Publications (3)5.17 Total impact
-
Article: Fenofibrate modulates cardiac and hepatic metabolism and increases ischemic tolerance in diet-induced obese mice.
[show abstract] [hide abstract]
ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) play an important role in the transcriptional regulation of lipid utilization and storage in several organs, including liver and heart. Our working hypothesis is that treatment of obesity/hyperlipedemia with the PPARalpha ligand fenofibrate leads to drainage of plasma lipids by the liver, resulting in reduced myocardial lipid supply, reduced myocardial fatty acid oxidation and improved myocardial tolerance to ischemic stress. Thus, we investigated changes in substrate utilization in heart and liver, as well as post-ischemic functional recovery in hearts from diet-induced obese (DIO) mice following long-term (11-12 weeks) treatment with fenofibrate. The present study shows that DIO mice express increased plasma lipids and glucose, as well as increased myocardial fatty acid oxidation and a concomitant decrease in glucose oxidation. The lipid-lowering effect of fenofibrate was associated with increased hepatic mitochondrial and peroxisomal fatty acid oxidation, as indicated by a more than 30% increase in hepatic palmiotyl-CoA oxidation and more than a 10-fold increase in acyl-CoA oxidase (ACO) activity. In line with an adaptation to the reduced myocardial lipid supply, isolated hearts from fenofibrate-treated DIO mice showed increased glucose oxidation and decreased fatty acid oxidation, as well as reduced ACO activity. Fenofibrate treatment also prevented the diet-induced decrease in cardiac function and improved post-ischemic functional recovery. We also found that, while fenofibrate treatment markedly increased the expression of PPARalpha target genes in the liver, there were no such changes in the heart. These data demonstrate that fenofibrate results in a direct activation of PPARalpha in the liver with increased hepatic drainage of plasma lipids, while the cardiac effect of the compound most likely is secondary to its lipid-lowering effect.Journal of Molecular and Cellular Cardiology 02/2008; 44(1):201-9. · 5.17 Impact Factor -
Article: Improved Cardiac Metabolism Following in Vivo Treatment of Type 2 Diabetic Mice with Fenofibrate Depends on Reduction of Plasma Lipids, as Well as Glucose
[show abstract] [hide abstract]
ABSTRACT: The plasma supply of energy substrates plays a key role in determining the cardiac metabolic phenotype. In diabetes, a high plasma supply of fatty acids (FA) leads to a predominant oxidation of FA for energy production, while glucose oxidation is markedly suppressed. The db/db mouse is a well accepted model of type 2 diabetes, showing hyperglycemia, hyperlipidemia, and hyperinsulinemia. Hearts from these mice exhibit altered substrate metabolism, characterized by an over-reliance on FA for energy production and low contribution of glucose. In the present study we tested whether the capacity for glucose utilization could be recovered in isolated working hearts from db/db mice following long-term (4 weeks) treatment with fenofibrate, using two different doses of the compound (0.1% and 0.2%, given as admixture to the diet). Mice treated with K-111 (a PPARα agonist, previously known as BM 17.0744) served as positive controls. In line with previous results, treatment with K-111 resulted in a significant reduction of the plasma concentrations of FA, triacylglycerol (TG) and glucose. Low-dose (0.1 %) fenofibrate treatment resulted in reduced plasma concentration of FA and TG, whereas the concentration of glucose was unaffected. With high-dose (0.2 %) fenofibrate, however, significant reductions of both lipids and glucose were obtained. Hearts from K-111-treated db/db mice showed a 74% decrease in FA oxidation and a near 2-fold increase in glucose oxidation. Treatment with low-dose fenofibrate failed to improve cardiac metabolism, whereas high-dose fenofibrate caused a similar shift in cardiac metabolism as seen with K-111. The alterations in cardiac metabolism were associated with changes in the myocardial and hepatic expression of PPARα-regulated target genes. These results indicate that reduction of plasma lipids alone is not sufficient for improving cardiac metabolism in diabetes, and that reduction of plasma glucose is also required. This article is part of Ahmed M. Khalid's PhD thesis, which is available in Munin: http://hdl.handle.net/10037/1802 -
Article: Treatment of obesity and type 2 diabetes with PPARα agonists – effects on myocardial metabolism, gene expression and ventricular function
[show abstract] [hide abstract]
ABSTRACT: Hos diabetikere fører mangel på insulin og/eller nedsatt følsomhet for insulin i vevene til at konsentrasjonen av glukose og fettsyrer i blodet stiger til svært høye verdier. Det diabetiske hjertet kan bare i svært liten grad nyttiggjøre seg glukose, og energiproduksjonen tilpasses derfor forbrenning av fettsyrer. Opptaket av fettsyrer kan imidlertid bli høyere enn forbrenningen, slik at det over tid avleires fettstoffer i hjertemuskelen som i neste omgang vil svekke hjertets pumpefunksjon. Hovedspørsmålet som stilles i avhandlingen er om behandling med medikamenter (såkalte PPARα agonister, som binder seg til spesifikke reseptorer i cellekjernen og påvirker aktiviteten av viktige enzymer i stoffskifteveiene) kan forhindre den ensidige forbrenningen av fett og gjenopprette hjertets evne til å forbrenne glukose. Vi behandlet overvektige og type 2 diabetiske mus med to ulike medikamenter, fenofibrat eller TTA (en kunstig fremstilt svovelholdig fettsyre) over en periode på opptil ti uker. Etter endt behandling ble det tatt blodprøver, og vi målte i tillegg hjertets pumpekraft og forbrenning av fettsyrer og glukose. Vi fant at begge stoffene reduserte innholdet av fettstoffer i blodet på grunn av økt opptak og forbrenning i leveren, og i tillegg falt konsentrasjonen av glukose - trolig som følge av bedret insulinfølsomhet. Behandlingen med fenofibrat reduserte fettforbrenningen i hjertemuskelen, samtidig som evnen til å forbrenne glukose ble bedret. Disse endringene hadde en oksygensparende effekt, slik at hjertet arbeidet mer effektivt. Behandlingen med TTA førte derimot til at den høye fettforbrenningen i de diabetiske hjertene ble ytterligere økt, uten at oksygenforbruket ble nevneverdig påvirket. De diabetiske hjertene hadde også god pumpefuksjon etter forbigående oksygenmangel, noe som sannsynligvis kan tilskrives anti-oksidative/anti-inflammatoriske effekter av stoffet. Samlet viser resultatene at endringene i hjertets energiomsetning som følge av diabetes kan forebygges med medikamenter som senker innholdet av fettstoffer i blodet. Paper 1 of the thesis is not available in Munin, due to publisher's restrictions. Paper 2, 3 and 4 was unpublished at the time the thesis was included in Munin, and are not available in Munin: 1. Aasum E, Khalid AM, Gudbrandsen OA, How OJ, Berge RK and Larsen TS. "Fenofibrate modulates cardiac and hepatic metabolism and increases ischemic tolerance in diet-induced obese mice." Journal of Molecular and Cellular Cardiology Volume 44, Issue 1, January 2008, Pages 201-209. (Elsevier) Available at http://dx.doi.org/10.1016/j.yjmcc.2007.08.020 2. Khalid AM, Aasum E, Hafstad AD, Lund T, Severson DL and Larsen TS. "Improved cardiac metabolism following in vivo treatment of type 2 diabetic mice with fenofibrate depends on reduction of plasma lipids, as well as glucose." (Submitted) 3. Hafstad AD, Khalid AM, Hagve M, Lund T, Larsen TS, Severson DL, Clarke K, Berge RK and Aasum E. "Administration of tetradecylthioacetic acid (TTA) stimulates myocardial fatty acid oxidation despite having a lipid-lowering effect." (Submitted) 4. Khalid AM, Hafstad AD, Larsen TS, Severson DL, Boardman N, Hagve M, Lund T, Berge RK and Aasum E. "Cardioprotective effect of the pan PPAR ligand tetradechylthioacetic acid (TTA) in type 2 diabetic hearts." (Manuscript)
