Abstract
Fatty liver (FL) disease is the most common type of chronic liver disease. We hypothesized that liver’s response to the process where large droplets of triglyceride fat accumulate in liver cells is reflected also in gene pathway expression in blood. Peripheral blood genome wide gene expression analysis and ultrasonic imaging of liver were performed for 1,650 participants (316 individuals with FL and 1,334 controls) of the Young Finns Study. Gene set enrichment analysis (GSEA) was performed for the expression data. Fourteen gene sets were upregulated (false discovery rate, FDR < 0.05) in subjects with FL. These pathways related to extracellular matrix (ECM) turnover, immune response regulation, prothrombotic state and neural tissues. After adjustment for known risk factors and biomarkers of FL, we found i) integrin A4B1 signaling, ii) leukocyte transendothelial migration, iii) CD40/CD40L and iv) netrin-1 signaling pathways to be upregulated in individuals with FL (nominal p < 0.05). From these all but not ii) remained significantly upregulated when analyzing only subjects without history of heavy alcohol use. In conclusion, FL was associated with blood gene sets of ECM turnover, inflammatory response, immune system activation and prothrombotic state. These may form a systemic link between FL and the development of cardiovascular diseases.
Highlights
The fatty liver disease (FLD) is a common liver disorder in western industrialized countries and an emerging problem in the Asia-Pacific region
We hypothesized that accumulated fatty acids and large droplets of triglycerides in liver cells trigger an inflammatory response in liver, which is visible via differential immuno-inflammatory gene pathway expression in blood
Individuals with FL were more often men and older and were metabolically less healthy. They had higher body mass index (BMI) and waist to hip ratio when compared to the normal liver (NL) group. 1.3% of the NL group had diabetes but for FL group the prevalence of diabetes was ten-fold (13.1%)
Summary
The fatty liver disease (FLD) is a common liver disorder in western industrialized countries and an emerging problem in the Asia-Pacific region. Innate immune system is deeply involved in pathophysiological events of fatty liver by following mechanisms: TLR-4 dependent signaling activates the Kupffer cells, complement pathway activation, balancing the cytokine network towards pro-inflammatory mediators, alternation in natural killer (NK) and NK T cell number and activity, and activation of the adaptive immune system leading to severe liver disease[8]. Immuno-inflammatory mechanisms are present in several comorbidities related with FLD, including obesity, type 2 diabetes, chronic kidney disease, metabolic syndrome, and cardiovascular diseases[5,12]. We hypothesized that accumulated fatty acids and large droplets of triglycerides in liver cells trigger an inflammatory response in liver, which is visible via differential immuno-inflammatory gene pathway expression in blood.
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