Network Modeling of Liver Metabolism to Predict Plasma Metabolite Changes During Short-Term Fasting in the Laboratory Rat.

Kalyan C Vinnakota,Jamey D Young,Mohsin Rahim,Venkat R Pannala,Martha L Wall,Shanea K Estes,Anders Wallqvist,Masakazu Shiota,Richard L Printz,Tracy P O’Brien,Jaques Reifman,Irina Trenary

doi:10.3389/fphys.2019.00161

Abstract

The liver—a central metabolic organ that integrates whole-body metabolism to maintain glucose and fatty-acid regulation, and detoxify ammonia—is susceptible to injuries induced by drugs and toxic substances. Although plasma metabolite profiles are increasingly investigated for their potential to detect liver injury earlier than current clinical markers, their utility may be compromised because such profiles are affected by the nutritional state and the physiological state of the animal, and by contributions from extrahepatic sources. To tease apart the contributions of liver and non-liver sources to alterations in plasma metabolite profiles, here we sought to computationally isolate the plasma metabolite changes originating in the liver during short-term fasting. We used a constraint-based metabolic modeling approach to integrate central carbon fluxes measured in our study, and physiological flux boundary conditions gathered from the literature, into a genome-scale model of rat liver metabolism. We then measured plasma metabolite profiles in rats fasted for 5–7 or 10–13 h to test our model predictions. Our computational model accounted for two-thirds of the observed directions of change (an increase or decrease) in plasma metabolites, indicating their origin in the liver. Specifically, our work suggests that changes in plasma lipid metabolites, which are reliably predicted by our liver metabolism model, are key features of short-term fasting. Our approach provides a mechanistic model for identifying plasma metabolite changes originating in the liver.

Highlights

The liver is the primary organ responsible for metabolizing drugs and toxicants, a process collectively known as xenobiotic metabolism
The plasma metabolite profile consists of contributions from all other organs in the body, each of which is determined by the physiological state of the organ
The flux values through individual reactions at 10 and 13 h of fasting (Figure 3, Studies 1–3) were measured by stable isotope tracer studies, and those at 5–7 h of fasting (Figure 3, Est. 5–7 h) were compiled from the literature under conditions similar to our studies

Summary

INTRODUCTION

The liver is the primary organ responsible for metabolizing drugs and toxicants, a process collectively known as xenobiotic metabolism. Metabolite profiles, as measured in the plasma and urine of laboratory animal models of liver injury, are actively being investigated for their potential to detect liver damage earlier than current clinical markers and thereby facilitate timely intervention (Kamp et al, 2012; Mattes et al, 2014; Beger et al, 2015; Iruzubieta et al, 2015; Chang et al, 2017; Jarak et al, 2017) They are being analyzed to identify canonical metabolic pathways (i.e., not including xenobiotic metabolism), such as lipid, amino acid, and oxidative stress pathways, which are perturbed during a drugor toxicant-induced liver injury. By comparing model predictions of the directions of metabolite changes with measured plasma metabolite profiles, we assessed the contributions of the liver to those changes

MATERIALS AND METHODS

Methods for Measuring Metabolite Flux

RESULTS AND DISCUSSION

CONCLUSION