Inhibition of Hepatic Bile Acid Uptake by Myrcludex B Promotes Glucagon-Like Peptide-1 Release and Reduces Obesity.,Cellular and Molecular Gastroenterology and Hepatology

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Inhibition of Hepatic Bile Acid Uptake by Myrcludex B Promotes Glucagon-Like Peptide-1 Release and Reduces Obesity.
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2020-04-21 , DOI: 10.1016/j.jcmgh.2020.04.009
Joanne M Donkers ₁ , Reinout L P Roscam Abbing ₁ , Michel van Weeghel ₂ , Johannes H M Levels ₃ , Anita Boelen ₄ , Alfred H Schinkel ₅ , Ronald P J Oude Elferink ₆ , Stan F J van de Graaf ₆

Affiliation

Background & Aims

Bile acids are important metabolic signaling molecules. Bile acid receptor activation promotes body weight loss and improves glycemic control. The incretin hormone GLP-1 and thyroid hormone activation of T4 to T3 have been suggested as important contributors. Here, we identify the hepatic bile acid uptake transporter Na⁺ taurocholate co-transporting polypeptide (NTCP) as target to prolong postprandial bile acid signaling.

Methods

Organic anion transporting polypeptide (OATP)1a/1b KO mice with or without reconstitution with human OATP1B1 in the liver were treated with the NTCP inhibitor Myrcludex B for 3.5 weeks after the onset of obesity induced by high fat diet-feeding. Furthermore, radiolabeled T4 was injected to determine the role of NTCP and OATPs in thyroid hormone clearance from plasma.

Results

Inhibition of NTCP by Myrcludex B in obese Oatp1a/1b KO mice inhibited hepatic clearance of bile acids from portal and systemic blood, stimulated GLP-1 secretion, reduced body weight, and decreased (hepatic) adiposity. NTCP inhibition did not affect hepatic T4 uptake nor lead to increased thyroid hormone activation. Myrcludex B treatment increased fecal energy output, explaining body weight reductions amongst unaltered food intake and energy expenditure.

Conclusions

Pharmacologically targeting hepatic bile acid uptake to increase bile acid signaling is a novel approach to treat obesity and induce GLP1- secretion.

中文翻译：

Myrcludex B 抑制肝胆汁酸摄取促进胰高血糖素样肽-1 释放并减少肥胖。

背景与目标

胆汁酸是重要的代谢信号分子。胆汁酸受体激活可促进体重减轻并改善血糖控制。肠促胰岛素激素 GLP-1 和 T4 至 T3 的甲状腺激素激活已被认为是重要的贡献者。在这里，我们确定肝胆汁酸摄取转运蛋白 Na ⁺牛磺胆酸共转运多肽 (NTCP) 作为延长餐后胆汁酸信号传导的目标。

方法

有机阴离子转运多肽 (OATP)1a/1b KO 小鼠在肝脏中重组或未重组人 OATP1B1 后，在高脂肪饮食诱导肥胖发作后，用 NTCP 抑制剂 Myrcludex B 治疗 3.5 周。此外，注射放射性标记的 T4 以确定 NTCP 和 OATP 在从血浆中清除甲状腺激素中的作用。

结果

Myrcludex B 在肥胖 Oatp1a/1b KO 小鼠中抑制 NTCP 抑制了肝脏从门静脉和全身血液中清除胆汁酸，刺激 GLP-1 分泌，减轻体重，并减少（肝脏）肥胖。NTCP 抑制不影响肝脏 T4 摄取，也不导致甲状腺激素激活增加。Myrcludex B 治疗增加了粪便能量输出，解释了在食物摄入和能量消耗不变的情况下体重减轻。