Pancreastatin inhibitor activates AMPK pathway via GRP78 and ameliorates dexamethasone induced fatty liver disease in C57BL/6 mice
Pancreastatin inhibitor activates AMPK pathway via GRP78 and ameliorates dexamethasone induced fatty liver disease in C57BL/6 mice
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DOI：
10.1016/j.biopha.2019.108959
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发表时间：
2019-08-01
影响因子：
7.5
通讯作者：
Gayen, Jiaur R.
中科院分区：
文献类型：
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作者：
Gupta, Anand P.;Singh, Pragati;Gayen, Jiaur R.
目的：为探讨胰蛋白酶抑制剂（PSTi 8）对地塞米松诱导的2型糖尿病相关性脂肪肝的脂质平衡和胰岛素敏感性的影响，采用HepG 2细胞葡萄糖释放试验、脂质O染色和ATP/AMP比值测定。将24只小鼠随机分为4组：对照组（生理盐水）、DEX（lmg/kg，im）17天、DEX + PSTi 8（急性5 mg/kg和慢性2 mg/kg，ip）10天。进行葡萄糖、胰岛素和丙酮酸耐量试验（GTT、ITT和PTT）、生化参数和Oxymax-CLAMS。为了进一步阐明PSTi 8的作用机制，我们对生物样品进行了基因表达和蛋白质印迹分析。主要发现：我们发现PSTi 8抑制由DEX诱导的肝脏葡萄糖释放、脂质沉积、氧化应激，刺激肝细胞的细胞能量水平并增强GRP 78活性。在DEX诱导的糖尿病小鼠中，它减少脂肪生成并增强脂肪酸氧化以改善胰岛素敏感性和葡萄糖耐量。上述细胞效应是肝脏中激活AMPK信号通路的结果，其增加Srebplc和ACC磷酸化。ACC磷酸化的增加抑制蛋白激酶C活性并增强胰岛素敏感性。UCP 3在肝脏中的表达增加可促进脂肪酸氧化和能量消耗，从而抑制氧化应激。意义：因此，通过GRP 78激活AMPK信号传导，改善脂质稳态，通过抑制PKC活性增强胰岛素敏感性。PSTi 8抑制与不完全脂肪酸氧化相关的炎症。因此，PSTi 8可能是治疗糖皮质激素诱导的脂肪肝相关的2型糖尿病的潜在治疗剂。
Aims: To investigate the role of pancreastatin inhibitor (PSTi8) in lipid homeostasis and insulin sensitivity in dexamethasone induced fatty liver disease associated type 2 diabetes.Main methods: Glucose releases assay, lipid O staining and ATP/AMP ratio were performed in HepG2 cells. Twenty four mice were randomly divided into 4 groups: Control group (saline), DEX (1 mg/kg, im) for 17 days, DEX + PSTi8 (acute 5 mg/kg and chronic 2 mg/kg, ip) for 10 days. The glucose, insulin and pyruvate tolerance tests (GTT, ITT and PTT), biochemical parameters and Oxymax-CLAMS were performed. Further to elucidate the action mechanisms of PSTi8, we performed genes expression and western blotting of biological samples.Key findings: We found that PSTi8 suppresses hepatic glucose release, lipid deposition, oxidative stress induced by DEX, stimulates the cellular energy level in hepatocytes and enhances GRP78 activity. It reduces lipogensis and enhances fatty acid oxidation to improve insulin sensitivity and glucose tolerance in DEX induced diabetic mice. The above cellular effects are the result of activated AMPK signalling pathway in liver, which increases Srebplc and ACC phosphorylation. The increased ACC phosphorylation suppresses protein kinase C activity and enhances insulin sensitivity. The increased expression of UCP3 in liver elicits fatty acid oxidation and energy expenditure, which suppress oxidative stress.Significance: Thus the activation of AMPK signalling through GRP78, improves lipid homeostasis, enhances insulin sensitivity via inhibition of PKC activity. PSTi8 suppresses inflammation associated with incomplete fatty acid oxidation. Hence, PSTi8 may be a potential therapeutic agent to treat glucocorticoid-induced fatty liver associated type 2 diabetes.