Ceramide inhibitor myriocin restores insulin/insulin growth factor signaling for liver remodeling in experimental alcohol-related steatohepatitis.
Ceramide inhibitor myriocin restores insulin/insulin growth factor signaling for liver remodeling in experimental alcohol-related steatohepatitis.
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DOI：
10.1111/jgh.12291
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发表时间：
2013-10
影响因子：
4.1
通讯作者：
de la Monte SM
中科院分区：
文献类型：
--
作者：
Lizarazo D;Zabala V;Tong M;Longato L;de la Monte SM
酒精相关性肝病（ALD）部分由胰岛素抵抗介导。伴随的脂质代谢失调增加肝神经酰胺的积累，其恶化胰岛素抵抗并损害肝脏的结构和功能完整性。胰岛素和胰岛素生长因子（IGF）刺激乙酰天冬酰胺酰-β-羟化酶（AAH），促进肝脏结构维持和重塑所需的细胞运动。AAH通过激活Notch介导其作用，并且在ALD中，胰岛素/IGF信号传导、AAH和Notch被抑制。为了检验ALD中肝神经酰胺负荷导致胰岛素、AAH和Notch信号传导受损的假设，对照和慢性乙醇喂养的成年Long-Evans大鼠用丝氨酸棕榈酰转移酶抑制剂多球壳菌素治疗。肝脏用于评估脂肪性肝炎、胰岛素/IGF途径活化和AAH-Notch信号传导分子的表达。慢性乙醇喂养大鼠出现脂肪性肝炎，神经酰胺水平升高;胰岛素受体、胰岛素受体底物和Akt信号传导受损; AAH、Notch、Jagged、分裂1的毛发增强子、低氧诱导因子1α和增殖细胞核抗原表达降低。多粒壳菌素消除了乙醇的许多这些不良作用，特别是肝神经酰胺积累、脂肪性肝炎和通过Akt、AAH和Notch的胰岛素信号传导的损伤。在ALD中，组织病理学和胰岛素/IGF反应性的损伤可以通过神经酰胺抑制剂治疗基本上解决，即使在持续慢性乙醇暴露的情况下。
Alcohol-related liver disease (ALD) is mediated in part by insulin resistance. Attendant dysregulation of lipid metabolism increases accumulation of hepatic ceramides that worsen insulin resistance and compromise the structural and functional integrity of the liver. Insulin and insulin growth factor (IGF) stimulate aspartyl-asparaginyl-β-hydroxylase (AAH), which promotes cell motility needed for structural maintenance and remodeling of the liver. AAH mediates its effects by activating Notch, and in ALD, insulin/IGF signaling, AAH, and Notch are inhibited. To test the hypothesis that in ALD, hepatic ceramide load contributes to impairments in insulin, AAH, and Notch signaling, control and chronic ethanol-fed adult Long–Evans rats were treated with myriocin, an inhibitor of serine palmitoyl transferase. Livers were used to assess steatohepatitis, insulin/IGF pathway activation, and expression of AAH–Notch signaling molecules. Chronic ethanol-fed rats had steatohepatitis with increased ceramide levels; impairments in signaling through the insulin receptor, insulin receptor substrate, and Akt; and decreased expression of AAH, Notch, Jagged, Hairy–Enhancer of Split-1, hypoxiainducible factor 1α, and proliferating cell nuclear antigen. Myriocin abrogated many of these adverse effects of ethanol, particularly hepatic ceramide accumulation, steatohepatitis, and impairments of insulin signaling through Akt, AAH, and Notch. In ALD, the histopathology and impairments in insulin/IGF responsiveness can be substantially resolved by ceramide inhibitor treatments, even in the context of continued chronic ethanol exposure.