Chertow B S, Driscoll H K, Goking N Q, Primerano D, Cordle M B, Matthews K A
Research and Medical Service, Huntington Veterans Affairs Medical Center, WV, USA.
Metabolism. 1997 Jun;46(6):656-60. doi: 10.1016/s0026-0495(97)90009-3.
Retinoid-X receptors (RXRs) are 9-cis-retinoic acid (9CRA)-dependent gene transcription factors, which modulate the action of all-trans-retinoic acid (ATRA), fatty acids, thyroid hormone (TH), and vitamin D (VD) by forming dimers with themselves or ATRA, TH, peroxisome proliferator activator receptors (PPARs), or VD receptors (VDRs). To determine if 9CRA and RXRs have a role in secretion, RINm5F cells were assayed for RXR transcripts and effects of 9CRA and ATRA on secretion. A single RXR alpha transcript and two RXR beta transcripts, but not RXR gamma, were evident by Northern blot. Cells were cultured for 48 hours without and with 9CRA 1 to 1,000 nmol/L and then stimulated with glucose 0, 0.5, 2.8, 7, and 11 mmol/L 9CRA increased secretion at each glucose concentration, 9CRA increased secretion by 50% to 100% (ANOVA, P < .001) with consistent concentration-dependent responses (eg. at glucose 2.8 mmol/L 9CRA: 0 nmol/L, 5.02 +/- .20 ng/(10(6) cells.h); 1 nmol/L, 6.97 +/- .30; 10 nmol/L, 8.36 +/- .18; 100 nmol/L, 9.15 +/- .28; 1,000 nmol/L, 10.24 +/- .24; n = 6). Although RINm5F cells respond slightly if at all to glucose, 9CRA facilitated glucose-induced insulin release (eg, at 9CRA 100 nmol/L, glucose: 0.5 mmol/L, 7.47 +/- .22 ng/(10(6) cells.h); 2.8 mmol/L, 9.15 +/- .27; 7 mmol/L, 9.81 +/- .19; 11 mmol/L, 11.16 +/- .23; n = 6). ATRA increased secretion by 28% to 57% (ANOVA, P < .001: at glucose 2.8 mmol/L, ATRA: 0 nmol/L, 6.17 +/- .32 ng/(10(6) cells.h); 1 nmol/L, 7.91 +/- .29; 10 nmol/L, 9.75 +/- .14; 100 nmol/L, 9.66 +/- .33; n = 6). 9CRA was more potent than ATRA (eg, at 2.8 mmol/L; baseline, 8.17 +/- .32 ng/(10(8) cells.h); ATRA 100 nmol/L, 9.66 +/- .33; 9CRA 100 nmol/L, 10.81 +/- .15; P < .05, n = 6). When 9CRA was combined with ATRA, the combination was not additive or synergistic (eg, at 2.8 mmol/L: ATRA 100 nmol/L, 9.66 +/- .33 ng/(10(6) cells.h); 9CRA 100 nmol/L, 10.81 +/- .15; ATRA 100 nmol/L + 9CRA 100 nmol/L, 10.79 +/- .28; P < .05, n = 6). These studies show that (1) 9CRA stimulates insulin secretion from RINm5F cells. This effect appears to be at least equal to if not greater than that observed with ATRA, but additive or synergistic effects with ATRA were not evident; (2) 9CRA may facilitate glucose-induced release; and (3) multiple RXR transcripts are present in insulin-secreting cells, implying specific functions. Our findings support the idea that the effects of 9CRA on insulin secretion are mediated through RXR homodimers or heterodimers with retinoic acid receptors (RARs) or possibly other nuclear receptors. Retinoid deficiency or alterations in retinoid receptor function could lead to abnormalities of cell growth or secretion.
维甲酸X受体（RXRs）是依赖9-顺式维甲酸（9CRA）的基因转录因子，它通过与自身或全反式维甲酸（ATRA）、甲状腺激素（TH）、过氧化物酶体增殖物激活受体（PPARs）或维生素D受体（VDRs）形成二聚体，来调节全反式维甲酸、脂肪酸、甲状腺激素和维生素D的作用。为了确定9CRA和RXRs是否在分泌过程中起作用，我们检测了RINm5F细胞中的RXR转录本以及9CRA和ATRA对分泌的影响。通过Northern印迹法可明显检测到单一的RXRα转录本和两种RXRβ转录本，但未检测到RXRγ转录本。细胞在无9CRA以及含有1至1000 nmol/L 9CRA的条件下培养48小时，然后分别用0、0.5、2.8、7和11 mmol/L的葡萄糖进行刺激。在每个葡萄糖浓度下，9CRA均能增加分泌量，9CRA使分泌量增加了50%至100%（方差分析，P <.001），呈现出一致的浓度依赖性反应（例如，在葡萄糖浓度为2.8 mmol/L时，9CRA浓度为0 nmol/L时，分泌量为5.02±0.20 ng/(10⁶个细胞·小时)；1 nmol/L时，为6.97±0.30；10 nmol/L时，为8.36±0.18；100 nmol/L时，为9.15±0.28；1000 nmol/L时，为10.24±0.24；n = 6）。尽管RINm5F细胞对葡萄糖的反应很微弱，但9CRA能促进葡萄糖诱导的胰岛素释放（例如，在9CRA浓度为100 nmol/L时，葡萄糖浓度为0.5 mmol/L时，分泌量为7.47±0.22 ng/(10⁶个细胞·小时)；2.8 mmol/L时，为9.15±0.27；7 mmol/L时，为9.81±0.19；11 mmol/L时，为11.16±0.23；n = 6）。ATRA使分泌量增加了28%至57%（方差分析，P <.001：在葡萄糖浓度为2.8 mmol/L时，ATRA浓度为0 nmol/L时，分泌量为6.17±0.32 ng/(10⁶个细胞·小时)；1 nmol/L时，为7.91±0.29；10 nmol/L时，为9.75±0.14；100 nmol/L时，为9.66±0.33；n = 6）。9CRA比ATRA更有效（例如，在2.8 mmol/L时；基线分泌量为8.17±0.32 ng/(10⁸个细胞·小时)；ATRA浓度为100 nmol/L时，为9.66±0.33；9CRA浓度为100 nmol/L时，为10.81±0.15；P <.05，n = 6）。当9CRA与ATRA联合使用时，二者没有相加或协同作用（例如，在2.8 mmol/L时：ATRA浓度为100 nmol/L时，分泌量为9.66±0.33 ng/(10⁶个细胞·小时)；9CRA浓度为100 nmol/L时，为10.81±0.15；ATRA浓度为100 nmol/L + 9CRA浓度为100 nmol/L时，为10.79±0.28；P <.05，n = 6）。这些研究表明：（1）9CRA能刺激RINm5F细胞分泌胰岛素。这种作用似乎至少与ATRA相当，甚至可能更强，但与ATRA没有明显的相加或协同作用；（2）9CRA可能促进葡萄糖诱导的胰岛素释放；（3）胰岛素分泌细胞中存在多种RXR转录本，这意味着它们具有特定的功能。我们的研究结果支持这样一种观点，即9CRA对胰岛素分泌作用是通过RXR同二聚体或与维甲酸受体（RARs）或其他可能的核受体形成的异二聚体介导的。维甲酸缺乏或维甲酸受体功能改变可能导致细胞生长或分泌异常。
