Department of Physiology, Monash University, Building 13F, Clayton, VIC, 3800, Australia.
Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia.
Diabetologia. 2012 Oct;55(10):2741-2746. doi: 10.1007/s00125-012-2649-3. Epub 2012 Jul 27.
AIMS/HYPOTHESIS: Plasma ceramide concentrations correlate with insulin sensitivity, inflammation and atherosclerotic risk. We hypothesised that plasma ceramide concentrations are increased in the presence of elevated fatty acid levels and are regulated by increased liver serine C-palmitoyltransferase (SPT) activity.
Lean humans and rats underwent an acute lipid infusion and plasma ceramide levels were determined. One group of lipid-infused rats was administered myriocin to inhibit SPT activity. Liver SPT activity was determined in lipid-infused rats, and obese, insulin resistant mice. The time and palmitate dose-dependent synthesis of intracellular and secreted ceramide was determined in HepG2 liver cells.
Plasma ceramide levels were increased during lipid infusion in humans and rats, and in obese, insulin-resistant mice. The increase in plasma ceramide was not associated with changes in liver SPT activity, and inhibiting SPT activity by ~50% did not alter plasma ceramide levels in lipid-infused rats. In HepG2 liver cells, palmitate incorporation into extracellular ceramide was both dose- and time-dependent, suggesting the liver cells rapidly secreted the newly synthesised ceramide.
CONCLUSIONS/INTERPRETATION: Elevated systemic fatty acid availability increased plasma ceramide but this was not associated with changes in hepatic SPT activity, suggesting that liver ceramide synthesis is driven by substrate availability rather than increased SPT activity. This report also provides evidence that the liver is sensitive to the intracellular ceramide concentration, and an increase in liver ceramide secretion may help protect the liver from the deleterious effects of intracellular ceramide accumulation.
目的/假设：血浆神经酰胺浓度与胰岛素敏感性、炎症和动脉粥样硬化风险相关。我们假设，在脂肪酸水平升高的情况下，血浆神经酰胺浓度升高，并受肝脏丝氨酸 C-棕榈酰转移酶（SPT）活性增加的调节。
瘦人及大鼠接受急性脂质输注，测定血浆神经酰胺水平。一组脂质输注大鼠给予霉菌素来抑制 SPT 活性。测定脂质输注大鼠、肥胖、胰岛素抵抗小鼠的肝脏 SPT 活性。在 HepG2 肝细胞中测定细胞内和分泌性神经酰胺的时间和棕榈酸剂量依赖性合成。
在人类和大鼠脂质输注期间以及肥胖、胰岛素抵抗小鼠中，血浆神经酰胺水平升高。血浆神经酰胺的增加与肝脏 SPT 活性的变化无关，并且抑制 SPT 活性约 50%不会改变脂质输注大鼠的血浆神经酰胺水平。在 HepG2 肝细胞中，棕榈酸掺入细胞外神经酰胺呈剂量和时间依赖性，表明肝细胞迅速分泌新合成的神经酰胺。
结论/解释：全身性脂肪酸可用性增加会增加血浆神经酰胺，但这与肝 SPT 活性的变化无关，表明肝神经酰胺合成是由底物可用性驱动的，而不是 SPT 活性增加。本报告还提供了证据表明肝脏对细胞内神经酰胺浓度敏感，增加肝脏神经酰胺分泌可能有助于保护肝脏免受细胞内神经酰胺积累的有害影响。
