A Spatial Model of Hepatic Calcium Signaling and Glucose Metabolism Under Autonomic Control Reveals Functional Consequences of Varying Liver Innervation Patterns Across Species

Abstract

Rapid breakdown of hepatic glycogen stores into glucose plays an important role during intense physical exercise to maintain systemic euglycemia. Hepatic glycogenolysis is governed by several different liver-intrinsic and systemic factors such as hepatic zonation, circulating catecholamines, hepatocellular calcium signaling, hepatic neuroanatomy, and the central nervous system (CNS). Of the factors regulating hepatic glycogenolysis, the extent of lobular innervation varies significantly between humans and rodents. While rodents display very few autonomic nerve terminals in the liver, nearly every hepatic layer in the human liver receives neural input. In the present study, we developed a multi-scale, multi-organ model of hepatic metabolism incorporating liver zonation, lobular scale calcium signaling, hepatic innervation, and direct and peripheral organ-mediated communication between the liver and the CNS. We evaluated the effect of each of these governing factors on the total hepatic glucose output and zonal glycogenolytic patterns within liver lobules during simulated physical exercise. Our simulations revealed that direct neuronal stimulation of the liver and an increase in circulating catecholamines increases hepatic glucose output mediated by mobilization of intracellular calcium stores and lobular scale calcium waves. Comparing simulated glycogenolysis between human-like and rodent-like hepatic innervation patterns (extensive vs. minimal) suggested that propagation of calcium transients across liver lobules acts as a compensatory mechanism to improve hepatic glucose output in sparsely innervated livers. Interestingly, our simulations suggested that catecholamine-driven glycogenolysis is reduced under portal hypertension. However, increased innervation coupled with strong intercellular communication can improve the total hepatic glucose output under portal hypertension. In summary, our modeling and simulation study reveals a complex interplay of intercellular and multi-organ interactions that can lead to differing calcium dynamics and spatial distributions of glycogenolysis at the lobular scale in the liver.

Numerical Analysis of Compound Biochemical Calcium Oscillations Process in Hepatocyte Cells

“…[15] Verma et al have used a multiscale modeling approach to study the effects of hepatic glucose metabolism on signaling and liver function. [16] Dokukina et al have studied the interaction between ER calcium, calcium in cytosol, and mitochondria in hepatocyte cells. [17] Balabin and Sveshnikova have studied the interaction between PLC and IP 3 and its impact on calcium concentration.…”

“…have used a multi‐scale modeling approach to study the effects of hepatic glucose metabolism on signaling and liver function. [ 16 ] Dokukina et al. have studied the interaction between ER calcium, calcium in cytosol, and mitochondria in hepatocyte cells.…”

Systems Engineering Approach to Modeling and Analysis of Chronic Obstructive Pulmonary Disease Part II: Extension for Variable Metabolic Rates

“…Systems engineering toolshighly regarded for the unprecedented growth they have produced in manufacturing and logisticshave recently catalyzed major advancements in the healthcare industry. − Through synchronizing and exploiting the information available, these mathematical methods have found immense applications in drug discovery and development, therapeutic planning, diagnostics, pharmaceutical manufacturing, and patient management. ,− Furthermore, they are being increasingly employed to generate novel insights into the nature and function of biological systemsidentifying reaction and signaling pathways in living cells, deciphering the interactions between organs and organ systems, homeostasis within the organism, or sometimes even multiscale biological phenomena. − In this work, combining a systems engineering model of the human cardiorespiratory system with formal methods for sensitivity analysis and parameter estimation, we seek to improve our understanding of a widely prevalent condition called chronic obstructive pulmonary disease (COPD).…”