Oniki Kentaro, Saruwatari Junji
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University.
Center for Clinical Pharmaceutical Sciences, Kumamoto University.
Yakugaku Zasshi. 2019;139(1):53-60. doi: 10.1248/yakushi.18-00163-3.
Adiponectin, the most abundant adipose tissue-derived adipocytokine, improves insulin sensitivity and has anti-inflammatory properties. Disulfide-bond A oxidoreductase-like protein (DsbA-L) is a key molecule in the multimerization of adiponectin (i.e., activation of adiponectin). In mice, liver-specific knockout of the Dsba-L gene impaired the mitochondrial function in hepatocytes and exacerbated the high-fat-diet-induced fatty liver. In addition, the DsbA-L mRNA level is negatively correlated with body mass index (BMI) in humans. We recently investigated the clinical impact of the DsbA-L gene on lifestyle-related diseases in Japanese subjects. We confirmed the influence of the common DsbA-L rs1917760 polymorphism on the multimerization of adiponectin, as well as the association of the polymorphism with the risk of obesity and non-alcoholic fatty liver disease, using prediction models based on a non-linear mixed effect model and/or structural equation models among elderly participants in a health screening program. We also observed a decreasing effect of DsbA-L polymorphism on the DsbA-L mRNA level in peripheral blood mononuclear cells, and an increasing effect of the polymorphism on the prevalence of excessive weight among schizophrenia patients at a high risk for obesity. These findings suggest that DsbA-L may be a key molecule associated with the development and progression of obesity and its related diseases. Therefore, genotyping the DsbA-L polymorphism and identifying patients at a high risk of developing obesity may help prevent obesity and its complications by facilitating targeted prevention and treatment programs for high-risk individuals.
脂联素是脂肪组织来源最为丰富的脂肪细胞因子，可改善胰岛素敏感性并具有抗炎特性。二硫键A氧化还原酶样蛋白（DsbA-L）是脂联素多聚化（即脂联素激活）过程中的关键分子。在小鼠中，肝脏特异性敲除Dsba-L基因会损害肝细胞的线粒体功能，并加剧高脂饮食诱导的脂肪肝。此外，人类的DsbA-L mRNA水平与体重指数（BMI）呈负相关。我们最近调查了DsbA-L基因对日本受试者生活方式相关疾病的临床影响。在一项健康筛查项目的老年参与者中，我们使用基于非线性混合效应模型和/或结构方程模型的预测模型，证实了常见的DsbA-L rs1917760多态性对脂联素多聚化的影响，以及该多态性与肥胖和非酒精性脂肪肝病风险的关联。我们还观察到DsbA-L多态性对外周血单核细胞中DsbA-L mRNA水平有降低作用，而该多态性对肥胖高危精神分裂症患者超重患病率有增加作用。这些发现表明，DsbA-L可能是与肥胖及其相关疾病的发生和发展相关的关键分子。因此，对DsbA-L多态性进行基因分型并识别肥胖高危患者，可能有助于通过为高危个体制定有针对性的预防和治疗方案来预防肥胖及其并发症。
