Hepatic cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing de novo synthesis of long-chain ceramides.
Hepatic cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing de novo synthesis of long-chain ceramides.
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DOI：
10.1002/hep.26606
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发表时间：
2014-01
期刊：
影响因子：
13.5
通讯作者：
Kunos, George
中科院分区：
文献类型：
--
作者：
Cinar, Resat;Godlewski, Grzegorz;Liu, Jie;Tam, Joseph;Jourdan, Tony;Mukhopadhyay, Bani;Harvey-White, Judith;Kunos, George
肥胖与两种脂质信号系统-内源性大麻素（EC）和神经酰胺-的活性增加有关，两者都与胰岛素抵抗有关。大麻素-1受体（CB 1 R）拮抗剂逆转肥胖和胰岛素抵抗，但有精神副作用。在这里，我们分析了神经酰胺在CB 1 R介导的胰岛素抵抗中的作用，在C57 B16/J小鼠高脂饮食诱导的肥胖症（DIO），使用JD 5037，外周限制CB 1 R反向激动剂。DIO小鼠的长期JD 5037治疗减轻了体重和脂肪变性，并改善了葡萄糖耐量和胰岛素敏感性。外周CB 1 R阻断还减弱了肝脏中C16或C18鞘氨醇碱引起的C14：0、C16：0、C18：0和C20：0神经酰胺物质的饮食诱导增加。神经酰胺水平的降低反映了其从头合成的减少，这是由于丝氨酸-棕榈酰转移酶（SPT）的活性及其SPTLC 3催化亚基的表达受到抑制，以及与CerS 1和CerS 6表达减少相关的神经酰胺合酶（CerS）活性降低。JD 5037处理还由于神经酰胺酶的表达增加而增加神经酰胺降解。在原代培养的小鼠肝细胞和HepG 2细胞中，EC anandamine以eIF 2 α依赖性方式增加神经酰胺合成，并通过增加IRS 1的丝氨酸磷酸化和增加丝氨酸/苏氨酸磷酸酶Phlpp 1的表达来抑制胰岛素诱导的akt磷酸化。这些作用被JD 5037或SPT抑制剂myriocin消除。用多球壳菌素或JD 5037慢性治疗DIO小鼠类似地逆转了肝脏胰岛素抵抗，如使用正常血糖/高胰岛素钳夹所验证的。结论：内皮细胞诱导CB 1 R介导的，ER应激依赖性的特定神经酰胺亚型在肝脏中的合成，这在肥胖相关的肝脏胰岛素抵抗中起着关键作用。
Obesity is associated with increased activity of two lipid signaling systems - endocannabinoids (ECs) and ceramides – with both being implicated in insulin resistance. Cannabinoid-1 receptor (CB1R) antagonists reverse obesity and insulin resistance, but have psychiatric side effects. Here we analyzed the role of ceramide in CB1R-mediated insulin resistance in C57Bl6/J mice with high-fat diet-induced obesity (DIO), using JD5037, a peripherally restricted CB1R inverse agonist. Chronic JD5037 treatment of DIO mice reduced body weight and steatosis, and improved glucose tolerance and insulin sensitivity. Peripheral CB1R blockade also attenuated the diet-induced increase in C14:0, C16:0, C18:0 and C20:0 ceramide species with either C16 or C18 sphingosine-base in the liver. Decreased ceramide levels reflected their reduced de novo synthesis, due to inhibition of the activity of serine-palmitoyl transferase (SPT) and the expression of its SPTLC3 catalytic subunit, as well as reduced ceramide synthase (CerS) activity related to reduced expression of CerS1 and CerS6. JD5037 treatment also increased ceramide degradation due to increased expression of ceramidases. In primary cultured mouse hepatocytes and HepG2 cells, the EC anandamide increased ceramide synthesis in an eIF2α-dependent manner, and inhibited insulin-induced akt phosphorylation by increased serine phosphorylation of IRS1 and increased expression of the serine/threonine phosphatase Phlpp1. These effects were abrogated by JD5037 or the SPT inhibitor myriocin. Chronic treatment of DIO mice with myriocin or JD5037 similarly reversed hepatic insulin resistance, as verified using a euglycemic/hyperinsulinemic clamp. Conclusions: ECs induce CB1R-mediated, ER stress-dependent synthesis of specific ceramide subspecies in the liver, which plays a key role in obesity-related hepatic insulin resistance.
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影响因子：
4.5
作者：
Hicks AA;Pramstaller PP;Johansson A;Vitart V;Rudan I;Ugocsai P;Aulchenko Y;Franklin CS;Liebisch G;Erdmann J;Jonasson I;Zorkoltseva IV;Pattaro C;Hayward C;Isaacs A;Hengstenberg C;Campbell S;Gnewuch C;Janssens AC;Kirichenko AV;König IR;Marroni F;Polasek O;Demirkan A;Kolcic I;Schwienbacher C;Igl W;Biloglav Z;Witteman JC;Pichler I;Zaboli G;Axenovich TI;Peters A;Schreiber S;Wichmann HE;Schunkert H;Hastie N;Oostra BA;Wild SH;Meitinger T;Gyllensten U;van Duijn CM;Wilson JF;Wright A;Schmitz G;Campbell H
通讯作者：
Campbell H
影响因子：
29.4
作者：
Fabbrini E;Tamboli RA;Magkos F;Marks-Shulman PA;Eckhauser AW;Richards WO;Klein S;Abumrad NN
通讯作者：
Abumrad NN
影响因子：
4.8
作者：
Chalfant, CE;Kishikawa, K;Hannun, YA
通讯作者：
Hannun, YA
DOI：
10.1111/j.1872-034x.2011.00934.x
发表时间：
2012-04
期刊：
Hepatology research : the official journal of the Japan Society of Hepatology
影响因子：
--
作者：
Longato L;Tong M;Wands JR;de la Monte SM
通讯作者：
de la Monte SM
影响因子：
4.1
作者：
del Pulgar, TG;Velasco, G;Guzmán, M
通讯作者：
Guzmán, M