Kim Dae Hyun, Kim Seong Min, Lee Bonggi, Lee Eun Kyeong, Chung Ki Wung, Moon Kyoung Mi, An Hye Jin, Kim Kyung Mok, Yu Byung Pal, Chung Hae Young
Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busandaehak-ro, 63 Beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea.
Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busandaehak-ro, 63 Beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea; Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), 70 Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea.
J Nutr Biochem. 2017 Jul;45:104-114. doi: 10.1016/j.jnutbio.2017.04.014. Epub 2017 Apr 22.
In the present study, we attempted to elucidate whether molecular modulation of inflammation by betaine through the forkhead box O1 (FOXO1)-induced NLRP3 inflammasome improves insulin resistance. Betaine is a major water-soluble component of Lycium chinense. It mainly functions as an oxidative metabolite of choline by suppressing superoxide-induced free radicals by donating methyl groups. The FOXO1 transcription factor regulates various genes involved in cellular metabolic processes related to cell death as well as oxidative stress responses through binding to the thioredoxin-interacting protein (TXNIP). Betaine is known to inhibit FOXO1 phosphorylation through phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) in liver cells exposed to insulin. To elucidate the molecular mechanism of inactivation of insulin-induced FOXO1 by the antioxidant betaine, we used HepG2 cells and the liver of db/db mice treated with betaine at a dose of 50 mg/kg/day for 3 weeks. We found that the activation of NLRP3 inflammasome genes was reduced by betaine, which resulted in the suppression of reactive species (RS) production in liver cells. In addition, betaine inhibited insulin-induced PI3K/AKT and FOXO1 activation. Therefore, betaine suppressed the cytokine interleukin-1β production by inhibiting the activation of the NLRP3 inflammasome via interaction of FOXO1 and TXNIP. Our results suggest that betaine inhibits the FOXO1 binding to TXNIP, leading to the suppression of RS-induced NLRP3 inflammasome activation in a diabetic liver.
在本研究中，我们试图阐明甜菜碱通过叉头框O1（FOXO1）诱导的NLRP3炎性小体对炎症进行分子调节是否能改善胰岛素抵抗。甜菜碱是枸杞的主要水溶性成分。它主要作为胆碱的氧化代谢产物，通过提供甲基来抑制超氧化物诱导的自由基。FOXO1转录因子通过与硫氧还蛋白相互作用蛋白（TXNIP）结合，调节与细胞死亡以及氧化应激反应相关的细胞代谢过程中的各种基因。已知在暴露于胰岛素的肝细胞中，甜菜碱可通过磷酸肌醇3激酶（PI3K）/蛋白激酶B（AKT）抑制FOXO1磷酸化。为了阐明抗氧化剂甜菜碱使胰岛素诱导的FOXO1失活的分子机制，我们使用了HepG2细胞和以50 mg/kg/天的剂量用甜菜碱处理3周的db/db小鼠的肝脏。我们发现甜菜碱可降低NLRP3炎性小体基因的激活，这导致肝细胞中活性物质（RS）生成的抑制。此外，甜菜碱抑制胰岛素诱导的PI3K/AKT和FOXO1激活。因此，甜菜碱通过抑制FOXO1与TXNIP的相互作用来抑制NLRP3炎性小体的激活，从而抑制细胞因子白细胞介素-1β的产生。我们的结果表明，甜菜碱抑制FOXO1与TXNIP的结合，导致糖尿病肝脏中RS诱导的NLRP3炎性小体激活受到抑制。
