Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea; Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, South Korea.
Department of Biochemistry, Yonsei University Wonju College of Medicine, Wonju, South Korea; Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, South Korea.
Biochem Biophys Res Commun. 2018 Jul 20;502(3):397-402. doi: 10.1016/j.bbrc.2018.05.180. Epub 2018 May 30.
Angiopoietin-like 6 (ANGPTL6) is a hepatokine that antagonizes obesity and insulin resistance by increasing energy expenditure. Despite its beneficial effects on metabolism, human studies have shown a paradoxical increase in ANGPTL6 level in the serum of patients with metabolic diseases, which has been interpreted as a compensatory upregulation. However, the regulatory mechanism of ANGPTL6 remains unclear. Since upregulation of ANGPTL6 is induced on metabolic stress, we investigated the hepatic expression of ANGPTL6 by leptin, a representative adipokine of obesity. Mice on a high-fat diet showed increased serum leptin levels and hepatic Angptl6 expression, which were attenuated by exercise training. A single leptin injection also induced hepatic ANGPTL6 expression and increased serum ANGPTL6 levels. In an in vitro model using primary hepatocytes, leptin treatment significantly upregulated ANGPTL6 expression at the mRNA and protein levels, as well as the amount of secreted ANGPTL6 protein in conditioned media. Similarly, exercise training on human participants also showed diminished serum levels of leptin and ANGPTL6. Altogether, these results strongly indicated that hepatic ANGPTL6 expression was determined by leptin.
血管生成素样蛋白 6（ANGPTL6）是一种肝源激素，可通过增加能量消耗来拮抗肥胖和胰岛素抵抗。尽管它对代谢有有益的影响，但人体研究表明，代谢疾病患者血清中的 ANGPTL6 水平呈反常增加，这被解释为代偿性上调。然而，ANGPTL6 的调节机制尚不清楚。由于 ANGPTL6 的上调是由代谢应激诱导的，我们研究了肥胖代表性脂肪因子瘦素对 ANGPTL6 的肝表达的影响。高脂肪饮食的小鼠表现出血清瘦素水平和肝 Angptl6 表达增加，运动训练可减弱这种增加。单次瘦素注射也诱导肝 ANGPTL6 表达，并增加血清 ANGPTL6 水平。在使用原代肝细胞的体外模型中，瘦素处理在 mRNA 和蛋白质水平上均显著上调 ANGPTL6 表达，以及条件培养基中分泌的 ANGPTL6 蛋白质的量。同样，对人类参与者进行的运动训练也显示出瘦素和 ANGPTL6 的血清水平降低。总之，这些结果强烈表明肝 ANGPTL6 表达由瘦素决定。
