A Combination of Leucine, Metformin, and Sildenafil Treats Nonalcoholic Fatty Liver Disease and Steatohepatitis in Mice.
A Combination of Leucine, Metformin, and Sildenafil Treats Nonalcoholic Fatty Liver Disease and Steatohepatitis in Mice.
复制标题
亮氨酸，二甲双胍和西地那非的组合可治疗小鼠的非酒精性脂肪肝病和脂肪性肝炎。
DOI：
10.1155/2016/9185987
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发表时间：
2016
影响因子：
1.8
通讯作者：
Zemel MB
中科院分区：
文献类型：
--
作者：
Bruckbauer A;Banerjee J;Fu L;Li F;Cao Q;Cui X;Wu R;Shi H;Xue B;Zemel MB
Sirt 1、AMPK和eNOS调节肝脏能量代谢和炎症，是NASH发展的关键参与者。L-亮氨酸是一种变构Sirt 1激活剂，与低剂量二甲双胍或西地那非协同作用于AMPK-eNOS-Sirt 1通路，以逆转临床前小鼠模型中的轻度NAFLD。在这里，我们测试了可能的多组分协同作用，以在NAFLD/NASH中产生更大的治疗效果。肝细胞和巨噬细胞或致动脉粥样硬化饮食诱导的NASH小鼠模型用双向和三向组合处理。三向组合Sild-Met-Leu在体外增加肝脂肪酸氧化并降低脂肪生成基因表达和炎症标志物。在小鼠中，Sild-Met-Leu降低了饮食诱导的ALT、TGFβ、派-1、IL 1 β和TNFα升高，肝胶原表达，几乎完全逆转了肝细胞气球样变和甘油三酯蓄积，而所有双向组合仅具有中等影响。因此，这些数据为Sild-Met-Leu治疗NAFLD和NASH的疗效提供了临床前证据。
Sirt1, AMPK, and eNOS modulate hepatic energy metabolism and inflammation and are key players in the development of NASH. L-leucine, an allosteric Sirt1 activator, synergizes with low doses of metformin or sildenafil on the AMPK-eNOS-Sirt1 pathway to reverse mild NAFLD in preclinical mouse models. Here we tested a possible multicomponent synergy to yield greater therapeutic efficacy in NAFLD/NASH. Liver cells and macrophages or an atherogenic diet induced NASH mouse model was treated with two-way and three-way combinations. The three-way combination Sild-Met-Leu increased hepatic fatty acid oxidation and reduced lipogenic gene expression and inflammatory marker in vitro. In mice, Sild-Met-Leu reduced the diet induced increases of ALT, TGFβ, PAI-1, IL1β, and TNFα, hepatic collagen expression, and nearly completely reversed hepatocyte ballooning and triglyceride accumulation, while all two-way combinations had only modest effects. Therefore, these data provide preclinical evidence for therapeutic efficacy of Sild-Met-Leu in the treatment of NAFLD and NASH.