The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents
Séverine Celton-Morizur, … , Germain Margall-Ducos, Chantal Desdouets
Séverine Celton-Morizur, … , Germain Margall-Ducos, Chantal Desdouets
Published June 15, 2009
Citation Information: J Clin Invest. 2009;119(7):1880-1887. https://doi.org/10.1172/JCI38677.
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Research Article Hepatology

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.

Authors

Séverine Celton-Morizur, Grégory Merlen, Dominique Couton, Germain Margall-Ducos, Chantal Desdouets

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Figure 4

Decreased insulin level abolishes generation of binucleated tetraploid hepatocytes.

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Decreased insulin level abolishes generation of binucleated tetraploid h...
(A) Rats from the same litter were injected with STZ or vehicle, weaned at 20 days of age, and fed a high-carbohydrate diet. After a postprandial phase, rats were sacrificed at 24 days for in vivo analysis (D) or for isolating primary hepatocytes (E and F). (B) Fed blood glucose and serum insulin concentrations were measured in all animals at 24 days. Results are mean ± SEM for at least 6 animals per group. Con, control. (C) Total RNA was extracted from control (Con) and STZ-treated rat livers (n = 3), and SREBP-1c, L-PK, and FAS mRNA levels were analyzed by quantitative real-time PCR. Values are normalized to cyclophilin mRNA. (D) Protein extracts were prepared from liver tissue from control or STZ-treated rats and subjected to immunoblotting with antibodies against the precursor form of SREBP-1c, GK, FAS, and phospho-Akt (Ser473) (P-Akt). γ-Tubulin was used as a loading control. A representative Western blot is shown. (E) Percentage of tetraploid cells. Histogram shows mean ± SEM of 3 independent experiments (n = 6 [control]; 15 [STZ]). (F) Primary hepatocytes isolated from control and STZ-treated rats were immunostained for β-catenin, β-tubulin, and Hoechst for analysis of normal cytokinesis and cytokinesis failure. Scale bars: 10 μm. (G) Percentage of cytokinesis failure events for rats in F. For each condition, 100 telophases were analyzed. Results are mean ± SEM (n = 2 per group). *P < 0.05, **P < 0.01, #P < 0.005 versus control.