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Teneligliptin Promotes Bile Acid Synthesis and Attenuates Lipid Accumulation in Obese Mice by Targeting the KLF15-Fgf15 Pathway.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-07-08 , DOI: 10.1021/acs.chemrestox.0c00192
Guang Wang 1 , Bing Wu 2 , Yang Cui 3 , Bo Zhang 4 , Chunyan Jiang 5 , Heyuan Wang 6
Affiliation  

Bile acids (BAs) play essential physiological roles not only by facilitating the absorption and transport of nutrients but also by acting as a complex molecular signaling system. Reduced levels of BAs have been observed in obesity and other metabolic disorders. In the present study, we explored the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin on BA synthesis, both in vitro and in vivo. In our in vivo experiments, we found that teneligliptin increased the liver, ileal, and serum BA concentrations in mice undergoing teneligliptin treatment for 10 weeks. We further found that in mice fed a high-fat diet, teneligliptin prevented an increase in markers of obesity (body weight, total cholesterol, total triglyceride, adipocyte size) while increasing the total serum and ileal levels of BA. Mechanistically, teneligliptin increased BA synthesis through the alternative synthesis pathway, as the levels of both 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1) along with downstream oxysterol 7α-hydroxylase (CYP7B1) but not sterol 12α-hydroxylase (CYP8B1) were increased. Importantly, teneligliptin suppressed the expression of the BA synthesis inhibitory factor Fgf15, which was mediated through phosphatidylinositol 3-kinase (PI3K)/AKT/Krüppel-like factor 15 (KLF15) signaling. Inhibition of KLF15 abolished this effect. Together, our results provide evidence of the potential benefit of teneligliptin in the treatment of metabolic disorders via increased BA production.

中文翻译:

Teneligliptin 通过靶向 KLF15-Fgf15 通路促进胆汁酸合成并减弱肥胖小鼠的脂质积累。

胆汁酸 (BAs) 不仅通过促进营养物质的吸收和运输,而且作为复杂的分子信号系统发挥重要的生理作用。在肥胖和其他代谢紊乱中观察到 BA 水平降低。在本研究中,我们在体外体内探索了二肽基肽酶-4 (DPP-4) 抑制剂特力列汀对 BA 合成的影响。在我们体内实验中,我们发现特力列汀增加了接受特力列汀治疗 10 周的小鼠的肝脏、回肠和血清 BA 浓度。我们进一步发现,在喂食高脂肪饮食的小鼠中,特力列汀可防止肥胖标志物(体重、总胆固醇、总甘油三酯、脂肪细胞大小)的增加,同时增加 BA 的总血清和回肠水平。从机制上讲,特力列汀通过替代合成途径增加了 BA 的合成,因为 7α-羟化酶 (CYP7A1) 和甾醇 27-羟化酶 (CYP27A1) 以及下游氧甾醇 7α-羟化酶 (CYP7B1) 的水平,而不是甾醇 12α-羟化酶 (CYP8B1)增加了。重要的是,特力列汀抑制了 BA 合成抑制因子 Fgf15 的表达,该因子通过磷脂酰肌醇 3-激酶 (PI3K)/AK 介导T /Krüppel 样因子 15 (KLF15) 信号。KLF15 的抑制消除了这种效果。总之,我们的结果提供了证据,证明了特力列汀通过增加 BA 产量治疗代谢紊乱的潜在益处。
更新日期:2020-08-17
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