BEGIN:VCALENDAR
VERSION:2.0
PRODID:-//Memento EPFL//
BEGIN:VEVENT
SUMMARY:Nutrient and hormonal signaling to mTORC1 in the coordination of h
 epatic homeostasis and metabolic zonation
DTSTART:20231010T093000
DTEND:20231010T103000
DTSTAMP:20260429T114753Z
UID:3dbdec5db84db76acf86eb406c27a11ccb95288429d8a5707cf74c66
CATEGORIES:Conferences - Seminars
DESCRIPTION:Dr. Ana Belén Plata Gómez Metabolism and Cell Signaling Grou
 p\, Spanish National Cancer Research Centre (CNIO)\, Madrid\, Spain\nThe l
 iver is a critical metabolic organ responsible for maintaining physiologic
 al homeostasis. The segregation of hepatocytes into functional areas insid
 e the liver lobule is referred to as “liver zonation”\, therefore the 
 hepatic lobule is partitioned in three metabolic zones: the periportal zon
 e 1\, which is directly exposed to nutrients from the gastrointestinal tra
 ct\, 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 z
 onation 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 t
 o mTORC1 are constitutively active in hepatocytes (Li-TSC1KORagAGTP mice)\
 , rendering them insensitive to variations in levels of nutrients and horm
 ones. Our results show that\, compared to the reported phenotypes of singl
 e mutant mice\, simultaneous deregulation of nutrient and hormonal signali
 ng results in a synergic hepatic phenotype. Furthermore\, based on transcr
 iptomic and proteomic analyses\, we have identified that simultaneous gene
 tic activation of nutrient and hormonal cues to mTORC1\, but not deregulat
 ed nutrient or hormonal signaling alone\, disrupts the zonal metabolic ide
 ntities of central and portal hepatocytes\, and leads to a profound deregu
 lation in the Wnt/-catenin signaling pathway. In particular\, a decreas
 ed secretion of Wnt2 ligand by liver endothelial cells is potentially resp
 onsible for abrogated molecular zonation in Li-TSC1KORagAGTP livers. These
  findings suggest that the detection of fluctuations in the levels of nutr
 ients and hormones by mTORC1 in hepatocytes is critical for the establishm
 ent and/or the maintenance of the hepatic zonation. To provide independent
  and non-genetic support to this concept\, we have assessed a potential di
 sruption of hepatic metabolic zonation in piglets subjected to a total par
 enteral nutrition (TPN) feeding regime. Under TPN\, nutrient supply is pro
 vided constantly and systemically through intravenous administration\, thu
 s nutrient and hormonal signaling are devoid of fluctuations normally impo
 sed by intermittent food intake. Strikingly\, liver transcriptome of TPN-f
 ed piglets and Li-TSC1KORagAGTP mice show a significant similarity. Among 
 the transcriptional likeness we have found identical abrogation of zonatio
 n and similar changes in expression of components of the Wnt/-catenin s
 ignaling pathway\, providing complementary endorsement for the concept tha
 t detection of nutrients and hormones fluctuations by hepatocytes is a det
 erminant of liver zonation.\n 
LOCATION:AI 1153 https://plan.epfl.ch/?room==AI%201153
STATUS:CANCELLED
END:VEVENT
END:VCALENDAR