Nutrient and hormonal signaling to mTORC1 in the coordination of hepatic homeostasis and metabolic zonation

The liver is a critical metabolic organ responsible for maintaining physiological homeostasis. The segregation of hepatocytes into functional areas inside the liver lobule is referred to as “liver zonation”, therefore the hepatic lobule is partitioned in three metabolic zones: the periportal zone 1, which is directly exposed to nutrients from the gastrointestinal tract, the midlobular or intermediate zone 2, and the pericentral zone 3, exposed to low concentrations of nutrients. The Wnt/-catenin signaling pathway is an important regulator of hepatic organogenesis and metabolic zonation in the liver through a gradient of Wnt ligands that dissipate from central to portal zones. In this work, we have genetically engineered a mouse strain in which hormonal signaling and cellular nutrient signaling to mTORC1 are constitutively active in hepatocytes (Li-TSC1^KORagA^GTP mice), rendering them insensitive to variations in levels of nutrients and hormones. Our results show that, compared to the reported phenotypes of single mutant mice, simultaneous deregulation of nutrient and hormonal signaling results in a synergic hepatic phenotype. Furthermore, based on transcriptomic and proteomic analyses, we have identified that simultaneous genetic activation of nutrient and hormonal cues to mTORC1, but not deregulated nutrient or hormonal signaling alone, disrupts the zonal metabolic identities of central and portal hepatocytes, and leads to a profound deregulation in the Wnt/-catenin signaling pathway. In particular, a decreased secretion of Wnt2 ligand by liver endothelial cells is potentially responsible for abrogated molecular zonation in Li-TSC1^KORagA^GTP livers. These findings suggest that the detection of fluctuations in the levels of nutrients and hormones by mTORC1 in hepatocytes is critical for the establishment and/or the maintenance of the hepatic zonation. To provide independent and non-genetic support to this concept, we have assessed a potential disruption of hepatic metabolic zonation in piglets subjected to a total parenteral nutrition (TPN) feeding regime. Under TPN, nutrient supply is provided constantly and systemically through intravenous administration, thus nutrient and hormonal signaling are devoid of fluctuations normally imposed by intermittent food intake. Strikingly, liver transcriptome of TPN-fed piglets and Li-TSC1^KORagA^GTP mice show a significant similarity. Among the transcriptional likeness we have found identical abrogation of zonation and similar changes in expression of components of the Wnt/-catenin signaling pathway, providing complementary endorsement for the concept that detection of nutrients and hormones fluctuations by hepatocytes is a determinant of liver zonation.