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

Abstract

Aging reduces the regenerative capacities of many tissues. In this paper, we show a critical role of the glycogen synthase kinase 3␤ (GSK3␤)-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 GSK3␤, which associates with cyclin D3 and triggers degradation of cyclin D3. In livers of old mice, the GSK3␤ promoter is repressed by C/EBP␤-histone deacetylase 1 (HDAC1) complexes, leading to the reduction of GSK3␤. The treatment of old mice with GH increases expression of GSK3␤ via removal of the C/EBP␤-HDAC1 complexes from the GSK3␤ promoter. We found that the GSK3␤-cyclin D3 pathway is also altered in young GH-deficient Little mice and that treatment of Little mice with GH corrects the GSK3␤-cyclin D3 pathway. We present evidence that GSK3␤ regulates liver proliferation by controlling growth-inhibitory activity of C/EBP␣. The downregulation of GSK3␤ in young mice inhibits liver proliferation after partial hepatectomy via the cyclin D3-C/EBP␣ pathway, while the elevation of GSK3␤ in old mice accelerates liver proliferation. Thus, this paper shows that GSK3␤ is a critical regulator of liver proliferation and that the reduction of GSK3␤ with age causes the loss of regenerative capacities of the liver.The decline of the regenerative capacities of tissues leads to the development of many age-related symptoms. Previous studies have identified several candidates which might contribute to the loss of regenerative capacities of tissues. Expression of p16INK4a has been found to be increased with age in many tissues and is involved in the loss of regenerative capacities of some tissues (19). Experiments with parabiotic animals have shown that the circulating systems of young mice contain some systemic factors which are able to rejuvenate progenitor cells in skeletal muscle and in the livers of old mice and correct proliferation of these tissues (7). Particularly, the young systemic environment reduces amounts of the C/EBP␣-Brm complex, which is abundant in livers of old mice and which reduces the regenerative capacity of the old livers (16, 34), through mechanisms that do not involve alterations in protein levels of components of the complex (7, 34). Several papers have suggested that growth hormone (GH) might be one of the systemic factors which correct regenerative capacities of tissues, including liver (11,14,20). For example, the treatment of old mice with GH corrects liver proliferation in old mice (20) and eliminates the C/EBP␣-Brm complex through reduction of cyclin D3 (34).Cyclin D3 belongs to a family of D-type cyclins which include cyclins D1, D2, and D3. D-type cyclins display significant homology, suggesting that they may perform overlapping functions. However, the expression patterns of the D-type cyclins vary widely, and individual cyclins D showed distinct functions in cell cycle progression and differentiation (2, 5, 17). Cyclin D1 is not detectable in quiescent livers but is induced after partial hepatectomy (PH) an...

Glycogen synthase kinase 3β-dependent Snail degradation directs hepatocyte proliferation in normal liver regeneration

“…In addition, a recent study indicated that GSK-3β contributes to hepatocyte proliferation and survival during rat liver regeneration (18). Moreover, the age-associated decline in GSK-3β is correlated with a reduced regenerative capacity of aged mouse liver (19). Taken together, our present results and these previous data imply that the mechanisms controlling the amount of GSK-3β in hepatocytes are important for regulating their proliferation state during the processes of development, regeneration, and aging.…”

GSK3β mediates muscle pathology in myotonic dystrophy

“…The cyclin D3 IPs were divided into two portions; one portion was examined by Western blotting with antibodies to p-Rb, and the other was probed with antibodies against p-T286-cyclin D1. The antibodies against p-T286 of cyclin D1 recognize both p-T286 and p-T283 in cyclins D1 and D3, respectively (36). We found that the phosphorylation of cyclin D3 at T283 was increased in DM1 muscle biopsy samples, whereas interaction of cyclin D3 with Rb was not changed in DM1 samples (Figure 1, D-F).…”

Ursolic acid enhances mouse liver regeneration after partial hepatectomy

“…Nuclear extracts were isolated from livers as described previously (Wang et al, 2001;Jin et al, 2009). Nuclear extracts (50 to 100 µg) were loaded on the gradient (4-20%, Bio-rad) polyacrylamide gels, and transferred onto membranes, and probed with antibodies.…”