肝细胞素是肝脏衍生的蛋白质,可能会影响代谢途径,例如胰岛素敏感性。最近,Sparc相关的模块化钙结合蛋白1(SMOC1)被鉴定为在非酒精性脂肪性肝病(NAFLD)的背景下失调的葡萄糖反应性肝细胞因子。虽然SMOC1可能会影响啮齿动物的葡萄糖-胰岛素稳态,尚不清楚SMOC1是否受人类NAFLD的影响。SMOC1是否与人类的代谢和疾病性状有因果关系也是未知的。因此,我们旨在确定NAFLD对肝脏中SMOC1基因表达的影响,并旨在探索SMOC1水平与NAFLD的潜在因果关系,T2D,和人类的血糖特征。使用来自216名NAFLD患者队列的RNA测序数据集,我们评估了整个NAFLD谱中SMOC1的表达水平.我们使用两种全基因组关联研究(GWAS)(Fenland研究,n=10,708和间隔研究,n=3301)。我们在8434例和770,180例对照中使用了NAFLD的GWAS汇总统计数据,以及用于2型糖尿病(T2D)的公开可用的GWAS,体重指数(BMI),腰臀比(WHR),空腹血胰岛素(FBI),空腹血糖(FBG),胰岛素抵抗的稳态模型评估(HOMA-B和HOMA-IR),和血红蛋白A1c(HbA1C)。我们发现SMOC1表达在NAFLD各阶段没有显著差异。我们还确定了与血液SMOC1水平相关的顶部单核苷酸多态性,与肝脏中的SMOC1基因表达有关,但不是在其他组织。使用MR,我们没有发现任何基因预测NAFLD的证据,T2D,和血糖性状影响SMOC1水平。我们也没有发现血液SMOC1水平与T2D有因果关系的证据,NAFLD,和血糖特征。总之,肝细胞因子SMOC1似乎不受NAFLD存在的调节,并且可能不调节人的葡萄糖-胰岛素稳态.这项研究的结果表明,调节啮齿动物代谢的血液因素可能并不总是转化为人类生物学。
Hepatokines are liver-derived proteins that may influence metabolic pathways such as insulin sensitivity. Recently, Sparc-related modular calcium-binding protein 1 (
SMOC1) was identified as glucose-responsive hepatokine that is dysregulated in the setting of non-alcoholic fatty liver disease (NAFLD). While
SMOC1 may influence glucose-insulin homeostasis in rodents, it is unknown if
SMOC1 is influenced by NAFLD in humans. It is also unknown if
SMOC1 is causally associated with metabolic and disease traits in humans. Therefore, we aimed to determine the effect of NAFLD on SMOC1 gene expression in the liver and aimed to explore the potential causal associations of SMOC1 levels with NAFLD, T2D, and glycemic traits in humans. Using an RNA sequencing dataset from a cohort of 216 patients with NAFLD, we assessed SMOC1 expression levels across the NAFLD spectrum. We performed a series of bidirectional inverse-variance weighted Mendelian randomization (MR) analyses on blood SMOC1 levels using two sources of genome-wide association studies (GWAS) (Fenland study, n = 10,708 and INTERVAL study, n = 3301). We utilized GWAS summary statistics for NAFLD in 8434 cases and 770,180 controls, as well as publicly available GWAS for type 2 diabetes (T2D), body mass index (BMI), waist-to-hip ratio (WHR), fasting blood insulin (FBI), fasting blood glucose (FBG), homeostatic Model Assessment of Insulin Resistance (HOMA-B and HOMA-IR), and hemoglobin A1c (HbA1C). We found that
SMOC1 expression showed no significant differences across NAFLD stages. We also identified that the top single-nucleotide polymorphism associated with blood SMOC1 levels, was associated with
SMOC1 gene expression in the liver, but not in other tissues. Using MR, we did not find any evidence that genetically predicted NAFLD, T2D, and glycemic traits influenced SMOC1 levels. We also did not find evidence that blood SMOC1 levels were causally associated with T2D, NAFLD, and glycemic traits. In conclusion, the hepatokine SMOC1 does not appear to be modulated by the presence of NAFLD and may not regulate glucose-insulin homeostasis in humans. Results of this study suggest that blood factors regulating metabolism in rodents may not always translate to human biology.