Evaluating the zone-specific regulation of hepatocyte metabolism

Abstract

The prevalence of insulin resistance and its associated comorbidities is increasing over time. The effects of insulin resistance on liver metabolism have been studied extensively, but few studies have incorporated the spatial and metabolic heterogeneity of hepatocytes based on their location within the liver lobule. Therefore, we do not know if conditions with dysregulated insulin signaling differentially affect subpopulations of hepatocytes. This thesis presents two studies focused on better understanding insulin resistance pathogenesis with consideration of the functional heterogeneity of hepatocytes. In the first study, we show that insulin can spatially segregate individual enzymes in a metabolic pathway within the liver. We find that in pericentral hepatocytes, insulin acts in synchrony with β-catenin to decrease the production of a group of pathogenic bile acid species, 12α-hydroxylated bile acids, by changing the localization of the enzyme CYP8B1. In the second study, we show that a known diabetes risk gene, Tcf7l2, modulates hepatic metabolic zonation to regulate metabolism. We find that TCF7L2 is necessary for pericentral-specific regulation of urea and lipid metabolism. Finally, I propose future studies to better understand how insulin, β-catenin, and TCF7L2 are exerting their zone-specific effects on metabolism. Collectively, this dissertation establishes that diabetic risk can be conferred by changes to the localization of metabolic pathways within the liver. This work highlights that the spatial dimension of hepatocyte metabolism is more than just an artifact: rather, it is a dynamic system, and its dysregulation is sufficient to cause physiological consequences.