Find in Library

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 <i>SMOC1</i> may influence glucose-insulin homeostasis in rodents, it is unknown if <i>SMOC1</i> is influenced by NAFLD in humans. It is also unknown if <i>SMOC1</i> is causally associated with metabolic and disease traits in humans. Therefore, we aimed to determine the effect of NAFLD on <i>SMOC1</i> gene expression in the liver and aimed to explore the potential causal associations of <i>SMOC1</i> levels with NAFLD, T2D, and glycemic traits in humans. Using an RNA sequencing dataset from a cohort of 216 patients with NAFLD, we assessed <i>SMOC1</i> expression levels across the NAFLD spectrum. We performed a series of bidirectional inverse-variance weighted Mendelian randomization (MR) analyses on blood <i>SMOC1</i> 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 <i>SMOC1</i> expression showed no significant differences across NAFLD stages. We also identified that the top single-nucleotide polymorphism associated with blood <i>SMOC1</i> levels, was associated with <i>SMOC1</i> 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 <i>SMOC1</i> levels. We also did not find evidence that blood <i>SMOC1</i> levels were causally associated with T2D, NAFLD, and glycemic traits. In conclusion, the hepatokine <i>SMOC1</i> 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.