Impact of exenatide on mitochondrial lipid metabolism in mice with nonalcoholic steatohepatitis
Impact of exenatide on mitochondrial lipid metabolism in mice with nonalcoholic steatohepatitis
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DOI：
10.1530/joe-19-0007
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发表时间：
2019-06-01
影响因子：
4
通讯作者：
Cusi, Kenneth
中科院分区：
文献类型：
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作者：
Kalavalapalli, Srilaxmi;Bril, Fernando;Cusi, Kenneth
艾塞那肽（Exe）是一种胰高血糖素样肽（GLP）-1受体激动剂，可增强胰岛素分泌，并与诱导饱腹感和体重减轻相关。由于线粒体功能障碍和脂毒性是非酒精性脂肪性肝炎（NASH）的中心特征，我们测试了在这种情况下Exe是否改善了线粒体功能。我们研究了C57 BL/6 J小鼠，它们被喂食24周的对照或高果糖、高反式脂肪（TFD）饮食（即，NASH模型先前由我们的实验室验证）。对于最后8周，用Exe（30 μ g/kg/天）或溶剂处理小鼠。通过输注[C-13（3）]丙酸盐、[3，4-C-13（2））葡萄糖和基于NMR的C-13-同位素异构体分析评估线粒体代谢。艾塞那肽显著降低空腹血糖、游离脂肪酸和甘油三酯，以及脂肪组织胰岛素抵抗。此外，Exe减少23%的肝葡萄糖产生，15%的三羧酸（TCA）循环流量，20%的回补和17%的丙酮酸循环，导致肝内甘油三酯含量显著降低31%（P = 0.02）。艾塞那肽改善了脂质组学特征，减少了与胰岛素抵抗和脂毒性相关的肝脏脂质副产物，如二酰基甘油（TFD：111 +/- 13 vs Exe：64 +/- 13 μ mol/g蛋白，P = 0.03）和神经酰胺（TFD：1.6 +/- 0.1 vs Exe：1.3 +/- 0.1 μ mol/g蛋白，P = 0.03）。Exenglutamine降低了肝脏脂肪生成基因（Srebp 1C，Cd 36）和参与炎症和纤维化的基因（Tnfa，Timp 1）的表达。总之，在饮食诱导的NASH小鼠模型中，Exe改善线粒体TCA循环通量，并显著降低胰岛素抵抗、脂肪变性和肝细胞脂毒性。这可能对GLP-1受体激动剂在NASH患者中的潜在作用机制具有重要的临床意义。未来的研究应该阐明直接与间接机制的相对贡献。
Exenatide (Exe) is a glucagon-like peptide (GLP)-1 receptor agonist that enhances insulin secretion and is associated with induction of satiety with weight loss. As mitochondrial dysfunction and lipotoxicity are central features of nonalcoholic steatohepatitis (NASH), we tested whether Exe improved mitochondrial function in this setting. We studied C57BL/6J mice fed for 24 weeks either a control- or high-fructose, high-trans-fat (TFD)-diet (i.e., a NASH model previously validated by our laboratory). For the final 8 weeks, mice were treated with Exe (30 mu g/kg/day) or vehicle. Mitochondrial metabolism was assessed by infusion of [C-13(3)]propionate, [3,4-C-13(2))glucose and NMR-based C-13-isotopomer analysis. Exenatide significantly decreased fasting plasma glucose, free fatty acids and triglycerides, as well as adipose tissue insulin resistance. Moreover, Exe reduced 23% hepatic glucose production, 15% tri-carboxylic acid (TCA) cycle flux, 20% anaplerosis and 17% pyruvate cycling resulting in a significant 31% decrease in intrahepatic triglyceride content (P = 0.02). Exenatide improved the lipidomic profile and decreased hepatic lipid byproducts associated with insulin resistance and lipotoxicity, such as diacylglycerols (TFD: 111 +/- 13 vs Exe: 64 +/- 13 mu mol/g protein, P = 0.03) and ceramides (TFD: 1.6 +/- 0.1 vs Exe: 1.3 +/- 0.1 mu mol/g protein, P = 0.03). Exenatide lowered expression of hepatic lipogenic genes (Srebp1C, Cd36) and genes involved in inflammation and fibrosis (Tnfa, Timp1). In conclusion, in a diet-induced mouse model of NASH, Exe ameliorates mitochondrial TCA cycle flux and significantly decreases insulin resistance, steatosis and hepatocyte lipotoxicity. This may have significant clinical implications to the potential mechanism of action of GLP-1 receptor agonists in patients with NASH. Future studies should elucidate the relative contribution of direct vs indirect mechanisms at play.