Baranowski Marcin, Blachnio Agnieszka, Zabielski Piotr, Gorski Jan
Department of Physiology, Medical University of Bialystok, Mickiewicza 2c, 15-230 Bialystok, Poland.
Prostaglandins Other Lipid Mediat. 2007 Feb;83(1-2):99-111. doi: 10.1016/j.prostaglandins.2006.10.004. Epub 2006 Nov 16.
Ceramide (CER) is an important mediator of lipotoxicity in the heart. It was found that Zucker diabetic fatty rats develop an age-dependent accumulation of myocardial CER leading to cardiomyocyte apoptosis. However, administration of peroxisome proliferator-activated receptor (PPAR) gamma agonist decreased the content of CER and prevented cardiomyocyte apoptosis [Zhou et al. Proc Natl Acad Sci USA 2000;97:1784-9]. These data suggest that PPARgamma activators affect myocardial CER metabolism. Therefore, the aim of our study was to examine the effects of pioglitazone, a selective PPARgamma agonist, on the content of CER and its metabolites and on the activity of key enzymes of CER metabolism in the heart. The experiments were conducted on rats fed either a standard chow (STD) or a high-fat diet (HFD) for 21 days. Each group was divided into two subgroups: control and treated with pioglitazone for 14 days. Surprisingly, administration of PPARgamma agonist significantly increased myocardial CER content in both STD and HFD rats. In the latter group an elevation in the amount of sphingomyelin was also observed. In STD rats pioglitazone treatment increased the activity of neutral sphingomyelinase and acid ceramidase. However, in HFD group the compound did not affect the activity of the aforementioned enzymes. Interestingly, the activity of serine palmitoyltransferase in both STD and HFD rats increased two-fold after pioglitazone treatment. We conclude that pioglitazone induced accumulation of CER in rat myocardium as a result of augmented CER synthesis de novo. However, in the STD group increased activity of neutral sphingomyelinase could also contributed to this effect.
神经酰胺（CER）是心脏脂毒性的重要介质。研究发现，Zucker糖尿病肥胖大鼠心肌中CER随年龄增长而蓄积，导致心肌细胞凋亡。然而，给予过氧化物酶体增殖物激活受体（PPAR）γ激动剂可降低CER含量并预防心肌细胞凋亡[Zhou等人，《美国国家科学院院刊》2000年；97:1784 - 9]。这些数据表明PPARγ激活剂会影响心肌CER代谢。因此，我们研究的目的是检测选择性PPARγ激动剂吡格列酮对心脏中CER及其代谢产物含量以及CER代谢关键酶活性的影响。实验在喂食标准饲料（STD）或高脂饮食（HFD）21天的大鼠身上进行。每组再分为两个亚组：对照组和接受吡格列酮治疗14天的组。令人惊讶的是，给予PPARγ激动剂后，STD和HFD大鼠的心肌CER含量均显著增加。在后一组中，还观察到鞘磷脂量的升高。在STD大鼠中，吡格列酮治疗增加了中性鞘磷脂酶和酸性神经酰胺酶的活性。然而，在HFD组中，该化合物并未影响上述酶的活性。有趣的是，吡格列酮治疗后，STD和HFD大鼠的丝氨酸棕榈酰转移酶活性均增加了两倍。我们得出结论，吡格列酮诱导大鼠心肌中CER蓄积是由于从头合成CER增加所致。然而，在STD组中，中性鞘磷脂酶活性增加也可能促成了这一效应。
