Department of Biochemical Science and Technology, College of Life Science, National Taiwan University , No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan.
J Agric Food Chem. 2013 Jun 26;61(25):5996-6006. doi: 10.1021/jf401197r. Epub 2013 Jun 13.
Abnormal cellular accumulation of the dicarbonyl metabolite methylglyoxal (MG) results in cell damage, inflammation, and oxidative stress. It is also associated with increased protein linkage to form advanced glycation end products (AGEs) or induce DNA strand breaks. The association between peroxisome proliferator-activated receptor-γ (PPARγ) and nuclear factor-erythroid 2-related factor 2 (Nrf2) is unclear. This study investigated Nrf2 activator protection against PPARγ phosphorylation and degradation to maintain pancreatic function. MG was used at a noncytotoxic concentration (200 μM) to induce protein kinase C (PKC) and PPARγ phosphorylation in pancreatic RINm5F cells. For in vivo studies, MG (60 mg/kg bw) was intraperitoneally (IP) injected into Balb/C mice for 28 d to induce pancreas damage, at which point we investigated the effect of monascin protection (PPARγ and Nrf2 activator), rosiglitazone (PPARγ activator), allyl isothiocyanate (AITC; Nrf2 activator), or N-acetylcysteine (NAC) on pancreatic function. The in vitro and in vivo results indicated that MG leads to marked PPARγ phosphorylation (serine 82); this effect led to reduction in pancreatic and duodenal homeobox-1 (PDX-1), glucokinase (GCK), and insulin expression. However, monascin and rosiglitazone may protect PPARγ degradation by elevating PDX-1, GCK, and as a result, insulin expression. Monascin and AITC can attenuate PKC activation to suppress PPARγ phosphorylation caused by oxidative stress through the Nrf2 pathway. Similarly, the N-acetylcysteine (NAC) antioxidant also improved oxidative stress and pancreatic function. This study examined whether MG caused impairment of PDX-1, GCK, and insulin through PPARγ phosphorylation and degradation. MG and AGE accumulation improved on Nrf2 activation, thereby protecting against pancreas damage. Taken together, PPARγ activation maintained pancreatic PDX-1, GCK, and insulin expression levels to regulate blood glucose levels.
异常细胞积聚二羰基代谢物甲基乙二醛 (MG) 会导致细胞损伤、炎症和氧化应激。它还与增加蛋白质键合以形成晚期糖基化终产物 (AGE) 或诱导 DNA 链断裂有关。过氧化物酶体增殖物激活受体-γ (PPARγ) 和核因子-红细胞 2 相关因子 2 (Nrf2) 之间的关联尚不清楚。本研究调查了 Nrf2 激活剂对 PPARγ 磷酸化和降解的保护作用，以维持胰腺功能。MG 以非细胞毒性浓度 (200 μM) 用于诱导胰腺 RINm5F 细胞中的蛋白激酶 C (PKC) 和 PPARγ 磷酸化。在体内研究中，MG (60 mg/kg bw) 腹腔内 (IP) 注射到 Balb/C 小鼠中 28 天以诱导胰腺损伤，此时我们研究了 monascin 保护 (PPARγ 和 Nrf2 激活剂)、罗格列酮 (PPARγ 激活剂)、丙烯基异硫氰酸酯 (AITC; Nrf2 激活剂) 或 N-乙酰半胱氨酸 (NAC) 对胰腺功能的影响。体外和体内结果表明，MG 导致明显的 PPARγ 磷酸化 (丝氨酸 82)；这种作用导致胰腺和十二指肠同源盒-1 (PDX-1)、葡糖激酶 (GCK) 和胰岛素表达减少。然而，monascin 和罗格列酮可能通过提高 PDX-1、GCK 并因此提高胰岛素表达来保护 PPARγ 降解。Monascin 和 AITC 可以通过 Nrf2 途径抑制氧化应激引起的 PKC 激活，从而抑制 PPARγ 磷酸化。同样，抗氧化剂 N-乙酰半胱氨酸 (NAC) 也改善了氧化应激和胰腺功能。本研究检查了 MG 是否通过 PPARγ 磷酸化和降解导致 PDX-1、GCK 和胰岛素受损。MG 和 AGE 积累通过 Nrf2 激活得到改善，从而保护胰腺免受损伤。总之，PPARγ 激活维持了胰腺 PDX-1、GCK 和胰岛素的表达水平，从而调节血糖水平。
