Antagonism of peripheral hepatic cannabinoid receptor-1 improves liver lipid metabolism in mice: Evidence from cultured explants
Antagonism of peripheral hepatic cannabinoid receptor-1 improves liver lipid metabolism in mice: Evidence from cultured explants
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DOI：
10.1002/hep.24733
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发表时间：
2012-03-01
期刊：
影响因子：
13.5
通讯作者：
Degrace, Pascal
中科院分区：
文献类型：
--
作者：
Jourdan, Tony;Demizieux, Laurent;Degrace, Pascal
已经确定，通过拮抗大麻素受体1（CB 1 R）使中枢内源性大麻素系统（ECS）失活可减少食物摄入并改善与肥胖相关的几种病理特征，如血脂异常和肝脏脂肪变性。然而，最近的数据表明，外周CB 1 R的失活也可以直接参与控制脂质代谢的中央CB 1 R独立。为了进一步研究这一概念，我们使用培养的肝脏切片测试了特异性CB 1 R拮抗剂SR 141716对肝脏碳水化合物和脂质代谢的直接影响。SR 141716强烈降低CB 1 R信使RNA表达，而CB 1 R激动剂花生四烯酸N-羟乙基酰胺（AEA）则增加CB 1 R信使RNA表达，表明治疗在调节瘦小鼠或ob/ob小鼠肝外植体中ECS活性方面的有效性。O2消耗的测量结果显示，根据细胞激素环境，SR 141716增加了碳水化合物或脂肪酸的利用。与此一致，SR 141716刺激β-氧化活性，当ECS被AEA过度激活时和在ob/ob组织中，CB 1 R在调节该途径中的作用特别突出。SR 141716还改善了碳水化合物和脂质代谢，减弱了AEA诱导的脂肪生成相关蛋白质基因表达的增加。此外，我们发现SR 141716诱导胆固醇从头合成和高密度脂蛋白摄取，揭示了CB 1 R和胆固醇代谢之间的关系。结论：这些数据表明，阻断肝脏CB 1 R可以改善碳水化合物和脂质代谢，并证实外周CB 1 R应被视为降低肥胖患者心脏代谢风险的有希望的靶点。（肝脏学2011）
It is well established that inactivation of the central endocannabinoid system (ECS) through antagonism of cannabinoid receptor 1 (CB1R) reduces food intake and improves several pathological features associated with obesity, such as dyslipidemia and liver steatosis. Nevertheless, recent data indicate that inactivation of peripheral CB1R could also be directly involved in the control of lipid metabolism independently of central CB1R. To further investigate this notion, we tested the direct effect of the specific CB1R antagonist, SR141716, on hepatic carbohydrate and lipid metabolism using cultured liver slices. CB1R messenger RNA expression was strongly decreased by SR141716, whereas it was increased by the CB1R agonist, arachidonic acid N-hydroxyethylamide (AEA), indicating the effectiveness of treatments in modulating ECS activity in liver explants both from lean or ob/ob mice. The measurement of O2 consumption revealed that SR141716 increased carbohydrate or fatty acid utilization, according to the cellular hormonal environment. In line with this, SR141716 stimulated beta-oxidation activity, and the role of CB1R in regulating this pathway was particularly emphasized when ECS was hyperactivated by AEA and in ob/ob tissue. SR141716 also improved carbohydrate and lipid metabolism, blunting the AEA-induced increase in gene expression of proteins related to lipogenesis. In addition, we showed that SR141716 induced cholesterol de novo synthesis and high-density lipoprotein uptake, revealing a relationship between CB1R and cholesterol metabolism. Conclusion: These data suggest that blocking hepatic CB1R improves both carbohydrate and lipid metabolism and confirm that peripheral CB1R should be considered as a promising target to reduce cardiometabolic risk in obesity. (HEPATOLOGY 2011)