Aldo-keto reductase 1B7 is a target gene of FXR and regulates lipid and glucose homeostasis.
*Aldehyde Reductase/genetics/metabolism; Adenoviridae; Animal; Animals; Blood Glucose/*metabolism; Cholesterol/analysis; Cytoplasmic and Nuclear/genetics/*metabolism; Diabetes Mellitus/genetics/*metabolism/physiopathology; Disease Models; Fatty Liver/genetics/*metabolism/physiopathology; Gene Expression; Genetic Vectors; Gluconeogenesis/genetics; Homeostasis; Humans; Liver/*metabolism/physiopathology; Malondialdehyde/blood; Mice; Polymerase Chain Reaction; Receptors; Transfection; Transgenic; Triglycerides/analysis
Aldo-keto reductase 1B7 (AKR1B7) is proposed to play a role in detoxification of by-products of lipid peroxidation. In this article, we show that activation of the nuclear receptor farnesoid X receptor (FXR) induces AKR1B7 expression in the liver and intestine, and reduces the levels of malondialdehyde (MDA), the end product of lipid peroxidation, in the intestine but not in the liver. To determine whether AKR1B7 regulates MDA levels in vivo, we overexpressed AKR1B7 in the liver. Overexpression of AKR1B7 in the liver had no effect on hepatic or plasma MDA levels. Interestingly, hepatic expression of AKR1B7 significantly lowered plasma glucose levels in both wild-type and diabetic db/db mice, which was associated with reduced hepatic gluconeogenesis. Hepatic expression of AKR1B7 also significantly lowered hepatic triglyceride and cholesterol levels in db/db mice. These data reveal a novel function for AKR1B7 in lipid and glucose metabolism and suggest that AKR1B7 may not play a role in detoxification of lipid peroxides in the liver. AKR1B7 may be a therapeutic target for treatment of fatty liver disease associated with diabetes mellitus.
Ge Xuemei; Yin Liya; Ma Huiyan; Li Tiangang; Chiang John Y L; Zhang Yanqiao
Journal of lipid research
2011
2011-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1194/jlr.M015859" target="_blank" rel="noreferrer noopener">10.1194/jlr.M015859</a>
Synthesis and biological evaluations of chalcones, flavones and chromenes as farnesoid x receptor (FXR) antagonists.
Animals; Antagonist; Benzopyrans/chemical synthesis/*pharmacology; Chalcones; Chalcones/chemical synthesis/*pharmacology; Chromenes; Cytoplasmic and Nuclear/*antagonists & inhibitors; Farnesoid X receptor; Flavones/chemical synthesis/*pharmacology; Liver Diseases/drug therapy; Liver/chemistry/*drug effects/metabolism; Mice; Receptors; Triglycerides/analysis
Farnesoid X receptor (FXR), a nuclear receptor mainly distributed in liver and intestine, has been regarded as a potential target for the treatment of various metabolic diseases, cancer and infectious diseases related to liver. Starting from two previously identified chalcone-based FXR antagonists, we tried to increase the activity through the design and synthesis of a library containing chalcones, flavones and chromenes, based on substitution manipulation and conformation (ring closure) restriction strategy. Many chalcones and four chromenes were identified as microM potent FXR antagonists, among which chromene 11c significantly decreased the plasma and hepatic triglyceride level in KKay mice.
Zhang Guoning; Liu Shuainan; Tan Wenjuan; Verma Ruchi; Chen Yuan; Sun Deyang; Huan Yi; Jiang Qian; Wang Xing; Wang Na; Xu Yang; Wong Chiwai; Shen Zhufang; Deng Ruitang; Liu Jinsong; Zhang Yanqiao; Fang Weishuo
European journal of medicinal chemistry
2017
2017-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ejmech.2017.02.037" target="_blank" rel="noreferrer noopener">10.1016/j.ejmech.2017.02.037</a>