The Age-Associated Decline of Glycogen Synthase Kinase 3β Plays a Critical Role in the Inhibition of Liver Regeneration

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Abstract
Aging reduces the regenerative capacities of many tissues. In this paper, we show a critical role of the glycogen synthase kinase 3β (GSK3β)-cyclin D3 pathway in the loss of the regenerative capacity of the liver. In young animals, high levels of growth hormone (GH) increase expression of GSK3β, which associates with cyclin D3 and triggers degradation of cyclin D3. In livers of old mice, the GSK3β promoter is repressed by C/EBPβ-histone deacetylase 1 (HDAC1) complexes, leading to the reduction of GSK3β. The treatment of old mice with GH increases expression of GSK3β via removal of the C/EBPβ-HDAC1 complexes from the GSK3β promoter. We found that the GSK3β-cyclin D3 pathway is also altered in young GH-deficient Little mice and that treatment of Little mice with GH corrects the GSK3β-cyclin D3 pathway. We present evidence that GSK3β regulates liver proliferation by controlling growth-inhibitory activity of C/EBPα. The downregulation of GSK3β in young mice inhibits liver proliferation after partial hepatectomy via the cyclin D3-C/EBPα pathway, while the elevation of GSK3β in old mice accelerates liver proliferation. Thus, this paper shows that GSK3β is a critical regulator of liver proliferation and that the reduction of GSK3β with age causes the loss of regenerative capacities of the liver.