LKB1 and AMPK differentially regulate pancreatic β-cell identity.
LKB1 and AMPK differentially regulate pancreatic β-cell identity.
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DOI：
10.1096/fj.14-257667
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发表时间：
2014-11
期刊：
影响因子：
--
通讯作者：
Rutter GA
中科院分区：
文献类型：
--
作者：
Kone M;Pullen TJ;Sun G;Ibberson M;Martinez-Sanchez A;Sayers S;Nguyen-Tu MS;Kantor C;Swisa A;Dor Y;Gorman T;Ferrer J;Thorens B;Reimann F;Gribble F;McGinty JA;Chen L;French PM;Birzele F;Hildebrandt T;Uphues I;Rutter GA
完全分化的胰腺β细胞对哺乳动物正常的血糖稳态是必不可少的。这些细胞的去分化被认为发生在2型糖尿病中，从而损害胰岛素的产生。由于慢性燃料过量(“糖毒性”)与这一过程有关，我们在此试图确定肿瘤抑制因子肝激酶B1(LKB1STK11)及其下游的燃料敏感蛋白激酶(AMPK)在β细胞识别中的潜在作用。因此，在小鼠中，使用INS1控制的Cre，高度β细胞限制的每个激酶的缺失，随后是生理、形态测量和大规模平行测序分析。LKB1的缺失显著增加了肝脏(Alb、Iyd、ELOVL2)和神经元(NPTX2、Dlgap2、Cartpt、Pdyn)基因亚组的表达，增强了谷氨酸信号转导。AMPK的丧失部分概括了这些变化，它还上调了β细胞“不允许”的基因(SLC16A1、LDHA1、MGST1、PDGFRA)1.8%至3.4%(E<；0.01)。相应地，靶向启动子富含神经元转录因子(Zfp206；P=1.3×10−33)和缺氧调节转录因子(HIF1；P=2.5×10−16)。综上所述，LKB1和AMPK仅通过部分重叠的机制，通过抑制导致神经元、肝脏和其他特征的交替通路来维持β细胞的同一性。--科恩，M.，普伦，T.J.，孙，G.，伊伯森，M.，马丁内斯-桑切斯，A.，塞耶斯，S.，阮图，M.S.，坎特，C.，Swisa，A.，Dor，Y.，Gorman，T.，Ferrer，J.，Thorens，B.，Reimann，F.，Grible，F.，McGinty，J.A.，Chen，L.，French，P.M.，Birzele，F.Hildebrandt，T.，Uphues，I.，Rutter，G.A.LKB1和AMPK对胰腺β细胞的识别有不同的调节作用。
Fully differentiated pancreatic β cells are essential for normal glucose homeostasis in mammals. Dedifferentiation of these cells has been suggested to occur in type 2 diabetes, impairing insulin production. Since chronic fuel excess (“glucotoxicity”) is implicated in this process, we sought here to identify the potential roles in β-cell identity of the tumor suppressor liver kinase B1 (LKB1/STK11) and the downstream fuel-sensitive kinase, AMP-activated protein kinase (AMPK). Highly β-cell-restricted deletion of each kinase in mice, using an Ins1-controlled Cre, was therefore followed by physiological, morphometric, and massive parallel sequencing analysis. Loss of LKB1 strikingly (2.0–12-fold, E<0.01) increased the expression of subsets of hepatic (Alb, Iyd, Elovl2) and neuronal (Nptx2, Dlgap2, Cartpt, Pdyn) genes, enhancing glutamate signaling. These changes were partially recapitulated by the loss of AMPK, which also up-regulated β-cell “disallowed” genes (Slc16a1, Ldha, Mgst1, Pdgfra) 1.8- to 3.4-fold (E<0.01). Correspondingly, targeted promoters were enriched for neuronal (Zfp206; P=1.3×10−33) and hypoxia-regulated (HIF1; P=2.5×10−16) transcription factors. In summary, LKB1 and AMPK, through only partly overlapping mechanisms, maintain β-cell identity by suppressing alternate pathways leading to neuronal, hepatic, and other characteristics. Selective targeting of these enzymes may provide a new approach to maintaining β-cell function in some forms of diabetes.—Kone, M., Pullen, T. J., Sun, G., Ibberson, M., Martinez-Sanchez, A., Sayers, S., Nguyen-Tu, M.-S., Kantor, C., Swisa, A., Dor, Y., Gorman, T., Ferrer, J., Thorens, B., Reimann, F., Gribble, F., McGinty, J. A., Chen, L., French, P. M., Birzele, F., Hildebrandt, T., Uphues, I., Rutter, G. A. LKB1 and AMPK differentially regulate pancreatic β-cell identity.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
3.7
作者：
Marselli L;Thorne J;Dahiya S;Sgroi DC;Sharma A;Bonner-Weir S;Marchetti P;Weir GC
通讯作者：
Weir GC
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
慢性高血糖引发糖尿病动物模型胰腺β细胞分化丧失
影响因子：
4.8
作者：
Jonas, JC;Sharma, A;Weir, GC
通讯作者：
Weir, GC
影响因子：
7.7
作者：
Butler, AE;Janson, J;Butler, PC
通讯作者：
Butler, PC