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AM80 与 AC261066 在高脂肪饮食诱导的肝病小鼠模型中的作用比较。

Effects of AM80 compared to AC261066 in a high fat diet mouse model of liver disease.

机构信息

Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States of America.

School of Urban Public Health, Hunter College, City University of New York, New York, NY, United States of America.

出版信息

PLoS One. 2019 Jan 24;14(1):e0211071. doi: 10.1371/journal.pone.0211071. eCollection 2019.

DOI:10.1371/journal.pone.0211071
PMID:30677086
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6345457/
Abstract

The roles of retinoids in nonalcoholic fatty liver disease (NAFLD) remain unclear and a better understanding may lead to therapies that prevent or limit NAFLD progression. We examined the actions of retinoic acid receptor (RAR) agonists- AM80 for RARα and AC261066 for RARβ2- in a murine model of NAFLD. We fed wild type C57Bl/6 mice a chow or a 45% high fat diet (HFD) for 12 weeks, followed by 4 additional weeks with the HFD+AM80; HFD+AC261066; or HFD. The HFD+AM80 group showed greater hyperglycemia and glucose intolerance compared to other groups. Histopathological evaluation of the livers showed the highest degree of steatosis, triglycerides levels, and inflammation, assessed by F4/80 staining, in the HFD+AM80-treated compared to the HFD, the HFD+AC261066, and chow-fed mice. Liver vitamin A (retinol (ROL)) and retinyl palmitate levels were markedly lower in all HFD groups compared to chow-fed controls. HFD+AC261066-treated mice showed higher levels of a key intracellular ROL transporter, retinol-binding protein-1 (RBP1) compared to the HFD and HFD+AM80 groups. In conclusion, these data demonstrate that the selective RARα agonist AM80 exacerbates HFD-induced NAFLD and hyperglycemia. These findings should inform future studies examining the therapeutic potential of RAR agonists in HFD-related disorders.

摘要

视黄酸受体激动剂在非酒精性脂肪性肝病（NAFLD）中的作用尚不清楚，更好地了解这一作用可能会导致预防或限制 NAFLD 进展的治疗方法。我们研究了视黄酸受体（RAR）激动剂 AM80（用于 RARα）和 AC261066（用于 RARβ2）在 NAFLD 小鼠模型中的作用。我们用标准饮食（chow）或 45%高脂肪饮食（HFD）喂养野生型 C57Bl/6 小鼠 12 周，然后再用 HFD+AM80、HFD+AC261066 或 HFD 喂养 4 周。与其他组相比，HFD+AM80 组表现出更高的血糖和葡萄糖不耐受。肝脏的组织病理学评估显示，与 HFD、HFD+AC261066 和 chow 喂养的小鼠相比，HFD+AM80 治疗组的脂肪变性、甘油三酯水平和炎症程度最高，用 F4/80 染色评估。与 chow 喂养的对照组相比，所有 HFD 组的肝脏维生素 A（视黄醇（ROL））和视黄醇棕榈酸酯水平明显降低。与 HFD 和 HFD+AM80 组相比，HFD+AC261066 治疗组的关键细胞内 ROL 转运蛋白视黄醇结合蛋白 1（RBP1）水平更高。总之，这些数据表明，选择性 RARα 激动剂 AM80 可加重 HFD 诱导的 NAFLD 和高血糖。这些发现应该为未来研究 RAR 激动剂在 HFD 相关疾病中的治疗潜力提供信息。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/519c/6345457/e5a6e1ee2d50/pone.0211071.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/519c/6345457/9a1ee7ebaf95/pone.0211071.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/519c/6345457/a5f61586d241/pone.0211071.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/519c/6345457/80f923681369/pone.0211071.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/519c/6345457/fe7665cf58b8/pone.0211071.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/519c/6345457/e5a6e1ee2d50/pone.0211071.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/519c/6345457/9a1ee7ebaf95/pone.0211071.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/519c/6345457/a5f61586d241/pone.0211071.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/519c/6345457/80f923681369/pone.0211071.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/519c/6345457/fe7665cf58b8/pone.0211071.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/519c/6345457/e5a6e1ee2d50/pone.0211071.g005.jpg

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