The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents

Abstract

The formation of polyploid cells is part of the developmental program of several tissues. During postnatal development, binucleated tetraploid cells arise in the liver, caused by failure in cytokinesis. In this report, we have shown that the initiation of cytokinesis failure events and the subsequent appearance of binucleated tetraploid cells are strictly controlled by the suckling-to-weaning transition in rodents. We found that daily light/dark rhythms and carbohydrate intake did not affect liver tetraploidy. In contrast, impairment of insulin signaling drastically reduced the formation of binucleated tetraploid cells, whereas repeated insulin injections promoted the generation of these liver cells. Furthermore, inhibition of Akt activity decreased the number of cytokinesis failure events, possibly through the mammalian target of rapamycin signaling complex 2 (mTORC2), which indicates that the PI3K/Akt pathway lies downstream of the insulin signal to regulate the tetraploidization process. To our knowledge, these results are the first demonstration in a physiological context that insulin signaling through Akt controls a specific cell division program and leads to the physiologic generation of binucleated tetraploid liver cells.

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

“…The binuclear fraction was lower in the liver parenchyma of ob/ob mice than in that of WT mice (ob/ob: 16.4% ± 1.3%; WT: 42.9% ± 2.1%) ( Figure 1B and Table 1). This result is consistent with observations made in the context of insulin resistance (20). We next investigated nuclear ploidy by measuring the nucleus area.…”

“…The liver is the only organ that modulates its ploidy content both during its life span and following different types of stress (13,19,70). The primary mechanism for physiological polyploidization involves a failure of cytokinesis, characterized by a modulation of insulin/AKT and E2F signaling (9,11,20). Interestingly, other factors can promote polyploidy in adults, such as regeneration following partial hepatectomy (48,71,72), fibrogenesis (5,73), and metabolic overload (18,74).…”

“…Total proteins were extracted from snap-frozen livers or from primary hepatocytes as described previously (20). Hepatocytes nuclear extracts were prepared using the NE-PER Nuclear and Cytoplasmic Extraction Reagent Kit (Thermo Fisher Scientific).…”

“…We showed previously that insulin signaling controls the genesis of polyploid hepatocytes during liver development through the PI3K/AKT pathway by regulating the late stages of mitosis (19,20). The close connection between liver physiology and insulin signaling prompted us to investigate whether polyploidy is modified during metabolic disorders of the liver, such as nonalcoholic fatty liver disease (NAFLD).…”

Endoreplication and polyploidy: insights into development and disease

“…An important principle emerging from these studies is that the developmental signals controlling endoreplication are the very same signals that control other aspects of the cell biology of specific cell types; in other words, endoreplication is just one aspect of the phenotype of differentiated cells. For example, the depletion of fibroblast growth factor 4 (FGF4) from trophoblast stem cells triggers both TGC development and endoreplication (Ullah et al, 2008), as does insulin signaling in hepatocytes (Celton-Morizur et al, 2009).…”