Differential effects of rexinoids and thiazolidinediones on metabolic gene expression in diabetic rodents
Differential effects of rexinoids and thiazolidinediones on metabolic gene expression in diabetic rodents
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DOI：
10.1124/mol.59.4.765
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发表时间：
2001-04-01
影响因子：
3.6
通讯作者：
Davies, PJA
中科院分区：
文献类型：
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作者：
Ahuja, HS;Liu, S;Davies, PJA
类维生素A X受体（RXR）选择性激动剂（rexinoids）和噻唑烷二酮（TZDs），过氧化物酶体增殖物激活受体（过氧化物酶体增殖物激活受体）-γ-特异性配体，在糖尿病啮齿动物中产生胰岛素敏化。体外研究表明，TZD通过RXR/PPAR-gamma复合物介导其作用。为了确定rexinoids是否通过在体内激活RXR/PPAR-gamma异源二聚体来降低高血糖，我们比较了rexinoids（LG 100268）和TZD（罗格列酮）对Zucker糖尿病肥胖大鼠（ZDF）的白色脂肪组织、骨骼肌和肝脏中基因表达的影响。在脂肪组织中，罗格列酮降低肿瘤坏死因子-α（TNF-α）mRNA，诱导葡萄糖转运蛋白4（GLUT 4）、肌肉肉毒碱棕榈酰转移酶（MCPT）、硬脂酰CoA去饱和酶（SCD 1）和脂肪酸转位酶（CD 36）。相反，LG 100268增加TNF-α，对GLUT 4、MCPT、SCD 1和CD 36的表达没有影响或抑制。在肝脏中，rexinoid增加MCPT，SCD 1和CD 36 mRNA，而罗格列酮仅诱导CD 36小幅增加。在骨骼肌中，罗格列酮和LG 100268具有相似的作用;均增加SCD 1和CD 36 mRNA。在这些研究中发现的rexinoids和TZD在糖尿病动物中诱导的基因模式的差异表明，这些化合物可能对体内代谢控制具有独立的和组织特异性的作用。
Both retinoid X receptor (RXR)-selective agonists (rexinoids) and thiazolidinediones (TZDs), PPAR (peroxisome proliferator-activated receptor)-gamma -specific ligands, produce insulin sensitization in diabetic rodents. In vitro studies have demonstrated that TZDs mediate their effects via the RXR/PPAR-gamma complex. To determine whether rexinoids lower hyperglycemia by activating the RXR/PPAR-gamma heterodimer in vivo, we compared the effects of a rexinoid (LG100268) and a TZD (rosiglitazone) on gene expression in white adipose tissue, skeletal muscle, and liver of Zucker diabetic fatty rats (ZDFs). In adipose tissue, rosiglitazone decreased tumor necrosis factor-alpha (TNF-alpha) mRNA and induced glucose transporter 4 (GLUT4), muscle carnitine palmitoyl-transferase (MCPT), stearoyl CoA desaturase (SCD1), and fatty acid translocase (CD36). In contrast, LG100268 increased TNF-alpha and had no effect or suppressed the expression of GLUT4, MCPT, SCD1, and CD36. In liver, the rexinoid increased MCPT, SCD1, and CD36 mRNAs, whereas rosiglitazone induced only a small increase in CD36. In skeletal muscle, rosiglitazone and LG100268 have similar effects; both increased SCD1 and CD36 mRNAs. The differences in the pattern of genes induced by the rexinoids and the TZDs in diabetic animals found in these studies suggests that these compounds may have independent and tissue-specific effects on metabolic control in vivo.