Division of Endocrinology and Metabolism, Department of Internal Medicine, Daejeon Eulji Medical Center, Eulji University, Daejeon, South Korea.
Research Institute for Medical Sciences, Chungnam National University School of Medicine, Daejeon, South Korea.
Biochem Biophys Res Commun. 2021 Jun 18;558:57-63. doi: 10.1016/j.bbrc.2021.04.038. Epub 2021 Apr 22.
Nonalcoholic fatty liver disease (NAFLD) refers to a series of diseases, including simple steatosis, caused by the excessive accumulation of fat in hepatocytes, nonalcoholic steatohepatitis with inflammation and fibrosis, and more advanced forms of cirrhosis. The pathogenic mechanisms underlying fatty liver and the progression from simple fatty liver to hepatitis and cirrhosis remain unclear. One potentially unifying mechanism may be a dysregulation of free fatty acid oxidation. The oversupply of fatty acids to the liver can result in mitochondrial dysfunction leading to the accumulation of lipids in the liver. Interestingly, there have been several reports showing that inhibitors of phosphodiesterase 5 (PDE5) can increase mitochondrial biogenesis, preserve mitochondrial function in vitro. And, we have recently demonstrated that the phosphodiesterase type 5 inhibitor udenafil improves insulin sensitivity by increasing mitochondrial function in adipocytes. In this study, we aimed to examine the effects of the PDE5 inhibitor udenafil on NAFLD in the ob/ob mouse model. Treatment of ob/ob mice for 6 weeks with udenafil reduced fat mass and fasting glucose. Importantly, udenafil caused a reduction in lipid accumulation in the liver of these mice, including hepatic triglyceride (TG) and cholesterol levels. Mechanistically, udenafil decreased the proinflammatory cytokines in the liver. Also, udenafil increased the levels in the liver of the important lipolytic enzymes and the levels of several mitochondrial β-oxidation related genes. Similar effects were seen in udenafil treated primary hepatocytes. We believe that our study makes a significant contribution to the literature because the results from our study suggest that udenafil may be an effective treatment for NAFLD by improving mitochondrial function.
非酒精性脂肪性肝病（NAFLD）是指一系列疾病，包括单纯性脂肪变性，由肝细胞内脂肪过度堆积引起，非酒精性脂肪性肝炎伴炎症和纤维化，以及更高级形式的肝硬化。脂肪性肝病和从单纯性脂肪肝发展为肝炎和肝硬化的发病机制尚不清楚。一个潜在的统一机制可能是游离脂肪酸氧化的失调。脂肪酸向肝脏的过度供应可导致线粒体功能障碍，导致肝脏内脂质堆积。有趣的是，有几项报道表明，磷酸二酯酶 5（PDE5）抑制剂可以增加线粒体生物发生，在体外维持线粒体功能。而且，我们最近证明，磷酸二酯酶 5 型抑制剂乌地那非通过增加脂肪细胞中线粒体功能来改善胰岛素敏感性。在这项研究中，我们旨在研究 PDE5 抑制剂乌地那非对 ob/ob 小鼠模型中非酒精性脂肪性肝病的影响。乌地那非治疗 ob/ob 小鼠 6 周可减少脂肪量和空腹血糖。重要的是，乌地那非可减少这些小鼠肝脏内的脂质堆积，包括肝甘油三酯（TG）和胆固醇水平。在机制上，乌地那非降低了肝脏中的促炎细胞因子。此外，乌地那非增加了肝脏中重要的脂肪分解酶的水平和几种线粒体β氧化相关基因的水平。乌地那非处理的原代肝细胞也出现了类似的效果。我们相信我们的研究对文献做出了重要贡献，因为我们的研究结果表明，乌地那非通过改善线粒体功能可能是治疗非酒精性脂肪性肝病的有效方法。
