title: 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.
authors: State Key Laboratory for Stress Cellular Biology and Department of Biomedical Sciences, School of Life Sciences, Xiamen University, Xiamen 361005, China.
authors: Longxin
authors: L
authors: Qiu
authors: Jianhui
authors: J
authors: Lin
authors: Fangui
authors: F
authors: Xu
authors: Yuehong
authors: Y
authors: Gao
authors: Cuilin
authors: C
authors: Zhang
authors: Ying
authors: Y
authors: Liu
authors: Yu
authors: Y
authors: Luo
authors: James Y
authors: JY
authors: Yang
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000172:deficiency; D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage; D003920:Diabetes Mellitus / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005234:Fatty Liver / Q000517:prevention & control*; D006943:Hyperglycemia / Q000378:metabolism; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D047493:PPAR alpha / Q000502:physiology*; D010766:Phosphorylation; D010793:Phthalazines / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000008:administration & dosage; D014280:Triglycerides / Q000032:analysis / Q000097:blood
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D047493:PPAR alpha; D010793:Phthalazines; D034741:RNA, Small Interfering; D014280:Triglycerides; C067172:zopolrestat; D000449:Aldehyde Reductase