Section of Clinical Molecular Biology, Akershus University Hospital, N-1474 Nordbyhagen, Norway; Institute of Clinical Medicine, Department of Clinical Molecular Biology, University of Oslo, N-0318 Oslo, Norway.
Research Institute of Internal Medicine, Oslo University Hospital, Institute of Clinical Medicine, N-0318 Oslo, Norway.
DNA Repair (Amst). 2022 Dec;120:103410. doi: 10.1016/j.dnarep.2022.103410. Epub 2022 Oct 3.
Fatty liver diseases are a major health threat across the western world, leading to cirrhosis and premature morbidity and mortality. Recently, a correlation between the base excision repair enzyme SMUG1 and metabolic homeostasis was identified. As the molecular mechanisms remain unknown, we exploited a SMUG1-knockout mouse model to gain insights into this association by characterizing the liver phenotype in young vs old SMUG1-null mice. We observed increased weight and fat content in one-year old animals, with altered activity of enzymes important for fatty acids influx and uptake. Consistently, lipidomic profiling showed accumulation of free fatty acids and triglycerides in SMUG1-null livers. Old SMUG1-knockout mice also displayed increased hepatocyte senescence and DNA damage at telomeres. Interestingly, RNA sequencing revealed widespread changes in the expression of lipid metabolic genes already in three months old animals. In summary, SMUG1 modulates fat metabolism favouring net lipogenesis and resulting in development of a fatty liver phenotype.
脂肪性肝病是整个西方世界的主要健康威胁，可导致肝硬化和过早发病和死亡。最近，碱基切除修复酶 SMUG1 与代谢稳态之间存在相关性。由于分子机制尚不清楚，我们利用 SMUG1 敲除小鼠模型，通过对年轻和年老 SMUG1 敲除小鼠的肝脏表型进行特征分析，来深入了解这种关联。我们观察到，一岁的动物体重和脂肪含量增加，脂肪酸流入和摄取所必需的酶活性发生改变。一致地，脂质组学分析显示 SMUG1 敲除肝脏中游离脂肪酸和甘油三酯的积累。年老的 SMUG1 敲除小鼠也显示出肝实质细胞衰老和端粒处 DNA 损伤增加。有趣的是，RNA 测序显示，在三个月大的动物中，脂质代谢基因的表达已经发生广泛变化。总之，SMUG1 调节脂肪代谢，有利于净脂肪生成，导致脂肪性肝病表型的发展。
