Metabolic adaptations in models of fatty liver disease:Of mice and math

The increasing incidence of overweight is accompanied by a plethora of medical symptoms together called the metabolic syndrome. Non-alcoholic fatty liver disease, characterized by persistent storage of lipids in the liver, is regarded as the hepatic component of the metabolic syndrome. An imbalance between influx to and efflux from the hepatic triglyceride pool results in hepatic lipid accumulation. How hepatic lipid accumulation or steatosis develops is incompletely understood and the molecular origin may vary between different individuals and different animal models. In this dissertation we examine adaptations in fatty acid and glucose metabolism in two mouse models that develop a fatty liver: pharmacological activation of liver X receptor (LXR) and genetic deletion of hepatic glucose-6-phosphatase (L-G6pc-/- mice). We show that the origin of hepatic steatosis can adapt to different circumstances in mouse models of fatty liver disease. In the case of LXR activation the origin of a fatty liver alters with treatment time, while in L-G6pc-/- mice the origin of hepatic fat accumulation varies between fasting and feeding. In L-G6pc-/- mice we furthermore investigate changes in hepatic glucose metabolism. We also describe how we use in vivo physiological data in a mathematical modeling approach to examine LXR-induced time-dependent changes in triglyceride metabolism. We provide data that show that including information about gene expression levels in this mathematical model can improve its predictive value. Next to this, we present a theoretical mechanism that explains the insulin resistance paradox from the viewpoint of zonation of metabolic processes in the liver