Nagai Yoshio, Yonemitsu Shin, Erion Derek M, Iwasaki Takanori, Stark Romana, Weismann Dirk, Dong Jianying, Zhang Dongyan, Jurczak Michael J, Löffler Michael G, Cresswell James, Yu Xing Xian, Murray Susan F, Bhanot Sanjay, Monia Brett P, Bogan Jonathan S, Samuel Varman, Shulman Gerald I
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06536-8012, USA.
Cell Metab. 2009 Mar;9(3):252-64. doi: 10.1016/j.cmet.2009.01.011.
Peroxisome proliferator-activated receptor gamma coactivator-1 beta (PGC-1beta) is known to be a transcriptional coactivator for SREBP-1, the master regulator of hepatic lipogenesis. Here, we evaluated the role of PGC-1beta in the pathogenesis of fructose-induced insulin resistance by using an antisense oligonucletoide (ASO) to knockdown PGC-1beta in liver and adipose tissue. PGC-1beta ASO improved the metabolic phenotype induced by fructose feeding by reducing expression of SREBP-1 and downstream lipogenic genes in liver. PGC-1beta ASO also reversed hepatic insulin resistance induced by fructose in both basal and insulin-stimulated states. Furthermore, PGC-1beta ASO increased insulin-stimulated whole-body glucose disposal due to a threefold increase in glucose uptake in white adipose tissue. These data support an important role for PGC-1beta in the pathogenesis of fructose-induced insulin resistance and suggest that PGC-1beta inhibition may be a therapeutic target for treatment of NAFLD, hypertriglyceridemia, and insulin resistance associated with increased de novo lipogenesis.
过氧化物酶体增殖物激活受体γ共激活因子1β（PGC-1β）是肝脏脂肪生成的主要调节因子固醇调节元件结合蛋白1（SREBP-1）的转录共激活因子。在此，我们通过使用反义寡核苷酸（ASO）敲低肝脏和脂肪组织中的PGC-1β，评估了PGC-1β在果糖诱导的胰岛素抵抗发病机制中的作用。PGC-1β反义寡核苷酸通过降低肝脏中SREBP-1及其下游脂肪生成基因的表达，改善了果糖喂养诱导的代谢表型。PGC-1β反义寡核苷酸还逆转了果糖在基础状态和胰岛素刺激状态下诱导的肝脏胰岛素抵抗。此外，由于白色脂肪组织中葡萄糖摄取增加了三倍，PGC-1β反义寡核苷酸增加了胰岛素刺激的全身葡萄糖处置。这些数据支持PGC-1β在果糖诱导的胰岛素抵抗发病机制中起重要作用，并表明抑制PGC-1β可能是治疗与从头脂肪生成增加相关的非酒精性脂肪性肝病、高甘油三酯血症和胰岛素抵抗的治疗靶点。
