Knut A Eliassen

University of Oslo, Oslo, Oslo, Norway

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Publications (12)22.56 Total impact

  • Atherosclerosis Supplements - ATHEROSCLER SUPPL. 01/2006; 7(3):532-532.
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    ABSTRACT: BACKGROUND:: Apolipoprotein(a) (apo(a)), which is part of the atherogenic lipoprotein Lp(a), shares structural homology with plasminogen (plg). Genes coding for plasminogen (PLG) and apo(a) (LPA) are linked and situated 40kb apart in the telomeric region of the long arm of chromosome 6. LPA is naturally expressed only in primates and hedgehogs. Thus, access to knowledge regarding the mechanism by which LPA expression is regulated is limited due to shortage of appropriate animal models. However, mice transgenic for the human LPA gene have been produced. Lp(a) levels in man are genetically determined and not altered significantly by dietary changes. In contrast, mice transgenic for LPA-yeast artificial chromosome (LPA-YAC) have markedly reduced apo(a) levels after maintenance on a high-fat diet. LPA-YAC carries the 40kb LPA-PLG intergenic region, which includes a putative binding site for peroxisome proliferator-activated receptor alpha (PPARalpha). Therefore, we examined if fibrates, which exert their effect via PPARalpha, could alter LPA expression in transgenic mice. METHODS:: Two LPA transgenic mouse lines with or without the LPA-PLG intergenic region we fed either PPARalpha agonist fenofibrate (FF) or 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY 14643) containing diets for 3 weeks. For the study of serum apo(a) levels, blood were sampled prior the experiment and when the animals were sacrificed. For the study of gene expression pattern pieces of livers were collected and submerged in RNAlater buffer and stored at -70 degrees C until analysis by quantitative PCR. RESULTS AND CONCLUSIONS:: The results showed that fibrates reduce LPA expression in LPA-YAC transgenic mice, but have no impact on hepatic apo(a) mRNA or serum apo(a) protein levels in LPA-cDNA transgenic mice, which lack the LPA-PLG intergenic region. This suggests that the effect of fibrates on LPA expression is mediated upstream of the LPA gene. However, on the basis of current data it is not possible to conclude that PPARalpha is the primary factor that represses LPA expression in LPA-YAC transgenic mice. Negative correlation between FXR and apo(a) mRNA levels, in addition to putative FXR DNA binding sequence in LPA-PLG intergenic region, suggest that it is equally likely that reduced expression of LPA could be a secondary consequence of PPARalpha activation on other genes, such as FXR.
    Pathophysiology 06/2005; 11(4):201-208.
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    ABSTRACT: In man, elevated levels of plasma plipoprotein (a) (Lp(a)) is a cardiovascular risk factor, and oxidized phospholipids are believed to play a role as modulators of inflammatory processes such as atherosclerosis. Polyamines are potent antioxidants and anti-inflammatory agents. It was therefore of interest to examine polyamines and their metabolism in LPA transgenic mice. Concentration of the polyamines putrescine, spermidine and spermine as well as the activity of peroxisomal polyamine oxidase and two other peroxisomal enzymes, acyl-CoA oxidase and catalase were measured. The mice were fed either a standard diet or a diet high in fat and cholesterol (HFHC). Some of the mice in each feeding group were in addition given aminoguanidine (AG), a specific inhibitor of diamine oxidase, which catalyses degradation of putrescine, and also inhibits non-enzymatic glycosylation of protein which is implicated in the aetiology of atherosclerosis in diabetic patients. Non-transgenic mice were used as controls. Intestinal peroxisomal polyamine oxidase activity was significantly higher in LPA transgenic mice than in the non-transgenic mice, while intestinal peroxisomal catalase activity was significantly lower. Hepatic beta-oxidation increased in Lp(a) transgenic mice fed the HFHC diet, but not in those on standard diet. Hepatic spermidine concentration was increased in all mice fed the HFHC diet compared to those fed a standard diet, while spermine concentration was decreased. With exception of the group fed only standard diet, transgenic mice showed a lower degree of hepatic steatosis than non-transgenic mice. AG had no significant effect on hepatic steatosis. The present results indicate a connection between peroxisomal enzyme activity and the presence of the human LPA gene in the murine genome. The effect may be a result of changes in oxidative processes in lipid metabolism rather than resulting from a direct effect of the LPA construct on the peroximal gene expression.
    Lipids in Health and Disease 02/2005; 4:23. · 2.02 Impact Factor
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    ABSTRACT: Background: Lp(a) lipoprotein (Lp(a)) contains polymorphic glycoprotein, apolipoprotein(a) (apo(a)) and low density lipoprotein (LDL). The extensive homology between apo(a) and plasminogen is believed to contribute to the pathogenicity of apo(a), but the precise mechanisms by which Lp(a) participates in atherogenesis is still unknown. We used LPA-yeast artificial chromosome (LPA-YAC) transgenic mice with or without the human APOB (hAPOB) gene to study pathogenicity of apo(a)/Lp(a) and illucidate its role in regulation of serum lipid levels. Methods: Middle-aged (1-year-old) mice were fed a control (AIN-76), a high-cholesterol (HC) or a high-cholesterol/high-fat (HCHF) diet for 7 weeks. For the study of serum total apo(a) and lipid levels, mice were sampled prior to the experiment, at 2 weeks and at 7 weeks when the animals were sacrificed. Hearts with ascending aorta were fixed in formalin, embedded in gelatine and prepared for sections on a cryostat. Livers were washed in ice cold saline and submerged in RNAlater trade mark buffer and stored at -70 degrees C until mRNA analysis. Results: Wild type mice fed the control diet did not develop aortic lesions. Presence of the LPA gene was sufficient to induce development of aortic lesions, but neither coexpression of the hAPOB gene nor feeding the HC diet or the HCHF diet augmented the development of aortic lesions in LPA-YAC transgenic mice. On the control diet transgenic females had larger aortic lesion size than transgenic males. Furthermore, aortic lesions in transgenic females were associated with calcification more often than in transgenic males. Serum total cholesterol levels were higher both in wild type and LPA-YAC transgenic males than in females mainly because of higher serum high-density lipoprotein cholesterol levels. HC and HCHF feeding had more pronounced effect on total cholesterol levels in LPA-YAC/hAPOB transgenic mice than in either wild type or LPA-YAC transgenic mice, due to increased low density lipoprotein cholesterol levels. Furthermore, these diets reduced serum total apo(a) levels in both transgenic mouse lines. Conclusion: Expression of the human LPA gene in mice is sufficient to trigger development of aortic lesions. Similar frequency of calcified lesions in LPA-YAC transgenic mice with or without hAPOB gene may suggest that apo(a) is the part of the Lp(a) molecule that causes aortic calcification. The basis for reduced serum total apo(a) level in response to cholesterol feeding is not clear, but interplay between LPA and factors involved in cholesterol or bile acid homeostasis is worth of future studies.
    Pathophysiology 11/2004; 11(2):113-120.
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    ABSTRACT: The Lp(a) lipoprotein (Lp(a)) consists of the polymorphic glycoprotein apolipoprotein(a) (apo(a)), which is attached by a disulfide bond to apolipoprotein B (apoB). Apo(a), which has high homology with plasminogen, is present only in primates and hedgehogs. However, transgenic mice and rabbits with high serum apo(a) levels exist. Liver is the main site for apo(a) synthesis, but the site of removal is uncertain. To examine differences between transgenic mice expressing the LPA gene and mice capable of forming Lp(a) particles, LPA-YAC transgenic mice and hAPOB transgenic mice were crossed and their offspring examined. Comparison of LPA-YAC with LPA-YAC/hAPOB transgenic mice showed that LPA-YAC/hAPOB transgenic mice have higher serum total apo(a) and total cholesterol level than mice lacking the hAPOB gene. However, hepatic apo(a) mRNA level was higher in LPA-YAC transgenic mice than in LPA-YAC/hAPOB transgenic mice. Feeding of a high-cholesterol/high-fat diet to male LPA-YAC transgenic mice with or without the hAPOB gene resulted in reduced serum total apo(a) and hepatic apo(a) mRNA level. In conclusion, the higher serum total apo(a) level in LPA-YAC/hAPOB transgenic mice than in LPA-YAC transgenic mice is not caused by increased apo(a) synthesis. Lower hepatic apo(a) mRNA level in LPA-YAC/hAPOB than in LPA-YAC transgenic mice may suggest that the increase in total apo(a) level is a result of apo(a) accumulation in serum. Furthermore, observed higher serum total cholesterol level in LPA-YAC/hAPOB transgenic mice than either in wild type or LPA-YAC transgenic mice may further suggest that human APOB transgenicity is a factor that contributes to increased serum total apo(a) and cholesterol levels. Our results on reduced serum total apo(a) and hepatic apo(a) mRNA levels in HCHF fed male LPA-YAC transgenic mice confirm earlier findings in females, and show that there are no sex difference in mechanisms for lowering apo(a) level in response to HCHF feeding.
    Lipids in Health and Disease 06/2004; 3:8. · 2.02 Impact Factor
  • Atherosclerosis Supplements - ATHEROSCLER SUPPL. 01/2003; 4(2):296-296.
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    ABSTRACT: Serum levels of Lp(a) lipoprotein are under genetic control and a high level is a risk factor for atherosclerotic disease. We have examined the aorta of LPA transgenic mice and their non-transgenic litter mates who had all been given a regular, not lipid fortified diet. When sacrificed, the animals had an average age of 66 weeks. Lipid lesions were observed in the aorta of 13 out of 18 LPA transgenic mice and in five out of 21 non-transgenic animals. The difference is statistically significant. We conclude that LPA transgenic mice develop lipid lesions in aorta more frequently than non-transgenic animals, even on a diet with a low fat content. LPA transgenic mice on a normal diet could be a useful animal model for the study of spontaneous human atherosclerosis, its treatment and prevention.
    Atherosclerosis 08/2002; 163(1):99-104. · 3.71 Impact Factor
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    ABSTRACT: Dietary polyamines contribute to the total body polyamine pool. As polyamines are important in health and disease, it is of interest to obtain information on the food polyamine content, making it possible to calculate and manipulate the polyamine intake. In this study, meat was found to contain considerably higher amounts of polyamines than fresh fish, though the levels in fish increased rapidly upon storage and processing. Whereas some cheeses were generally high in polyamines, the content in other dairy products was low. Most fruits and vegetables normally contained low levels of polyamines, although spermidine was high in broccoli and cauliflower, and putrescine in citrus fruits. Cooking did not significantly alter the polyamine concentration. From a sensory and a nutritious point of view, these results provide a means to compose a diet high or low in polyamines.
    Food Chemistry. 01/2002;
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    ABSTRACT: The aortic root from 21 LPA transgenic mice and 18 control litter mates on cholesterol enriched chow were studied histologically for the presence of atherosclerotic lesions. Serial sections were cut and the total area of the lesions was measured by use of computerised image analysis. Lipid staining lesions were found in 17 aortas of the transgenic mice and were five times more common than in the controls. Foam cell lesions were the only type of lesion in 12 of the aortas from transgenic animals, while five animals had developed fibrofatty lesions. Immunostaining revealed monocytes/macrophages on the endothelial surface, and in the subendothelial space of foam cell lesions. In fibrofatty lesions, spindle shaped cells formed a cap around the lipid core. This study supports the view that transgenic mice expressing human apolipoprotein (a) on a high fat and cholesterol diet, are more susceptible to aortic lesions than control mice and develop early atherosclerotic lesions comparable to lesions in man. Aminoguanidin in the drinking water had no effect on the aortic lesions, but lesion size was significantly, negatively correlated with plasma glucose concentration.
    Atherosclerosis 01/2001; 153(2):349-54. · 3.71 Impact Factor
  • K A Eliassen, O V Sjaastad
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    ABSTRACT: The aim of the present study was to investigate whether temporal changes in polyamine concentration and synthesis could be found in the luminal content and wall tissue of the rumen and abomasum, two organs which have entirely different growth patterns during the first month of life. In the abomasal mucosa there was a marked gradual decrease in the ornithine decarboxylase (ODC) activity during the first month of life, while the ODC activity in the ruminal mucosa was low during the whole experimental period. However, injury of the rumen wall was followed by increased ODC activity. The ODC activity in duodenal mucosa was about 10 times higher than in the ileal mucosa and the ruminal epithelium. In ruminal liquid a clear peak in ODC activity was observed during the period 51-70 days after birth. The polyamine concentration did not parallel the ODC activity, in either the ruminal epithelium or the ruminal liquid. Of the polyamines, the spermine concentration was always highest, and with the exception of duodenal mucosa, the putrescine concentration was lowest. In liver a clear decrease in spermidine concentration from day 1 to about day 60 after birth was observed. Otherwise no marked temporal changes in tissue polyamine concentrations were observed. Two and a half hours after oral administration of 14C-labelled spermine, nearly all of the radioactivity was found in the lumen of the gastrointestinal tract. On the other hand, 1 h after intravenous injection of polyamines the walls of the gastrointestinal tract were strongly labelled. In conclusion, the polyamines needed for ruminal epithelial development seem to come from sources other than the ruminal epithelium itself or the ruminal lumen.
    Journal of Veterinary Medicine Series A 07/2000; 47(5):297-310. · 0.93 Impact Factor
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    ABSTRACT: The activities of catalase, polyamine oxidase, diamine oxidase, ornithine decarboxylase, and peroxisomal beta-oxidation were assayed in homogenates from liver and small intestinal mucosa of rats which had been fed either a diet very low in polyamines or a diet containing five times the levels of dietary polyamines (putrescine, spermine, and spermidine) found in a standard rat diet. In rats fed the high polyamine diet, hepatic activities of catalase and polyamine oxidase were significantly decreased. Levels of the other activities were unchanged, except that intestinal ornithine decarboxylase was decreased. In rats treated simultaneously with clofibrate, the high polyamine diet restored activities of catalase, ornithine decarboxylase, and polyamine oxidase back to levels found in rats fed the low polyamine diet. The expected increase in activity of peroxisomal beta-oxidation was observed, although this was somewhat diminished in rats fed the high polyamine diet. Intestinal diamine oxidase activity was stimulated by clofibrate, particularly in rats fed the high polyamine diet. For the duration of the experiment (20 days), levels of putrescine, spermine, and spermidine in blood remained remarkably constant irrespective of treatment, suggesting that polyamine homeostasis is essentially independent of dietary supply of polyamines. It is suggested that intestinal absorption/metabolism of polyamines is of significance in this respect. Treatment with clofibrate appeared to alter polyamine homeostasis.
    The Journal of Nutritional Biochemistry 12/1999; 10(12):700-8. · 4.55 Impact Factor
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    ABSTRACT: We have examined whether dietary polyamines influence the formation and initial growth of azoxymethane (AOM)-induced aberrant crypt foci (ACF) in rat colon. Effects of a combination of dietary polyamines at three dose levels (putrescine: 50, 280, 740 nmol/g; spermidine: 10, 261, 763 nmol/g; spermine: 1, 31, 91 nmol/g) in the polyamine-poor AIN-76A diet were studied in animals in two different experimental situations: animals treated with AOM alone and animals treated with AOM + difluoromethylornithine (DFMO), a specific inhibitor of endogenous polyamine synthesis. In both experimental situations, dietary polyamines enhanced the growth of ACF, expressed as the number of large ACF (foci with three or more aberrant crypts, ACF > or = 3), whereas the formation of ACF, expressed as the number of ACF, was apparently not altered. In animals treated with AOM alone, maximal growth enhancing effect on ACF was nearly obtained with the median level of dietary polyamine. In rats fed a low polyamine diet, basic AIN-76A, DFMO reduced the growth of AOM-induced ACF by 83%. This inhibitory effect of DFMO was counteracted by dietary polyamines in a dose-dependent manner, and it was abolished at the highest level of polyamines. In conclusion, it was demonstrated that dietary polyamines are able to enhance the growth of AOM-induced ACF. Further, dietary polyamines reversed the DFMO-caused inhibition of ACF growth, probably by compensating for the DFMO-reduced endogenous polyamine synthesis.
    Carcinogenesis 10/1997; 18(10):1871-5. · 5.64 Impact Factor