Abstract
The liver plays a vital role in glucose homeostasis, the synthesis of bile acids and the detoxification of foreign substances. Liver culture systems are widely used to test adverse effects of drugs and environmental toxicants. The two most prevalent liver culture systems are hepatocyte monolayers (HMs) and collagen sandwiches (CS). Despite their wide use, comprehensive transcriptional programs and interaction networks in these culture systems have not been systematically investigated. We integrated an existing temporal transcriptional dataset for HM and CS cultures of rat hepatocytes with a functional interaction network of rat genes. We aimed to exploit the functional interactions to identify statistically significant linkages between perturbed biological processes. To this end, we developed a novel approach to compute Contextual Biological Process Linkage Networks (CBPLNs). CBPLNs revealed numerous meaningful connections between different biological processes and gene sets, which we were successful in interpreting within the context of liver metabolism. Multiple phenomena captured by CBPLNs at the process level such as regulation, downstream effects, and feedback loops have well described counterparts at the gene and protein level. CBPLNs reveal high-level linkages between pathways and processes, making the identification of important biological trends more tractable than through interactions between individual genes and molecules alone. Our approach may provide a new route to explore, analyze, and understand cellular responses to internal and external cues within the context of the intricate networks of molecular interactions that control cellular behavior.
Highlights
The liver is one of the important organs in our bodies, playing a vital role in glucose homeostasis, the synthesis of bile acids for the metabolism of cholesterol, and the secretion of proteins to aid clotting [1]
We focused our analysis on nearly 20 Molecular Signature Database (MSigDB) gene sets we had identified as up-regulated in hepatocyte cultures in an earlier study
Contextual Biological Process Linkage Networks (CBPLNs) revealed numerous meaningful connections between different biological processes and gene sets, which we were successful in interpreting within the context of liver metabolism
Summary
The liver is one of the important organs in our bodies, playing a vital role in glucose homeostasis, the synthesis of bile acids for the metabolism of cholesterol, and the secretion of proteins to aid clotting [1]. Hepatocytes are the principal cells in the liver, comprising over 80% of its mass and performing several characteristic functions of this organ Liver culture systems such as hepatocyte monolayers (HMs) and collagen sandwiches (CSs) are routinely used to test adverse effects of drugs and environmental toxicants. Gene sets up-regulated in CS cultures included several hepatic functions, such as metabolism of lipids, amino acids, carbohydrates, and alcohol, and synthesis of bile acids. Monooxygenases such as Cytochrome-P450 enzymes did not show any change between the culture systems after one day, but exhibited significant up-regulation in CS cultures after three days and later in comparison to HMs
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