The survival pathways phosphatidylinositol-3 kinase (PI3-K)/phosphoinositide-dependent protein kinase 1 (PDK1)/Akt modulate liver regeneration through hepatocyte size rather than proliferation

Abstract

Liver regeneration comprises a series of complicated processes. The current study was designed to investigate the roles of phosphoinositide-dependent protein kinase 1 (PDK1)-associated pathways in liver regeneration after partial hepatectomy (PH) using liver-specific Pdk1-knockout (L-Pdk1KO) and Pdk1/STAT3 double KO (L-DKO) mice. There was no liver regeneration, and 70% PH was lethal in L-Pdk1KO mice. Liver regeneration was severely impaired equally in L-Pdk1KO and L-DKO mice, even after nonlethal 30% PH. There was no cell growth (measured as increase of cell size) after hepatectomy in L-Pdk1KO mice, although the post-PH mitotic response was the same as in controls. As expected, hepatectomy did not induce hepatic Akt-phosphorylation (Thr308) in L-Pdk1KO mice, and post-PH phosphorylation of Akt, mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase (p70 S6K ), and S6 were also reduced. To examine the specific role of PDK1-associated signals, a "pif-pocket" mutant of PDK1, which allows PDK1 only to phosphorylate Akt, was used.

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

“…Next, we investigated the mechanisms underlying enhanced liver regeneration in IL-10 Ϫ/Ϫ mice by analyzing the activation of the STAT3 pathway, which promotes hepatocyte survival and liver regeneration, [13][14][15] as well as STAT1 activation, which induces hepatocyte apoptosis and inhibits liver regeneration. 22 As illustrated in Figure 6, hepatic STAT3 was activated after PHx in wild-type mice, as reflected by elevated levels of phospho-STAT3 (pSTAT3) with peak effect occurring 3 to 6 hours after surgery.…”

“…Since hepatic STAT3 has been shown to play an important role in promoting liver regeneration, [13][14][15] we hypothesized that enhanced STAT3 may contribute to the increased liver regeneration in IL-10 Ϫ/Ϫ mice. To test this hypothesis, we made an additional deletion of hepatocyte STAT3 in IL-10 Ϫ/Ϫ mice to generate STAT3 HepϪ/Ϫ IL-10 Ϫ/Ϫ mice.…”

“…Previous studies reported that STAT3 plays an important role in constraining hepatocyte size after PHx. 14,30 Since IL-10 Ϫ/Ϫ mice had higher levels of hepatic STAT3 activation than wildtype mice, it is plausible to speculate that IL-10 Ϫ/Ϫ mice have a smaller size of hepatocytes than wild-type mice after PHx. Future studies are required to confirm this speculation.…”

“…11 The action of IL-6 is mediated via binding the IL-6 receptor complex (gp80/gp130) on hepatocytes, followed by activation of STAT3 and promoting hepatocyte survival and proliferation. [12][13][14][15][16] The findings from these published reports suggest that the inflammatory response and cytokine production are particularly active during the first 24 hours after PHx, a time when hepatocyte transition from a quiescent state into the cell cycle occurs. However, how these inflammatory responses are controlled during liver regeneration remains largely unknown.…”

p66Shc has a pivotal function in impaired liver regeneration in aged mice by a redox-dependent mechanism

“…24 Briefly, individual hepatocytes were outlined and cross-sectional area was determined with a computer-assisted image analyzing system (LSM Image Browser, Carl Zeiss GmBH, Jena, Germany). Cell areas of at least 500 hepatocytes were randomly selected in zone 2 and calculated in triplicate using different sections in each group.…”