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p21 is required for dextrose-mediated inhibition of mouse liver regeneration
Alexander Weymann1, Eric Hartman, Vered Gazit
1Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Unlabelled:
The inhibitory effect of dextrose supplementation on liver regeneration was first described more than 4 decades ago. Nevertheless, the molecular mechanisms responsible for this observation have not been elucidated. We investigated these mechanisms using the partial hepatectomy model in mice given standard or 10% dextrose (D10)-supplemented drinking water. The results showed that D10-treated mice exhibited significantly reduced hepatic regeneration compared with controls, as assessed by hepatocellular bromodeoxyuridine (BrdU) incorporation and mitotic frequency. D10 supplementation did not suppress activation of hepatocyte growth factor (HGF), induction of transforming growth factor alpha (TGF-alpha) expression, or tumor necrosis factor alpha-interleukin-6 cytokine signaling, p42/44 extracellular signal-regulated kinase (ERK) activation, immediate early gene expression, or expression of CCAAT/enhancer binding protein beta (C/EBPbeta), but did augment expression of the mito-inhibitory factors C/EBPalpha, p21(Waf1/Cip1), and p27(Kip1). In addition, forkhead box M1 (FoxM1) expression, which is required for normal liver regeneration, was suppressed by D10 treatment. Finally, D10 did not suppress either FoxM1 expression or hepatocellular proliferation in p21 null mice subjected to partial hepatectomy, establishing the functional significance of these events in mediating the effects of D10 on liver regeneration.
Conclusion:
These data show that the inhibitory effect of dextrose supplementation on liver regeneration is associated with increased expression of C/EBPalpha, p21, and p27, and decreased expression of FoxM1, and that D10-mediated inhibition of liver regeneration is abrogated in p21-deficient animals. Our observations are consistent with a model in which hepatic sufficiency is defined by homeostasis between the energy-generating capacity of the liver and the energy demands of the body mass, with liver regeneration initiated when the functional liver mass is no longer sufficient to meet such demand.
Insights
Dextrose supplementation inhibits liver regeneration by increasing inhibitory factors like C/EBPalpha and p21, and decreasing FoxM1. This effect is nullified in p21-deficient mice, highlighting the role of these molecules in liver repair.
Area of Science:
- Hepatology
- Molecular Biology
- Cellular Biology
Background:
- Dextrose supplementation's inhibitory effect on liver regeneration is known but poorly understood.
- The precise molecular mechanisms remain elusive despite decades of observation.
Purpose of the Study:
- To elucidate the molecular mechanisms by which dextrose supplementation inhibits liver regeneration.
- To investigate the roles of specific gene expressions and signaling pathways in this process.
Main Methods:
- Utilized a partial hepatectomy model in mice.
- Administered standard or 10% dextrose (D10) supplemented drinking water.
- Assessed liver regeneration via hepatocellular bromodeoxyuridine (BrdU) incorporation and mitotic frequency.
- Analyzed expression levels of key growth factors, cytokines, signaling molecules, and cell cycle regulators.
Main Results:
- D10-treated mice showed significantly reduced hepatic regeneration.
- D10 increased expression of mito-inhibitory factors (C/EBPalpha, p21, p27) and decreased forkhead box M1 (FoxM1) expression.
- Key signaling pathways like HGF, TGF-alpha, and TNF-alpha/IL-6 remained active.
- Inhibition was abrogated in p21-deficient mice, indicating p21's crucial role.
Conclusions:
- Dextrose supplementation inhibits liver regeneration through increased C/EBPalpha, p21, and p27, and decreased FoxM1 expression.
- p21 deficiency abrogates the inhibitory effect of dextrose, confirming its critical role.
- Liver regeneration is regulated by energy homeostasis between the liver's capacity and the body's demands.
