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首页> 外文期刊>American Journal of Physiology >Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice
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Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice

机译：胰高血糖素样肽1受体激动剂可改善小鼠非酒精性脂肪性肝炎的代谢，生化和组织病理学指标

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These preclinical studies aimed to 1) increase our understanding the dietary induction of nonalcoholic steatohepatitis (NASH), and, 2) further explore the utility and mechanisms of glucagon-like peptide-1 receptor (GLP-1R) agonism in NASH. We compared the effects of a high trans-fat (HTF) or high lard fat (HLF) diet on key facets of nonalcoholic fatty liver disease (NAFLD)/NASH in Lep ob/Lep ob and C57BL6J (B6) mice. Although HLF-fed mice experienced overall greater gains in weight and adiposity, the addition of trans-fat better mirrored pathophysiological features of NASH (e.g., hepatomegaly, hepatic lipid, and fibrosis). Administration of AC3174, an exenatide analog, and GLP-1R agonist to Lep ob/Lep ob and B6 ameliorated hepatic endpoints in both dietary models. Next, we assessed whether AC3174-mediated improvements in diet-induced NASH were solely due to weight loss in HTF-fed mice. AC3174-treatment significantly reduced body weight (8.3%), liver mass (14.2%), liver lipid (12.9%), plasma alanine aminotransferase, and triglycerides, whereas a calorie-restricted, weight-matched group demonstrated only modest nonsignificant reductions in liver mass (9%) and liver lipid (5.1%) relative to controls. Treatment of GLP-1R-deficient (GLP-1RKO) mice with AC3174 had no effect on body weight, adiposity, liver or plasma indices pointing to the GLP-1R-dependence of AC3174's effects. Interestingly, the role of endogenous GLP-1Rs in NASH merits further exploration as the GLP-1RKO model was protected from the deleterious hepatic effects of HTF. Our pharmacological data further support the clinical evaluation of the utility of GLP-1R agonists for treatment of NASH. ? 2012 the American Physiological Society.
机译：这些临床前研究旨在：1）增进我们对非酒精性脂肪性肝炎（NASH）的饮食诱导的了解，以及2）进一步探索胰高血糖素样肽-1受体（GLP-1R）激动作用在NASH中的作用和机制。我们比较了高脂肪（HTF）或高猪油脂肪（HLF）饮食对Lep ob / Lep ob和C57BL6J（B6）小鼠非酒精性脂肪肝疾病（NAFLD）/ NASH关键方面的影响。尽管由HLF喂养的小鼠在体重和肥胖方面总体上有更大的增长，但添加反脂脂肪可以更好地反映NASH的病理生理特征（例如，肝肿大，肝脂质和纤维化）。在两种饮食模型中，向Lep ob / Lep ob和B6施用艾塞那肽类似物AC3174和GLP-1R激动剂可改善肝终点。接下来，我们评估了AC3174介导的饮食诱导NASH改善是否仅归因于HTF喂养小鼠的体重减轻。 AC3174-治疗显着降低了体重（8.3％），肝质量（14.2％），肝脂质（12.9％），血浆丙氨酸氨基转移酶和甘油三酸酯，而热量限制，体重匹配的组仅显示出适度的肝脏显着降低质量（9％）和肝脂质（5.1％）相对于对照组。用AC3174治疗GLP-1R缺乏症（GLP-1RKO）小鼠对体重，肥胖，肝或血浆指标无影响，这表明AC3174的作用具有GLP-1R依赖性。有趣的是，内源性GLP-1R在NASH中的作用值得进一步探讨，因为GLP-1RKO模型受到保护，免受HTF的有害肝作用。我们的药理数据进一步支持了GLP-1R激动剂治疗NASH的实用性的临床评估。 ？ 2012年美国生理学会。

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