Endotoxin and cytokines increase hepatic sphingolipid biosynthesis and produce lipoproteins enriched in ceramides and sphingomyelin
Endotoxin and cytokines increase hepatic sphingolipid biosynthesis and produce lipoproteins enriched in ceramides and sphingomyelin
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DOI：
10.1161/01.atv.18.8.1257
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发表时间：
1998-08-01
影响因子：
8.7
通讯作者：
Feingold, KR
中科院分区：
文献类型：
--
作者：
Memon, RA;Holleran, WM;Feingold, KR
甘油三酯和胆固醇代谢的改变通常伴随炎性疾病和感染。我们研究了内毒素（脂多糖[LPS]）和细胞因子对叙利亚仓鼠肝鞘脂合成，丝氨酸棕榈酰转移酶（SPT），鞘脂合成的第一和限速酶，脂蛋白鞘脂含量的活性的影响。给予LPS诱导肝脏SPT活性增加2倍。活性的增加首先发生在16小时，在24小时达到峰值，并持续至少48小时。低剂量的LPS使SPT活性产生最大增加，在接近0.3 μ g LPS/100 g体重时观察到半数最大效应。LPS使肝脏SPT mRNA水平增加2倍，表明SPT活性的增加是由于SPT mRNA的增加。脂多糖治疗也产生了75%和2.5倍的增加，肝鞘磷脂和神经酰胺的合成，分别。LPS的许多代谢作用由细胞因子介导。白细胞介素1（IL-1），但不是肿瘤坏死因子，增加SPT的活性和mRNA水平：在完整的动物的肝脏，而IL-1和肿瘤坏死因子增加SPTmRNA水平在HepG 2细胞。IL-1使HepG 2细胞中SPT mRNA增加3倍，半数最大剂量为2 ng/mL。IL-1还增加鞘脂分泌到培养基中。血清脂蛋白组分的分析表明，极低密度脂蛋白，中密度脂蛋白，低密度脂蛋白与LPS治疗的动物分离含有显着更高的量的神经酰胺，葡萄糖神经酰胺，鞘磷脂。总之，这些结果表明，LPS和细胞因子刺激肝鞘脂合成，这导致循环脂蛋白的结构改变，并可能促进动脉粥样硬化形成。
Alterations in triglyceride and cholesterol metabolism often accompany inflammatory diseases and infections. We studied the effects of endotoxin (lipopolysaccharide [LPS]) and cytokines on hepatic sphingolipid synthesis, activity of serine palmitoyltransferase (SPT), the first and rate-limiting enzyme in sphingolipid synthesis, and lipoprotein sphingolipid content in Syrian hamsters. Administration of LPS induced a 2-fold increase in hepatic SPT activity. The increase in activity first occurred at 16 hours, peaked at 24 hours, and was sustained for at least 48 hours. Low doses of LPS produced maximal increases in SPT activity, with half-maximal effect seen at approximate to 0.3 mu g LPS/100 g body weight. LPS increased hepatic SPT mRNA levels 2-fold, suggesting that the increase in SPT activity was due to an increase in SPT mRNA. LPS treatment also produced 75% and 2.5-fold increases in hepatic sphingomyelin and ceramide synthesis, respectively. Many of the metabolic effects of LPS are mediated by cytokines. Interleukin 1 (IL-1), but not tumor necrosis factor, increased both SPT activity and mRNA levels in the :liver of intact animals, whereas both IL-1 and tumor necrosis factor increased SPT mRNA levels in HepG2 cells. IL-1 produced a 3-fold increase in SPT rnRNA in HepG2 cells, and the half-maximal dose was 2 ng/mL. IL-1 also increased the secretion of sphingolipids into the medium. Analysis of serum lipoprotein fractions demonstrated that very low density lipoprotein, intermediate density lipoprotein, and low density lipoprotein isolated from animals treated with LPS contained significantly higher amounts of ceramide, glucosylceramide, and sphingomyelin. Taken together, these results indicate that LPS and cytokines stimulate hepatic sphingolipid synthesis, which results in an altered structure of circulating lipoproteins and may promote atherogenesis.