Liganded Thyroid Hormone Receptor-α Enhances Proliferation of Pancreatic β-Cells

Fumihiko Furuya,Hiroki Shimura,Sayaka Yamashita,Toyoshi Endo,Tetsuro Kobayashi

doi:10.1074/jbc.m109.100222

Fumihiko Furuya, Hiroki Shimura + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m109.100222

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Abstract

Failure of the functional pancreatic beta-cell mass to expand in response to increased metabolic demand is a hallmark of type 2 diabetes. Lineage tracing studies indicate that replication of existing beta-cells is important for beta-cell proliferation in adult animals. In rat pancreatic beta-cell lines (RIN5F), treatment with 100 nM thyroid hormone (triiodothyronine, T(3)) enhances cell proliferation. This result suggests that T(3) is required for beta-cell proliferation or replication. To identify the role of thyroid hormone receptor alpha (TR(alpha)) in the processes of beta-cell growth and cell cycle regulation, we constructed a recombinant adenovirus vector, AdTR(alpha). Infection with AdTR(alpha) to RIN5F cells increased the expression of cyclin D1 mRNA and protein. Overexpression of the cyclin D1 protein in AdTR(alpha)-infected cells led to activation of the cyclin D1/cyclin-dependent kinase/retinoblastoma protein/E2F pathway, along with cell cycle progression and cell proliferation following treatment with 100 nM T(3). Conversely, lowering cellular cyclin D1 by small interfering RNA knockdown in AdTR(alpha)-infected cells led to down-regulation of the cyclin D1/CDK/Rb/E2F pathway and inhibited cell proliferation. Furthermore, in immunodeficient mice with streptozotocin-induced diabetes, intrapancreatic injection of AdTR(alpha) led to the restoration of islet function and to an increase in the beta-cell mass. These results support the hypothesis that liganded TR(alpha) plays a critical role in beta-cell replication and in expansion of the beta-cell mass during postnatal development. Thus, liganded TR(alpha) may be a target for therapeutic strategies that can induce the expansion and regeneration of beta-cells.

Highlights

Ostasis are largely unknown [2]
RIN5F cells were incubated in T3-depleted medium for 24 h and infected with 30 m.o.i. of AdTR␣ or control AdLacZ
To further explore the role of Thyroid hormone nuclear receptors (TRs)␣ in the processes of ␤-cell proliferation, we determined the effect of overexpression of TR␣ using a recombinant adenovirus vector that expresses TR␣ (AdTR␣)

Summary

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Several recent reports have indicated that proliferation or replication of existing ␤-cells rather than differentiation of new ␤-cells from stem cells, is one mechanism involved in maintenance of the ␤-cell mass in adults [3, 4]. It has been reported that complexes of CDK 4 with cyclin D1 or D2 are critical regulators of ␤-cell proliferation and ␤-cell mass homeostasis after birth [6]. Thyroid hormone influences various physiological processes, including cell cycle progression and cell differentiation/development in the vertebrate nervous system. It was reported that ligand-binding TR regulates the transcription of cyclin D1 [10]. The mechanisms by which ligand binding to TRs induce the proliferation of pancreatic ␤-cells are not clear, it was recently reported that activation of the phosphatidylinositol 3-kinase pathway by liganded TR mediates pancreatic ␤-cell proliferation [13]. Our findings led to the hypothesis that TR␣ might be involved in a positive regulatory mechanism that controls the maintenance of the pancreatic ␤-cell mass

EXPERIMENTAL PROCEDURES

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DISCUSSION