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

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.
AuthorsLongxin Qiu, Jianhui Lin, Fangui Xu, Yuehong Gao, Cuilin Zhang, Ying Liu, Yu Luo, James Y Yang
JournalExperimental diabetes research (Exp Diabetes Res) Vol. 2012 Pg. 789730 ( 2012) ISSN: 1687-5303 [Electronic] United States
PMID22110479 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzothiazoles
  • Enzyme Inhibitors
  • PPAR alpha
  • Phthalazines
  • RNA, Small Interfering
  • Triglycerides
  • zopolrestat
  • Aldehyde Reductase
Topics
  • Aldehyde Reductase (antagonists & inhibitors, deficiency)
  • Animals
  • Benzothiazoles (administration & dosage)
  • Diabetes Mellitus (drug therapy)
  • Diabetes Mellitus, Type 2 (complications, drug therapy)
  • Enzyme Inhibitors (administration & dosage)
  • Fatty Liver (prevention & control)
  • Hyperglycemia (metabolism)
  • Liver (chemistry)
  • Male
  • Mice
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease
  • PPAR alpha (physiology)
  • Phosphorylation
  • Phthalazines (administration & dosage)
  • RNA, Small Interfering (administration & dosage)
  • Triglycerides (analysis, blood)

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