Adiponectin homolog novel osmotin protects obesity/diabetes-induced NAFLD by upregulating AdipoRs/PPARα signaling in ob/ob and db/db transgenic mouse models
Adiponectin homolog novel osmotin protects obesity/diabetes-induced NAFLD by upregulating AdipoRs/PPARα signaling in ob/ob and db/db transgenic mouse models
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DOI：
10.1016/j.metabol.2018.10.004
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发表时间：
2019-01-01
影响因子：
9.8
通讯作者：
Kim, Myeong Ok
中科院分区：
文献类型：
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作者：
Ahmad, Ashfaq;Ali, Tahir;Kim, Myeong Ok
背景：在代谢紊乱中，脂联素和脂联素受体(AdipoR1/R2)信号在改善肥胖相关糖尿病的非酒精性脂肪性肝病(NAFLD)中起着关键作用。目的：据我们所知，首次报道了新型渗透素脂联素(与哺乳动物脂联素同源物)对瘦素缺乏的ob/ob和db/db小鼠的潜在机制治疗作用。为了与体内结果相关联，我们使用了人肝癌HepG2细胞，用AdipoR1/R2和PPARα基因的小siRNAs敲除，并用渗透素和棕榈酸(PA)处理。结果：在ob/ob和db/db小鼠中，Omotin刺激AdipoR1/R2及其下游的APPL1/PPAR-α/AMPK/Sirti通路，而PA作用于HepG2细胞后，我们从机制上证实，分别下调AdipoR1/R2和PPARα的siRNAs可以抑制染毒的HepG2细胞的渗透素活性。改善糖耐量，减轻胰岛素抵抗和肝糖生成，调节血脂参数，增加脂肪酸氧化和线粒体功能。结论：新的渗透素可能是一种潜在的治疗肥胖/糖尿病诱导的NAFLD和其他代谢紊乱的新工具。(C)2018 Elsevier Inc.保留所有权利。
Background: In metabolic disorders, adiponectin and adiponectin receptors (AdipoR1/R2) signaling has a key role in improving nonalcoholic fatty liver disease (NAFLD) in obesity-associated diabetes.Objective: To the best of our knowledge, here, we reported for the first time the underlying mechanistic therapeutic efficacy of the novel osmotin, a homolog of mammalian adiponectin, against NAFLD in leptin-deficient ob/ob and db/db mice.Methods: The ob/ob and db/db mice were treated with osmotin at a dose of 5 mu g/g three times a week for two weeks. To co-relate the in vivo results we used the human liver carcinoma HepG2 cells, subjected to knockdown with small siRNAs of AdipoR1/R2 and PPAR alpha genes and treated with osmotin and palmitic acid (PA). MTT assay, Western blotting, immunohistofluorescence assays, and plasma biochemical analyses were applied.Results: Osmotin stimulated Ad ipoR1/R2 and its downstream APPL1/PPAR-alpha/AMPK/SIRTI pathways in ob/ob and db/db mice, and HepG2 cells exposed to PA Mechanistically, we confirmed that knockdown of AdipoR1/R2 and PPAR alpha by their respective siRNAs abolished the osmotin activity in HepG2 cells exposed to P.A. Overall, the in vivo and in vitro results suggested that osmotin protected against NAFLD through activation of AdipoR1/R2 and its downstream APPL1/PPAR-alpha/AMPK/SIRT1 pathways as shown by the reduced body weight, blood glucose level and glycated hemoglobin, improved glucose tolerance, attenuated insulin resistance and hepatic glucogenesis, regulated serum lipid parameters, and increased fatty acid oxidation and mitochondrial functions.Conclusion: Our findings strongly suggest that novel osmotin might be a potential novel therapeutic tool against obesity/diabetes-induced NAFLD and other metabolic disorders. (C) 2018 Elsevier Inc. All rights reserved.