Blood glucose-lowering nuclear receptor agonists only partially normalize hepatic gene expression in db/db mice
Blood glucose-lowering nuclear receptor agonists only partially normalize hepatic gene expression in db/db mice
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DOI：
10.1124/jpet.105.093831
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发表时间：
2006-02-01
影响因子：
3.5
通讯作者：
Stulnig, TM
中科院分区：
文献类型：
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作者：
Loffler, M;Bilban, M;Stulnig, TM
核受体过氧化物酶体增殖物激活受体（PPAR）γ、PPAR α和肝X受体（LXR）的激动剂可降低2型糖尿病患者和可比较小鼠模型的血糖。由于这些药物使肝脏基因表达正常化的能力尚不清楚，我们比较了用PPAR γ [罗格列酮（Rosi）; 10 mg/kg/天]、PPAR α [Wy 14643]和PPAR β [罗格列酮（Rosi）; 10 mg/kg/天]激动剂治疗的肥胖糖尿病db/db小鼠组，（Wy; 4-氯-6-（2，3-亚甲基）-2-嘧啶基）硫代乙酸）; 30 mg/kg/天]和LXR [T0901317（T09; N-（2，2，2-三氟乙基）N-[ 4-[2，2，2-三氟-1-羟基-1-甲基-IH-吡唑-4-基]苯基]-1-甲基-IH-吡唑并[3，4-d]嘧啶-4-基）-N-[3，4-d]嘧啶-4-酮（三氟甲基）-乙基]苯基]苯磺酰胺）; 40 mg/kg/天]和未治疗的非糖尿病同窝仔（db/+）。用Rosi、Wy和T09对db/db小鼠进行的10天治疗期分别改变了300、620和735个基因的表达，包括激动剂特异性靶基因。然而，在未处理db/+与db/db动物中差异调节的337个基因中，分别只有34个（10%）、51个（15%）和82个（24%）在db/+组的方向上被Rosi、Wy和T09调节。通过药物治疗使基因表达正常化涉及葡萄糖稳态、脂质稳态和局部糖皮质激素激活。此外，我们的数据指出，迄今未知的干扰这些核受体与生长激素受体基因表达和内质网应激。然而，许多糖尿病相关的基因改变不受影响，甚至加重了核受体激动剂治疗。这些结果表明，糖尿病诱导的基因表达是最低限度地逆转强效降糖核受体激动剂。
Agonists of the nuclear receptors peroxisome proliferator-activated receptor ( PPAR) gamma, PPAR alpha, and liver X receptors (LXRs) reduce blood glucose in type 2 diabetic patients and comparable mouse models. Since the capacity of these drugs to normalize hepatic gene expression is not known, we compared groups of obese diabetic db/db mice treated with agonists for PPAR gamma [rosiglitazone (Rosi); 10 mg/kg/day], PPAR alpha [Wy 14643 ( Wy; 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl) thioacetic acid); 30 mg/kg/day], and LXR [T0901317 (T09; N-(2,2,2-trifluoroethyl)N-[ 4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)-ethyl]phenyl]benzenesulfonamide); 40 mg/kg/day] and from untreated nondiabetic litter mates (db/+) by oligonucleotide microarrays and quantitative reverse transcriptase-polymerase chain reaction. The 10-day treatment period of db/db mice with Rosi, Wy, and T09 altered expression of 300, 620, and 735 genes including agonist-specific target genes, respectively. However, from the 337 genes differentially regulated in untreated db/+ versus db/db animals, only 34 (10%), 51 (15%), and 82 (24%) were regulated in the direction of the db/+ group by Rosi, Wy, and T09, respectively. Gene expression normalization by drug treatment involved glucose homeostasis, lipid homeostasis, and local glucocorticoid activation. In addition, our data pointed to hitherto unknown interference of these nuclear receptors with growth hormone receptor gene expression and endoplasmic reticulum stress. However, many diabetes-associated gene alterations remained unaffected or were even aggravated by nuclear receptor agonist treatment. These results suggest that diabetes-induced gene expression is minimally reversed by potent blood glucose-lowering nuclear receptor agonists.