ml per kilo ody weight). The tretment strted when the rts were ten weeks old nd hd plple tumours. One rt in the control group ws killed fter three dys of tretment due severe illness, nd one rt treted with Tm+ choked on the feeding tue. Both rts were excluded from the experiment. Otherwise, no mortlity ws oserved. The percent chnge in the odyweight during the experiment ws comprle in ll experimentl groups (+2.6 ± 3.1 for controls, -3.9 ± 4.1 for tmoxifen, +1.7 ± 2.7 for Tm+ nd -0.2 ± 3.3 for treted rts). The rts were nesthetised with 2-5% Isoflurne (Forene, Aott Scndinvi AB, Solne, Sweden) mixed with nitric oxide nd oxygen, under non-fsting conditions. Blood ws drwn from the hert nd collected in BD Vcutiner tues contining heprin or no dditive (Becton, Dickinson nd Compny, Plymouth, UK), nd the liver ws immeditely removed.

5 5 The protocol ws pproved y the Norwegin Stte Bord of Biologicl Experiments with Living Animls. Quntifiction of lipids, trnsminses nd ftty cids Lipids nd serum trnsminses were mesured on the Hitchi 917 system (Roche Dignostics, GmH, Mnnheim, Germny) using the following kits: Triglyceride (Byer, Trrytown, NY, USA), Totl Cholesterol (Byer), Free Cholesterol (Wko Chemicls, Dlton, USA), choline-contining phospholipids (PAP150 from iomerieux, Lyon, Frnce), Non-esterified ftty cids (Wko Chemicls), Alnine trnsminse (Roche) nd Asprtte trnsminse (Roche). The mount of cholesteryl esters in plsm ws clculted s the difference etween totl cholesterol nd free cholesterol. Liver lipids were extrcted (11), evported under nitrogen nd re-dissolved in isopropnol efore nlysis. The ftty cid composition in liver were nlyzed s previously descried (12,13). Enzyme ctivities The livers were homogenised nd frctionted (14), nd the plmitoyl-coa oxidtion (mesured s cid-solule products) (15) nd the ctivities of cyl-coa:cholesterol cyltrnsferse (ACAT) (16), cetyl-coa croxylse (ACC) (17), ftty cyl-coa oxidse (ACO) (18), crnitine plmitoyltrnsferse (CPT)-I nd CPT-II (19), dicylglycerol cyltrnsferse (DGAT) (20), ftty cid synthse (FAS) (21,22) nd glycerol-3-phosphte cyltrnsferse (GPAT) (23) were mesured in post-nucler frction. The HMG-CoA synthse ctivity (24) ws mesured in mitochondril frction. Ketone odies, Kres cycle intermedites nd short CoAs

6 6 Ketone odies nd Kres cycle intermedites were mesured in plsm (25). Short CoAs were mesured in liver (12). Rel-time quntittive RT-PCR Totl RNA ws purified from frozen liver using RNesy Midi Kit (Qigen, GmH, Germny). Primers nd Tqmn proes for rt 6 desturse, 5 desturse nd glycerldehyde-3-phosphte dehydrogense were designed using Primer Express (Applied Biosystems, CA, USA), nd the gene expressions were determined using Tqmn proes. The following sequences were used: 5 desturse forwrd 5 -TGG ATC TTT GGA ACT TCC TTG GT-3, reverse 5 -CAA AGT CAT GCT GTA GCC AAC CT-3, nd proe 5 -CAG TTC AGG CCC AGG C-3. 6 desturse forwrd 5 -CAG CGG GCA CCT CAA TTT-3, reverse 5 -TGC TTG GCG CAG AGA GAC T-3, nd proe 5 -CAG ATT GAG CAC CAC CTC TTC CCC AC-3. Glycerldehyde-3-phosphte dehydrogense forwrd 5 -TGC ACC ACC AAC TGC GC-3, reverse 5 -CAG TCT TCT GAG TGG CAG TGA TG-3, nd proe 5 -TGG AAG GGC TCA TGA CCA CAG TCC A-3. Arylcetmide decetylse (AADA, Rn _m1), ACO (sutype Acox-1, Rn _m1), polipoprotein-b (Rn _g1), CPT-I (sutype CPT-I, Rn _m1) nd CPT-II (Rn _m1), DGAT (sutype DGAT-1, Rn _m1), ftty cid trnslocse (FAT/CD36, Rn _m1), LDL receptor (Rn _m1), liver ftty cid inding protein (L-FABP, sutype FABP-1, Rn _m1), mitochondril HMG-CoA synthse (sutype Hmgcs2, Rn _m1), PPARα (Rn _m1), PPARδ (Rn _m1), PPARγ (Rn _m1), steroyl- CoA desturse (SCD-1, Rn _g1) nd VLDL receptor (Rn _m1) re Assy-On-Demnd designed y Applied Biosystems. FAS ( F) ws purchsed from Applied Biosystems. Rel-time RT-PCR ws crried out in triplictes on n ABI 7900

7 7 sequence detection system (Applied Biosystems). Results were normlised to 18S rrna (RT- CKFT-18S from MedProe, Oslo, Norwy) nd glycerldehyde-3-phosphte dehydrogense, ut only results normlised to 18S re shown since oth reference genes gve similr results. Sttisticl nlysis The results re presented s men vlues with their stndrd devitions for seven (control group nd the comintion tretment group) or eight ( nd tmoxifen groups) rts per group. The dt were evluted y one-wy ANOVA nd Tukey test with the level of sttisticl significnce set t P<0.05 (GrphPd Prism version 3.0, Sn Diego, CA, USA).

8 8 Results Co-tretment with reduced the heptic tricylglycerol nd serum lnine trnsminse levels in tmoxifen-treted rts It is well known tht tmoxifen tretment is ssocited with n incresed risk of developing non-lcoholic ftty liver (stetosis) (2-4). In the present work, tmoxifen tretment incresed the heptic tricylglycerol level y more thn 50% (Fig. 1A) ut did not chnge the heptic mounts of cholesterol (Fig. 1B) or choline-contining phospholipids (Fig. 1C). The comintion tretment with tmoxifen nd (Tm+) decresed the heptic levels of tricylglycerol (Fig. 1A) nd cholesterol (Fig. 1B) nd incresed the phospholipid level (Fig. 1C) when compred to tmoxifen treted rts. The serum trnsminses re regrded s relile mrkers of heptic stetosis nd liver dmge, nd indeed, tmoxifen tretment incresed the serum levels of lnine trnsminse (Fig. 2A) nd sprtte trnsminse (Fig. 2B). Tm+ reduced serum lnine trnsminse level (Fig. 2A) wheres the sprtte trnsminse level ws similr to the tmoxifen group (Fig. 2B). Co-tretment with incresed the heptic β-oxidtion nd ketogenesis in tmoxifentreted rts Tmoxifen tretment did not ffect the plmitoyl-coa β-oxidtion mesured s cid solule products in the liver (Fig. 3A). Also, no chnge ws seen in the ctivities of CPT-I (Fig. 3B) nd CPT-II (Fig. 3C), or in the mrna levels of CPT-I nd CPT-II (Tle 1). In ddition, tmoxifen did not chnge the plsm levels of the Kres cycle intermedites pyruvte, citrte, mlte nd α-ketoglutrte (Tle 2) or the heptic levels of the β-oxidtion degrdtion products cetyl-coa (Fig. 4A) nd propionyl-coa (Fig. 4B). Prllel with this, the ctivity nd mrna level of mitochondril HMG-CoA synthse in liver (Fig. 3D, Tle 1) nd the

9 9 plsm levels of the ketone odies cetocette nd β-hydroxyutyrte (Tle 2) were not chnged, nd thus the ketogenesis ppered not to e influenced y tmoxifen tretment. The peroxisoml β-oxidtion, mesured s the ctivity of ACO (Fig. 3E), nd the mrna levels of ACO, PPARα nd PPARδ (Tle 1) were not ffected y tmoxifen tretment. The β-oxidtion of plmitoyl-coa ws mrkedly incresed in liver from rts treted with Tm+ when compred to rts treted with tmoxifen lone (Fig. 3A). This ws ccompnied with incresed ctivities of CPT-II (Fig. 3C), HMG-CoA synthse (Fig. 3D) nd ACO (Fig. 3E) nd incresed mrna levels of CPT-I, CPT-II, HMG-CoA synthse nd ACO (Tle 1), wheres the CPT-I ctivity (Fig. 3B) ws decresed when compred to tmoxifen treted rts. The plsm levels of pyruvte, citrte, mlte nd cetocette (Tle 2) nd the heptic levels of cetyl-coa (Fig. 4A) nd propionyl-coa (Fig. 4B) were incresed in Tm+ rts when compred to tmoxifen treted rts, ut no chnges were seen in the mrna levels of the PPARs (Tle 1). Co-tretment with incresed the heptic lipogenesis nd tricylglycerol iosynthesis in tmoxifen-treted rts Tmoxifen tretment decresed the ACC ctivity (Fig. 5A), the FAS ctivity (Fig. 5B) nd the FAS mrna level (Tle 1), indicting reduced iosynthesis of ftty cids in these rts, ut did not ffect the heptic level of mlonyl-coa (Fig. 4C). The incresed PPARγ mrna level (Tle 1) nd GPAT ctivity (Fig. 5C) indicted incresed esterifiction of ftty cids to glycerolipids. The iosynthesis of tricylglycerol from dicylglycerol my hve een incresed, s the ctivity of DGAT tended to increse (Fig. 5D) (p=0.06, tmoxifen versus control), however, the mrna level of DGAT ws unchnged y tmoxifen tretment (Tle1). The decresed ACAT ctivity (Fig. 5E) fter tmoxifen tretment suggested reduced cpcity for esterifiction of cholesterol in these rts.

10 10 When rts were treted with Tm+, the ctivities of ACC (Fig 5A), FAS (Fig. 5B), GPAT (Fig. 5C) nd DGAT (Fig. 5D) nd the mrna levels of FAS nd DGAT were incresed s compred to the tmoxifen group, wheres the mlonyl-coa level (Fig. 4C) ws unchnged. The esterifiction of cholesterol seemed unffected, s the ACAT ctivity ws similr in the tmoxifen nd the Tm+ groups (Fig. 5C). Co-tretment with incresed the heptic uptke of ftty cids nd VLDL nd incresed the serum tricylglycerol level in tmoxifen-treted rts Tmoxifen did not chnge the mrna levels of FAT/CD36, LDL receptor or VLDL receptor, ut mrkedly decresed the mrna level of L-FABP (Tle 1), indicting tht the ccumultion of tricylglycerol in the liver could not e explined y n incresed heptic uptke of lipids from the circultion. The gene expressions of AADA nd polipoprotein-b, which plys importnt roles for the ssemly of VLDL (26), were not chnged in liver fter tmoxifen tretment (Tle 1). The serum levels of tricylglycerol (Fig. 6A), non-esterified ftty cids (Fig. 6B), totl cholesterol (Fig. 6C), cholesteryl esters (Fig. 6D) nd phospholipids (Fig. 6E) were decresed fter tmoxifen tretment. Tm+ tretment incresed the mrna levels of FAT/CD36, L-FABP nd VLDL receptor when compred to tmoxifen treted rts, ut hd no significnt effect on the gene expression of the LDL receptor, AADA or polipoprotein-b (Tle 1). The comintion tretment incresed the serum tricylglycerol level (Fig. 6A), ut did not chnge the mounts of the other serum lipids when compred to the tmoxifen group (Figs. 6B-6E). Co-tretment with incresed the gene expression of desturses nd chnged the ftty cid composition in liver from tmoxifen-treted rts

11 11 Since dministrtion of tmoxifen nd Tm+ hd n impct on the iosynthesis of sturted ftty cids y reducing the ctivities of ACC (Fig. 5A) nd FAS (Fig. 5B), it ws of interest to see if these drug tretments lso could ffect the cpcity for insertion of doule onds nd consequently the ftty cid composition in the liver. SCD-1 is the rte-limiting enzyme in the synthesis of 9 desturted ftty cids from sturted ftty cids, wheres the 6 nd 5 desturses re involved in iosynthesis of long chin n-3 nd n-6 polyunsturted ftty cids. Tmoxifen did not chnge the mrna levels of SCD-1, 6 desturse or 5 desturses (Tle 1) or the 18:1n-9/18:0 rtio (Tle 3), ut decresed the 20:4n-6/18:2n-6 nd 20:5n-3/18:3n-3 rtios (Tle 3). Contrrily, Tm+ tretment incresed the mrna levels of SCD-1, 6 nd 5 desturses s compred to tmoxifen treted rts (Tle 1). No chnge ws seen in the 18:1n-9/18:0 rtio, ut the 20:4n-6/18:2n-6 nd 20:5n-3/18:3n-3 rtios were incresed in Tm+ rts when compred to the tmoxifen group (Tle 3). tretment did not ffect the heptic tricylglycerol level ut incresed the heptic β-oxidtion, lipogenesis nd tricylglycerol iosynthesis The effects of treting rts with in the sence of tmoxifen were in most cses similr to wht were seen fter Tm+ tretment, ut certin differences were oserved. When compred to the Tm+ group, tretment hd less pronounced effects on the mrna levels of CPT-II, 6 desturse, PPARγ nd SCD-1 (Tle 1), ut hd stronger impct on the mrna level of L-FABP nd the rtio of 20:4n-6 to 18:2n-6 (Tle 3) when compred to controls. The cholesterol level in liver (Fig. 1B) nd serum (Fig. 6C) nd the serum levels of cholesteryl ester (Fig. 6D), non-esterified ftty cids (Fig. 6B) nd phospholipids (Fig. 6D) were higher in the treted rts compred to rts treted with Tm+. However, the ctivities of enzymes involved in β-oxidtion, lipogenesis nd lipid iosynthesis (Figs. 3 nd 5), nd the liver nd serum levels of tricylglycerol were similr when rts were treted with

12 12 lone or in comintion with tmoxifen (Figs. 1A nd 6A). In ddition, tretment lone did not ffect the serum lnine trnsminse level (Fig. 2A).

13 13 Discussion For more thn 25 yers, tmoxifen hs een the gold stndrd for endocrine tretment of ll stges of oestrogen-receptor positive rest cncer. However, tmoxifen tretment is ssocited with n incresed risk of development of non-lcoholic ftty liver (stetosis) (2-4), nd it is reported tht s mny s 43% of women with rest cncer treted with tmoxifen my develop stetosis within the first two yers of tretment (4). In the present study we hd two ims: first we wnted to elucidte the mechnisms ehind the ccumultion of tricylglycerol in liver of femle rts treted with tmoxifen, nd secondly we wnted to investigte whether co-tretment with the modified ftty cid could olish this undesirle side-effect of tmoxifen. The incresed heptic tricylglycerol level fter tmoxifen tretment ws ccompnied with incresed serum levels of trnsminses, indicting heptocellulr injury, nd is in line with findings in rest cncer ptients tht developed ftty liver fter tmoxifen therpy (2,4). Interestingly, comintion tretment with tmoxifen nd normlized the heptic tricylglycerol level nd prtilly restored the level of serum lnine trnsminse, which is specific mrker of liver dmge, indicting tht co-tretment with my hve potentil for prevention of liver dmge induced y tmoxifen. The incresed tricylglycerol content in liver in tmoxifen treted rts my e cused y incresed iosynthesis, reduced β-oxidtion, incresed uptke or reduced secretion of lipids, or comintion of these fctors. Since the ctivities of ACC nd FAS were reduced y tmoxifen, possily s compenstory response to the incresed level of tricylglycerol in the liver, the incresed heptic tricylglycerol level is proly not due to incresed lipogenesis, s lso hs een demonstrted y others (6). However, the mount of mlonyl- CoA, the importnt inhiitor of CPT-I, ws not chnged, nd no chnge ws seen in the cpcity for ftty cid β-oxidtion or in the ctivities nd mrna levels of enzymes involved

14 14 in mitochondril nd peroxisoml β-oxidtion or ketogenesis, or in the levels of degrdtion products nd metolites thereof in tmoxifen treted rts. This strongly indictes tht the ccumultion of tricylglycerol in liver oserved fter tmoxifen tretment could not e scried to reduced oxidtion of ftty cids. Tmoxifen tretment seemed to increse the synthesis of glycerolipids, s the PPARγ gene expression nd the GPAT ctivity were incresed. In ccordnce with others (27), we found tht tmoxifen reduced the ctivity of ACAT, suggesting tht the ftty cids were directed towrds synthesis of tricylglycerol nd phospholipids insted of cholesteryl esters. In view of the fct tht no chnge ws seen in the heptic phospholipid level wheres the tricylglycerol level in liver ws incresed, together with the strong tendency incresed DGAT ctivity (p=0.06), it ppered tht the tricylglycerol synthesis my e fvoured over the synthesis of phospholipids fter tmoxifen tretment. The incresed heptic level of tricylglycerol fter tmoxifen tretment ws ccompnied with decresed levels of tricylglycerol, cholesteryl esters nd phospholipids in serum, nd we therefore suspected tht the heptic secretion nd/or the uptke of ftty cids nd lipids could e ffected. The secretion of VLDL from the liver ws not mesured directly, ut the unchnged mrna levels of AADA nd polipoprotein-b indicted tht tmoxifen did not ffect the VLDL-secretion, resulting in n ccumultion of newly synthesized tricylglycerol in the liver. However, incresed secretion of VLDL hs een oserved y others without ny chnge in the AADA mrna content (26), nd only direct mesurements of the VLDL-secretion cn give n nswer to whether tmoxifen ffects the secretion of tricylglycerol-rich lipoproteins. The mrna level of genes involved in the uptke of lipoproteins from the circultion, such s LDL receptor nd VLDL receptor, ws not ffected y tmoxifen tretment, suggesting tht the uptke of tricylglycerol contining lipoproteins ws not chnged. On the

15 15 other hnd, the unchnged mrna level of FAT/CD36 nd the decresed gene expression of L-FABP implied tht the uptke of non-esterified ftty cids from the circultion ws decresed. Thus, the incresed tricylglycerol content in liver of tmoxifen treted rts ws proly not cused y incresed uptke of lipids nd ftty cids. The descried chnges in ftty cid metolism fter tmoxifen tretment were expected to influence the ftty cid composition in liver. The mrna level of SCD-1 is reported to e determinnt of the iosynthesis of tricylglycerol nd cholesteryl esters, since 18:1n-9 is the preferred sustrte for esterifiction (28). However, lthough the ACAT ctivity ws decresed, the GPAT ctivity ws incresed nd the DGAT ctivity tended to increse (p=0.06) fter tmoxifen tretment, no chnge ws seen in the mrna level of SCD- 1. Tmoxifen did not fully induce ftty liver in the present experiment, ut we found tht tmoxifen tretment decresed the 20:5n-3/18:3n-3 nd 20:4n-6/18:2n-6 rtios, s hs een reported in severe ftty liver induced y ethnol, oesity or the hyperlipidemic drug tridecylthiopropnoic cid (13,29,30). These chnges in ftty cids rtios suggested tht the ctivities of the desturses involved in the iosynthesis of long chin polyunsturted ftty cids were decresed, lthough no chnges were seen in the gene expressions of 6 nd 5 desturses. Comintion tretment with normlized the heptic tricylglycerol level when compred to tmoxifen treted rts, nd the β-oxidtion of plmitoyl-coa ws incresed prllel with this. It is generlly ccepted tht β-oxidtion in liver is regulted through CPT-I, ut in the present experiment we found tht the incresed plmitoyl-coa β-oxidtion fter tretment with Tm+ ws ccompnied with decresed ctivity of CPT-I nd n unchnged heptic level of mlonyl-coa, comined with incresed ctivities of CPT-II nd HMG-CoA synthse. This suggested tht the β-oxidtion could e regulted eyond CPT-I, s we hve shown erlier (31), nd tht CPT-II nd HMG-CoA synthse re potentil control

16 16 sites for mitochondril ftty cid β-oxidtion nd ketogenesis in liver of rts treted with Tm+. Although the mrna levels of PPARα nd PPARδ were similr in rts treted with tmoxifen lone nd in comintion with, the expressions of the PPARα trget genes CPT-I, CPT-II nd ACO were mrkedly incresed in the ltter group, further supporting n incresed β-oxidtion of ftty cid. The clernce of the mitochondril metolites pyruvte, citrte nd mlte ws not mesured, ut the incresed plsm levels of these metolites nd the incresed heptic levels of the β-oxidtion degrdtion products cetyl- CoA nd propionyl-coa together with the incresed β-oxidtion pointed towrds n incresed comustion of ftty cids. Thus, co-tretment with my prevent the tmoxifen-induced ccumultion of tricylglycerol in liver through incresed β-oxidtion. The iosynthesis of ftty cids, tricylglycerol nd phospholipids seemed to e incresed fter co-tretment with, s the ctivities of ACC, FAS, GPAT nd DGAT were incresed when compred to tmoxifen treted rts, lthough the mrna level of PPARγ ws similr in the two groups. As the heptic level of tricylglycerol ws decresed nd tht of phospholipids ws incresed, it seems tht the ftty cids were directed towrds esterifiction s phospholipids rther thn s tricylglycerol fter co-tretment with. The ACAT ctivity fter Tm+ tretment ws not significntly different from tht in tmoxifen treted rts, indicting tht the iosynthesis of cholesteryl esters ws similr in these groups. The incresed β-oxidtion reduced, wheres the incresed tricylglycerol synthesis incresed the vilility of tricylglycerol for VLDL synthesis nd secretion fter cotretment with, nd the comprle mrna levels of AADA nd polipoprotein-b in rts treted with tmoxifen or Tm+ suggested tht the secretion of VLDL ws similr in these groups. The gene expression of the LDL-receptor ws lso similr in the two tretment groups, prlleled with equl serum cholesterol nd cholesteryl ester levels. Tm+ incresed the gene expressions of FAT/CD36, L-FABP nd VLDL receptor when compred

17 17 to tmoxifen treted rts, suggesting tht the uptke of non-esterified ftty cids nd VLDL ws incresed. However, the serum levels of non-esterified ftty cids nd phospholipids were similr in these groups, wheres the serum tricylglycerol ws significntly higher fter Tm+ s compred to tmoxifen tretment. These findings indicte tht the liver tricylglycerol-lowering effect of comintion-tretment of tmoxifen nd did not olish the tmoxifen-induced ccumultion of tricylglycerol through mechnisms of reduced iosynthesis of ftty cids nd tricylglycerol, y incresed secretion of VLDL, or y reduced uptke of ftty cids nd lipoproteins. Peroxisome prolifertors re reported to increse the ctivities of SCD-1, 6 nd 5 desturses (32,33), nd therey increse the iosynthesis of long chin unsturted ftty cids including 18:1n-9, 20:4n-6 nd 20:5n-3. is peroxisome prolifertor (8), nd in the present experiment we show tht Tm+ incresed the mrna levels of SCD-1, 6 nd 5 desturses when compred to rts treted with tmoxifen. This ws ccompnied with incresed 20:4n-6/18:2n-6 nd 20:5n-3/18:3n-3 rtios in the Tm+ treted rts, wheres no chnge ws seen in the 18:1n-9/18:0 rtio. It hs een speculted tht the reson for the incresed formtion of unsturted ftty cid y peroxisome prolifertors is to supply phospholipids with proper chin length nd desturtion for the uilding of memrnes of the rpidly proliferting peroxisomes (8). This is in line with the incresed GPAT ctivity nd the elevted heptic phospholipid level oserved fter Tm+ tretment, which suggest tht the iosynthesis of not only tricylglycerol ut lso of phospholipids could e incresed. Tretment of rts with lone showed mny of the sme effects s Tm+ when compred to controls. Surprisingly, wheres comintion-tretment of tmoxifen with reduced the heptic tricylglycerol level nd incresed β-oxidtion nd lipid iosynthesis when compred to rts treted with only tmoxifen, no lowering of the heptic tricylglycerol level ws oserved fter tretment when compred to controls, lthough

18 18 the β-oxidtion nd the iosynthesis of lipids were incresed. We hve recently presented similr results in study of mle Wistr rts, where tretment lone did not ffect the heptic tricylglycerol level, ut significntly improved the ftty liver induced y tridecylthiopropnoic cid (34). From this it seemed tht my hve the cpcity to normlize rther thn to reduce the heptic tricylglycerol content under certin circumstnces, ut the mechnism ehind this remins to e solved. In conclusion, the tmoxifen-induced ccumultion of tricylglycerol in liver of rts in the present study is possily consequence of incresed tricylglycerol iosynthesis comined with unchnged β-oxidtion, VLDL secretion nd uptke of lipids to the liver. We lso presented evidence tht tmoxifen-induced tricylglycerol ccumultion could e prevented y comintion tretment with, through mechnisms of incresed mitochondril nd peroxisoml β-oxidtion. Acknowledgements Svein Kryger, Kri Hellnd Mortensen, Rndi Sndvik, Rndi Solheim nd Kri Willims re cknowledged for their technicl ssistnce. This work ws supported y grnts from The Norwegin Cncer Society (OAG) nd The Western Norwy Regionl Helth Authority (THR).

19 19 References Cited Tmoxifen for erly rest cncer: n overview of the rndomised trils.erly Brest Cncer Trilists' Collortive Group. Lncet 351: Ogw, Y., Y. Murt, A. Nishiok, T. Inomt, nd S. Yoshid Tmoxifeninduced ftty liver in ptients with rest cncer. Lncet 351: Coskun, U., F. B. Toruner, nd N. Gunel Tmoxifen therpy nd heptic stetosis. Neoplsm 49: Nishino, M., K. Hykw, Y. Nkmur, T. Morimoto, nd S. Mukihr Effects of tmoxifen on heptic ft content nd the development of heptic stetosis in ptients with rest cncer: high frequency of involvement nd rpid reversl fter completion of tmoxifen therpy. AJR Am J Roentgenol 180: Egw, T., K. Tod, Y. Nemoto, M. Ono, N. Akisw, T. Sir, Y. Hyshi, M. Hiroi, H. Enzn, nd S. Onishi Pitvsttin meliortes severe heptic stetosis in romtse-deficient (Ar-/-) mice. Lipids 38: Lelliott, C. J., M. Lopez, R. K. Curtis, N. Prker, M. Ludes, G. Yeo, M. Jimenez- Linn, J. Grosse, A. K. Sh, D. Wiggins, D. Huton, M. D. Brnd, S. O'Rhilly, J. L. Griffin, G. F. Gions, nd A. Vidl-Puig Trnscript nd metolite nlysis of the effects of tmoxifen in rt liver revels inhiition of ftty cid synthesis in the presence of heptic stetosis. Fse J 19: Westergrd, M., J. Henningsen, M. L. Svendsen, C. Johnsen, U. B. Jensen, H. D. Schroder, I. Krtchmrov, R. K. Berge, L. Iversen, L. Bolund, K. Krglle, nd K. Kristinsen Modultion of kertinocyte gene expression nd differentition y PPAR-selective lignds nd tetrdecylthiocetic cid. J Invest Dermtol 116: Berge, R. K., J. Skorve, K. J. Tronstd, K. Berge, O. A. Gudrndsen, nd H. Grv Metolic effects of thi ftty cids. Curr Opin Lipidol 13:

20 20 9. Berge, R. K., nd E. Hvttum Impct of cytochrome P450 system on lipoprotein metolism. Effect of norml ftty cids (3-thi ftty cids). Phrmcol Ther 61: Spydevold, O., nd J. Bremer Induction of peroxisoml et-oxidtion in 7800 C1 Morris heptom cells in stedy stte y ftty cids nd ftty cid nlogues. Biochim Biophys Act 1003: Bligh, E. G., nd W. J. Dyer A rpid method of totl lipid extrction nd purifiction. Cndin Journl of Biochemistry nd Physiology 37: Wergedhl, H., B. Liset, O. A. Gudrndsen, E. Lied, M. Espe, Z. Mun, S. Mork, nd R. K. Berge Fish Protein Hydrolyste Reduces Plsm Totl Cholesterol, Increses the Proportion of HDL Cholesterol, nd Lowers Acyl-CoA:Cholesterol Acyltrnsferse Activity in Liver of Zucker Rts. J Nutr 134: Gudrndsen, O. A., E. Dyroy, P. Bohov, J. Skorve, nd R. K. Berge The metolic effects of thi ftty cids in rt liver depend on the position of the sulfur tom. Chem Biol Interct 155: Berge, R. K., T. Fltmrk, nd H. Osmundsen Enhncement of long-chin cyl- CoA hydrolse ctivity in peroxisomes nd mitochondri of rt liver y peroxisoml prolifertors. Eur J Biochem 141: Willumsen, N., S. Hexeerg, J. Skorve, M. Lundquist, nd R. K. Berge Docoshexenoic cid shows no triglyceride-lowering effects ut increses the peroxisoml ftty cid oxidtion in liver of rts. J Lipid Res 34: Field, F. J., E. Alright, nd S. Mthur Inhiition of cylcoenzyme A: cholesterol cyltrnsferse ctivity y PD128O42: effect on cholesterol metolism nd secretion in CCo-2 cells. Lipids 26: 1-8.

21 Tne, T., S. Nknishi, T. Hshimoto, H. Ogiwr, J. Nikw, nd S. Num Acetyl-CoA croxylse from rt liver. Methods Enzymol 71 Pt C: Smll, G. M., K. Burdett, nd M. J. Connock A sensitive spectrophotometric ssy for peroxisoml cyl-coa oxidse. Biochem J 227: Mdsen, L., L. Froylnd, E. Dyroy, K. Hellnd, nd R. K. Berge Docoshexenoic nd eicospentenoic cids re differently metolized in rt liver during mitochondri nd peroxisome prolifertion. J Lipid Res 39: Colemn, R., nd R. M. Bell Tricylglycerol synthesis in isolted ft cells. Studies on the microsoml dicylglycerol cyltrnsferse ctivity using ethnoldispersed dicylglycerols. J Biol Chem 251: Roncri, D. A Ftty cid synthse from humn liver. Methods Enzymol 71 Pt C: Skorve, J., A. l-shurji, D. Asiedu, I. Bjorkhem, L. Berglund, nd R. K. Berge On the mechnism of the hypolipidemic effect of sulfur-sustituted hexdecnedioic cid (3-thidicroxylic cid) in normolipidemic rts. J Lipid Res 34: Btes, E. J., nd D. Sggerson A selective decrese in mitochondril glycerol phosphte cyltrnsferse ctivity in livers from streptozotocin-dietic rts. FEBS Lett 84: Clinkenerd, K. D., W. D. Reed, R. A. Mooney, nd M. D. Lne Intrcellulr locliztion of the 3-hydroxy-3-methylglutryl coenzme A cycle enzymes in liver. Seprte cytoplsmic nd mitochondril 3-hydroxy-3-methylglutryl coenzyme A generting systems for cholesterogenesis nd ketogenesis. J Biol Chem 250:

22 Dish, P., nd J. V. Leonrd Rpid profiling of plsm orgnic cids y high performnce liquid chromtogrphy. Clin Chim Act 146: Trickett, J. I., D. D. Ptel, B. L. Knight, E. D. Sggerson, G. F. Gions, nd R. J. Pese Chrcteriztion of the rodent genes for rylcetmide decetylse, puttive microsoml lipse, nd evidence for trnscriptionl regultion. J Biol Chem 276: de Medin, P., B. L. Pyre, J. Bernd, I. Bosser, B. Pipy, S. Silvente-Poirot, G. Fvre, J. C. Fye, nd M. Poirot Tmoxifen is potent inhiitor of cholesterol esterifiction nd prevents the formtion of fom cells. J Phrmcol Exp Ther 308: Miyzki, M., Y. C. Kim, M. P. Gry-Keller, A. D. Attie, nd J. M. Ntmi The iosynthesis of heptic cholesterol esters nd triglycerides is impired in mice with disruption of the gene for steroyl-coa desturse 1. J Biol Chem 275: Venktesn, S., J. M. Rideout, nd K. J. Simpson Microsoml delt 9, delt 6 nd delt 5 desturse ctivities nd liver memrne ftty cid profiles in lcohol-fed rts. Biomed Chromtogr 4: Videl, L. A., R. Rodrigo, J. Ary, nd J. Ponichik Oxidtive stress nd depletion of heptic long-chin polyunsturted ftty cids my contriute to nonlcoholic ftty liver disese. Free Rdic Biol Med 37: Mdsen, L., A. Grrs, G. Asins, D. Serr, F. G. Hegrdt, nd R. K. Berge Mitochondril 3-hydroxy-3-methylglutryl coenzyme A synthse nd crnitine plmitoyltrnsferse II s potentil control sites for ketogenesis during mitochondrion nd peroxisome prolifertion. Biochem Phrmcol 57:

23 Kwshim, Y., N. Uy-Yu, nd H. Kozuk Sex-relted differences in the enhncing effects of perfluoro-octnoic cid on steroyl-coa desturse nd its influence on the cyl composition of phospholipid in rt liver. Comprison with clofiric cid nd tidenol. Biochem J 263: Kwshim, Y., K. Musoh, nd H. Kozuk Peroxisome prolifertors enhnce linoleic cid metolism in rt liver. Incresed iosynthesis of omeg 6 polyunsturted ftty cids. J Biol Chem 265: Dyrøy, E., H. Wergedhl, J. Skorve, O. A. Gudrndsen, J. Songstd, nd R. K. Berge Thi ftty cids with the sulfur tom in even or odd positions hve opposite effect on ftty cid ctolism. Lipids 41: in press.

24 24 Tle 1 Heptic mrna levels in control rt nd rts treted with tmoxifen, Tm+ or. The mrna levels re shown reltive to 18S rrna nd normlized to controls. Control Tmoxifen Tm+ AADA 1.00 ± ± ± ± 0.23 ACO 1.00 ± ± ± ± 3.04 Apolipoprotein- B 1.00 ± ± ± ± 0.26 CPT-I 1.00 ± ± ± ± 0.56 CPT-II 1.00 ± ± ± ± 0.95 c 5 desturse 1.00 ± ± ± ± desturse 1.00 ± ± ± ± 0.56 c DGAT ± ± ± 0.43 c 1.41 ± 0.45 c FAS 1.00 ± ± ± ± 0.35 FAT/CD ± ± ± ± 0.19 HMG-CoA synthse (mit.) 1.00 ± ± ± ± 0.69 L-FABP 1.00 ± ± ± 0.34 c 2.71 ± 0.33 d LDL receptor 1.00 ± ± ± ± 0.32 PPARα 1.00 ± ± ± ± 1.18 PPARδ 1.00 ± ± ± ± 0.33 PPARγ 1.00 ± ± ± ± 0.17 SCD ± ± ± ± 0.85 VLDL receptor 1.00 ± ± ± 1.01 c 2.23 ± 1.26 c Mens in row without common superscript re significntly different, P<0.05

25 25 Tle 2 Kres cycle intermedites nd ketone odies in plsm of control rts nd rts treted with tmoxifen, Tm+ or. Control Tmoxifen Tm+ pyruvte 347 ± ± ± ± 142 citrte 220 ± ± ± 56 c 329 ± 67 c mlte 22 ± 9 24 ± 5 49 ± 8 54 ± 11 α-ketoglutrte 30 ± 9 37 ± 4 32 ± 4 29 ± 2 cetocette 90 ± ± ± ± 41 β-hydroxyutyrte 240 ± ± ± ± 108 Mens in row without common superscript re significntly different, P<0.05

26 26 Tle 3 Ftty cid rtios in liver of control rts nd rts treted with tmoxifen, Tm+ or. Control Tmoxifen Tm+ 18:1n-9/18: ± ± ± ± :4n-6/18:2n ± ± ± ± 0.52 c 20:5n-3/18:3n ± ± ± 0.95 c 2.14 ± 1.05 c Mens in row without common superscript re significntly different, P<0.05

27 27 Figure legends Figure 1. Heptic levels of tricylglycerol (A), cholesterol (B) nd phospholipids (C) in control rts nd rts treted with tmoxifen (Tm), Tm+ or. Vlues re mens with stndrd devitions depicted y verticl rs. Brs without common letter re significntly different, P<0.05. Figure 2. Serum levels of lnine trnsminse (ALT) (A) nd sprtte trnsminse (AST) (B) in control rts nd rts treted with tmoxifen (Tm), Tm+ or. Vlues re mens with stndrd devitions depicted y verticl rs. Brs without common letter re significntly different, P<0.05. Figure 3. Plmitoyl-CoA oxidtion (mesured s cid-solule products) (A) nd the ctivities of crnitine plmitoyltrnsferse (CPT)-I (B), CPT-II (C), HMG-CoA synthse (D) nd cyl- CoA oxidse (ACO) (E) in liver from control rts nd rts treted with tmoxifen (Tm), Tm+ or. Vlues re mens with stndrd devitions depicted y verticl rs. Brs without common letter re significntly different, P<0.05. Figure 4. Heptic levels of cetyl-coa (A), propionyl-coa (B) nd mlonyl-coa (C) in control rts nd rts treted with tmoxifen (Tm), Tm+ or. Vlues re mens with stndrd devitions depicted y verticl rs. Brs without common letter re significntly different, P<0.05. Figure 5. Heptic ctivities of cetyl-coa croxylse (ACC) (A), ftty cid synthse (FAS) (B), glycerol-3-phosphte cyltrnsferse (GPAT) (C), dicylglycerol cyltrnsferse (DGAT) (D) nd cyl-coa:cholesterol cyltrnsferse (ACAT) (E) in control rts nd rts

28 28 treted with tmoxifen (Tm), Tm+ or. Vlues re mens with stndrd devitions depicted y verticl rs. Brs without common letter re significntly different, P<0.05. Figure 6. Serum levels of tricylglycerol (A), non-esterified ftty cids (B), totl cholesterol (C), cholesteryl esters (D) nd phospholipids (E) in control rts nd rts treted with tmoxifen (Tm), Tm+ or. Vlues re mens with stndrd devitions depicted y verticl rs. Brs without common letter re significntly different, P<0.05.

29 A umol/g liver Liver tricylglycerol Control Tm Tm + B umol/g liver Liver cholesterol c Control Tm Tm + C 30 Liver phospholipids c c umol/g liver Control Tm Tm + Fig. 1

30 A U/L Serum ALT c B U/L Serum AST Control Tm Tm + Control Tm Tm + Fig. 2

31 A Plmitoyl-CoA β-oxidtion pmol/mg protein/min Control Tm Tm + B CPT-I C CPT-II nmol/mg protein/min Control Tm Tm + nmol/mg protein/min Control Tm Tm + D HMG-CoA synthse E ACO nmol/mg protein/min Control Tm Tm + nmol/mg protein/min Control Tm Tm + Fig. 3

32 A (ritrry units, reltive to controls) Acetyl-CoA B (ritrry units, reltive to controls) Propionyl-CoA Control Tm Tm + Control Tm Tm + C (ritrry units, reltive to controls) Mlonyl-CoA Control Tm Tm + Fig. 4

33 A ACC B FAS nmol/mg protein/min c c nmol/mg protein/min Control Tm Tm + Control Tm Tm + C nmol/mg protein/min GPAT c Control Tm Tm + c D nmol/mg protein/min 6 DGAT Control Tm Tm + E nmol/mg protein/min ACAT Control Tm Tm + Fig. 5

34 A mmol/l serum Serum tricylglycerol Control Tm Tm + mmol/l serum B Serum non-esterified ftty cids c c Control Tm Tm + C 4 Serum totl cholesterol D 2.0 Serum cholesterylester mmol/l serum c mmol/l serum c c 0 Control Tm Tm Control Tm Tm + E mmol/l serum Serum phospholipids c Fig Control Tm Tm +

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