Liganded Thyroid Hormone Receptor-α Enhances Proliferation of Pancreatic β-Cells
Liganded Thyroid Hormone Receptor-α Enhances Proliferation of Pancreatic β-Cells
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DOI：
10.1074/jbc.m109.100222
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发表时间：
2010-08-06
影响因子：
4.8
通讯作者：
Kobayashi, Tetsuro
中科院分区：
文献类型：
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作者：
Furuya, Fumihiko;Shimura, Hiroki;Kobayashi, Tetsuro
功能性胰腺β细胞团不能响应增加的代谢需求而扩增是2型糖尿病的标志。谱系追踪研究表明，现有β细胞的复制对于成年动物中的β细胞增殖是重要的。在大鼠胰腺β细胞系（RIN 5 F）中，用100 nM甲状腺激素（三碘甲状腺原氨酸，T-3）处理可增强细胞增殖。这一结果表明，T-3是β细胞增殖或复制所必需的。为了研究甲状腺激素受体α（TR α）在β细胞生长和细胞周期调控中的作用，我们构建了腺病毒载体AdTR α。AdTR α感染RIN 5 F细胞后，细胞周期蛋白D1 mRNA和蛋白表达增加。在AdTR α感染的细胞中细胞周期蛋白D1蛋白的过表达导致细胞周期蛋白D1/细胞周期蛋白依赖性激酶/视网膜母细胞瘤蛋白/E2 F途径的激活，沿着细胞周期进展和用100 nM T-3处理后的细胞增殖。相反，在AdTR α感染的细胞中，通过小干扰RNA敲低降低细胞周期蛋白D1导致细胞周期蛋白D1/CDK/Rb/E2 F通路的下调并抑制细胞增殖。此外，在免疫缺陷小鼠链脲佐菌素诱导的糖尿病，胰腺内注射腺病毒受体α导致胰岛功能的恢复和β细胞质量的增加。这些结果支持了以下假设：配体TR α在出生后发育期间的β细胞复制和β细胞群扩增中起关键作用。因此，配体化的TR α可能是可诱导β细胞扩增和再生的治疗策略的靶标。
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.