Inhibition of aldose reductase activates hepatic peroxisome proliferator-activated receptor-α and ameliorates hepatosteatosis in diabetic db/db mice.

Experimental Diabetes Research Pub Date : 2012-01-01 Epub Date: 2011-11-03 DOI:10.1155/2012/789730
Longxin Qiu, Jianhui Lin, Fangui Xu, Yuehong Gao, Cuilin Zhang, Ying Liu, Yu Luo, James Y Yang
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引用次数: 33

Abstract

We previously demonstrated in streptozotocin-induced diabetic mice that deficiency or inhibition of aldose reductase (AR) caused significant dephosphorylation of hepatic transcriptional factor PPARα, leading to its activation and significant reductions in serum lipid levels. Herein, we report that inhibition of AR by zopolrestat or by a short-hairpin RNA (shRNA) against AR caused a significant reduction in serum and hepatic triglycerides levels in 10-week old diabetic db/db mice. Meanwhile, hyperglycemia-induced phosphorylation of hepatic ERK1/2 and PPARα was significantly attenuated in db/db mice treated with zopolrestat or AR shRNA. Further, in comparison with the untreated db/db mice, the hepatic mRNA expression of Aco and ApoA5, two target genes for PPARα, was increased by 93% (P < 0.05) and 73% (P < 0.05) in zopolrestat-treated mice, respectively. Together, these data indicate that inhibition of AR might lead to significant amelioration in hyperglycemia-induced dyslipidemia and nonalcoholic fatty liver disease.

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抑制醛糖还原酶可激活肝过氧化物酶体增殖物激活受体-α,改善糖尿病db/db小鼠的肝骨化病。
我们之前在链脲霉素诱导的糖尿病小鼠中证明,醛糖还原酶(AR)的缺乏或抑制导致肝脏转录因子PPARα的显著去磷酸化,导致其激活和血清脂质水平的显著降低。在本研究中,我们报告了唑来司他或短发夹RNA (shRNA)对AR的抑制作用可显著降低10周龄糖尿病小鼠的血清和肝脏甘油三酯水平。同时,zopolrestat或AR shRNA处理的db/db小鼠高血糖诱导的肝脏ERK1/2和PPARα磷酸化显著减弱。此外,与未处理的db/db小鼠相比,唑复司他处理小鼠肝脏中PPARα的两个靶基因Aco和ApoA5的mRNA表达量分别提高了93% (P < 0.05)和73% (P < 0.05)。总之,这些数据表明,抑制AR可能导致高血糖诱导的血脂异常和非酒精性脂肪肝疾病的显著改善。
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来源期刊
Experimental Diabetes Research
Experimental Diabetes Research 医学-内分泌学与代谢
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3-8 weeks
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