A Computational Model of the Hepatic Lobule

Abstract

While many inter-organ and intra-organ gene regulations have been found recently, raison d’étre of such regulations are hardly explicated. We aimed liver ammonia detoxification as a prospective target because of its simple histological structure and adopted systems biology approach to elucidate the question. In the mammalian liver, many metabolic systems including ammonia metabolism are heterogeneously processed among hepatocyte position in the lobule.1–5 Three enzymes that are incorporated in ammonia metabolism are expressed gradually between the periportal zone (influx side) and the pericentral zone (efflux side) in the lobule.6,7 To investigate the cause of the heterogeneous gene expression, a simple eight-compartments model, in which each compartment represented hepatocellular ammonia metabolism by largely enzyme kinetics equations, was developed as a lobule model.8 In silico simulation indicated that regulated enzyme gradient reduced ATP requirement for ammonia detoxification, suggesting that these enzyme gradients by gene regulations improve the fitness of organism by saving energy (ATP consumption).