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首页> 外文期刊>EBioMedicine >Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models
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Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models

机译：在啮齿动物和灵长类动物临床前模型中，用PF-06409577激活肝AMPK可纠正NAFLD并降低胆固醇

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Dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver lipid accumulation and ultimately non-alcoholic steatohepatitis (NASH). Therapeutic activators of the AMP-Activated Protein Kinase (AMPK) have been proposed as a treatment for metabolic diseases; we show that the AMPK β1-biased activator PF-06409577 is capable of lowering hepatic and systemic lipid and cholesterol levels in both rodent and monkey preclinical models. PF-06409577 is able to inhibit de novo lipid and cholesterol synthesis pathways, and causes a reduction in hepatic lipids and mRNA expression of markers of hepatic fibrosis. These effects require AMPK activity in the hepatocytes. Treatment of hyperlipidemic rats or cynomolgus monkeys with PF-06409577 for 6 ? weeks resulted in a reduction in circulating cholesterol. Together these data suggest that activation of AMPK β1 complexes with PF-06409577 is capable of impacting multiple facets of liver disease and represents a promising strategy for the treatment of NAFLD and NASH in humans.
机译：肝脂质和胆固醇代谢失调是心脏代谢健康的重要因素，导致肝脏脂质过多积聚，最终导致非酒精性脂肪性肝炎（NASH）。有人提出了AMP活化蛋白激酶（AMPK）的治疗性激活剂，用于治疗代谢性疾病。我们表明，在啮齿动物和猴子的临床前模型中，AMPKβ1偏置的活化剂PF-06409577能够降低肝脏和全身性脂质和胆固醇水平。 PF-06409577能够抑制从头脂质和胆固醇的合成途径，并导致肝脏脂质减少和肝纤维化标志物的mRNA表达减少。这些作用需要肝细胞中的AMPK活性。用PF-06409577治疗高脂血症大鼠或食蟹猴6例？周减少了循环胆固醇。这些数据加在一起表明，用PF-06409577激活AMPKβ1复合物能够影响肝脏疾病的多个方面，并代表了一种有前景的人类NAFLD和NASH治疗策略。

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