GR113808, a serotonin receptor 4 antagonist, prevents high-fat-diet-induced obesity, fatty liver formation, and insulin resistance in C57BL/6J mice.

IF 2.8 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Min Hee Kim, Su-Jeong Kim, Woo-Jae Park, Dae Ho Lee, Kyoung-Kon Kim
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Abstract

Background: The burden of nonalcoholic fatty liver disease is increasing, and limited therapeutic drugs are available for its treatment. Serotonin binds to approximately 14 serotonin receptors (HTR) and plays diverse roles in obesity and metabolic complications. In this study, we focused on the function of HTR4 on nonalcoholic fatty liver disease using GR113808, a selective HTR4 antagonist.

Methods: Male C57BL/6J mice were fed high-fat diet for 12 weeks with intraperitoneal GR113808 injection, and HTR expression, weight changes, glucose and lipid metabolism, hepatic fat accumulation, changes in adipose tissue, the changes in transcriptional factors of signaling pathways, and inflammations were assessed. Hep3B cells and 3T3-L1 cells were treated with siRNA targeting HTR4 to downregulate its expression and then cultured with palmitate to mimic a high-fat diet. The changes in transcriptional factors of signaling pathways, and inflammations were assessed in those cells.

Results: After feeding a high-fat diet to male C57BL/6J mice, HTR4 expression in the liver and adipose tissues decreased. GR113808 suppressed body weight gain and improved glucose intolerance. Furthermore, GR113808 not only decreased fatty liver formation but also reduced adipose tissue size. Additionally, GR113808 reduced inflammatory cytokine serum levels and inflammasome complex formation in both tissues. Palmitate treatment in HTR4-downregulated Hep3B cells, also reduced peroxisome proliferator-activated receptor γ and sterol regulatory element-binding protein-1 pathway induction as well as inflammasome complex formation, thus decreasing inflammatory cytokine levels. HTR4 downregulation in 3T3-L1 cells also reduced palmitate-induced inflammasome complex formation and inflammatory cytokine production. Palmitate-induced insulin resistance in Hep3B cells, but not in 3T3-L1 cells, was improved by HTR4 downregulation.

Conclusions: In summary, GR113808 protected against fatty liver formation and improved inflammation in the liver and adipose tissue. Downregulation of HTR4 ameliorated insulin resistance in the liver. These results suggest that HTR4 could serve as a promising therapeutic target for metabolic diseases.

GR113808是一种5-羟色胺受体4拮抗剂,可防止高脂饮食引起的C57BL/6J小鼠肥胖、脂肪肝形成和胰岛素抵抗。
背景:非酒精性脂肪肝的负担日益加重,而可用于治疗的药物却十分有限。羟色胺与大约 14 种羟色胺受体(HTR)结合,在肥胖和代谢并发症中发挥着多种作用。在这项研究中,我们使用选择性 HTR4 拮抗剂 GR113808 重点研究了 HTR4 对非酒精性脂肪肝的作用:方法:雄性 C57BL/6J 小鼠以高脂肪饮食喂养 12 周,腹腔注射 GR113808,评估 HTR 表达、体重变化、糖脂代谢、肝脏脂肪堆积、脂肪组织变化、信号通路转录因子变化和炎症。用靶向 HTR4 的 siRNA 处理 Hep3B 细胞和 3T3-L1 细胞以下调其表达,然后用棕榈酸酯模拟高脂饮食进行培养。结果表明,高脂饮食会导致细胞中信号通路转录因子的变化以及炎症反应:结果:雄性 C57BL/6J 小鼠摄入高脂饮食后,肝脏和脂肪组织中 HTR4 的表达量减少。GR113808 可抑制体重增加并改善葡萄糖不耐受。此外,GR113808 不仅能减少脂肪肝的形成,还能缩小脂肪组织的体积。此外,GR113808 还降低了炎性细胞因子的血清水平,并减少了两种组织中炎性体复合物的形成。棕榈酸酯处理 HTR4 下调的 Hep3B 细胞,还能减少过氧化物酶体增殖激活受体 γ 和固醇调节元件结合蛋白-1 通路的诱导以及炎症小体复合物的形成,从而降低炎症细胞因子水平。在 3T3-L1 细胞中下调 HTR4 也能减少棕榈酸酯诱导的炎性体复合物的形成和炎性细胞因子的产生。下调 HTR4 能改善棕榈酸酯诱导的 Hep3B 细胞的胰岛素抵抗,但不能改善 3T3-L1 细胞的胰岛素抵抗:总之,GR113808 能防止脂肪肝的形成,并改善肝脏和脂肪组织的炎症。下调 HTR4 可改善肝脏的胰岛素抵抗。这些结果表明,HTR4 可以作为代谢性疾病的治疗靶点。
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来源期刊
BMC Pharmacology & Toxicology
BMC Pharmacology & Toxicology PHARMACOLOGY & PHARMACYTOXICOLOGY&nb-TOXICOLOGY
CiteScore
4.80
自引率
0.00%
发文量
87
审稿时长
12 weeks
期刊介绍: BMC Pharmacology and Toxicology is an open access, peer-reviewed journal that considers articles on all aspects of chemically defined therapeutic and toxic agents. The journal welcomes submissions from all fields of experimental and clinical pharmacology including clinical trials and toxicology.
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