Quercetin and allopurinol reduce liver thioredoxin‐interacting protein to alleviate inflammation and lipid accumulation in diabetic rats

Background and Purpose Thioredoxin‐interacting protein (TXNIP), a regulator of cellular oxidative stress, has been associated with activation of NOD‐like receptor 3 (NLRP3) inflammasome, inflammation and lipid metabolism, suggesting it has a role in the pathogenesis of non‐alcoholic fatty liver dise...

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Published in:British journal of pharmacology 2013-07, Vol.169 (6), p.1352-1371
Main Authors: Wang, Wei, Wang, Chuang, Ding, Xiao‐Qin, Pan, Ying, Gu, Ting‐Ting, Wang, Ming‐Xing, Liu, Yang‐Liu, Wang, Fu‐Meng, Wang, Shui‐Juan, Kong, Ling‐Dong
Format: Article
Language:English
Subjects:
allopurinol
Allopurinol - pharmacology
Allopurinol - therapeutic use
Animals
Anti-Inflammatory Agents, Non-Steroidal - administration & dosage
Anti-Inflammatory Agents, Non-Steroidal - metabolism
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Anti-Inflammatory Agents, Non-Steroidal - therapeutic use
Antioxidants - administration & dosage
Antioxidants - metabolism
Antioxidants - pharmacology
Antioxidants - therapeutic use
Carrier Proteins - antagonists & inhibitors
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Cycle Proteins
Cell Line
Diabetes Mellitus, Type 1 - complications
Dietary Supplements
Fatty Liver - complications
Fatty Liver - metabolism
Fatty Liver - pathology
Fatty Liver - prevention & control
Gene Silencing
hepatic lipid accumulation
Humans
hyperglycaemia
Inflammasomes - drug effects
Inflammasomes - metabolism
Lipid Metabolism - drug effects
Liver - drug effects
Liver - immunology
Liver - metabolism
Liver - pathology
Male
Molecular Targeted Therapy
NLRP3 inflammasome
Non-alcoholic Fatty Liver Disease
Oxidative Stress - drug effects
PPARα
quercetin
Quercetin - administration & dosage
Quercetin - metabolism
Quercetin - therapeutic use
Random Allocation
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species - antagonists & inhibitors
Reactive Oxygen Species - metabolism
Research Papers
SREBPs
thioredoxin‐interacting protein
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Summary:Background and Purpose Thioredoxin‐interacting protein (TXNIP), a regulator of cellular oxidative stress, has been associated with activation of NOD‐like receptor 3 (NLRP3) inflammasome, inflammation and lipid metabolism, suggesting it has a role in the pathogenesis of non‐alcoholic fatty liver disease (NAFLD) in diabetes. In this study we investigated whether TXNIP is involved in type 1 diabetes‐associated NAFLD and whether antioxidants, quercetin and allopurinol, alleviate NAFLD by targeting TXNIP. Experimental Approach Diabetes was induced in male Sprague‐Dawley rats by a single i.p. injection of 55 mg·kg−1 streptozotocin. Quercetin and allopurinol were given p.o. to diabetic rats for 7 weeks. Hepatic function, oxidative stress, inflammation and lipid levels were determined. Rat BRL‐3A and human HepG2 cells were exposed to high glucose (30 mM) in the presence and absence of antioxidants, TXNIP siRNA transfection or caspase‐1 inhibitor, Ac‐YVAD‐CMK. Key Results Quercetin and allopurinol significantly inhibited the TXNIP overexpression, activation of NLRP3 inflammasome, down‐regulation of PPARα and up‐regulation of sterol regulatory element binding protein‐1c (SREBP‐1c), SREBP‐2, fatty acid synthase and liver X receptor α, as well as elevation of ROS and IL‐1β in diabetic rat liver. These effects were confirmed in hepatocytes in vitro and it was further shown that TXNIP down‐regulation contributed to the suppression of NLRP3 inflammasome activation, inflammation and changes in PPARα and SREBPs. Conclusions and Implications Inhibition of hepatic TXNIP by quercetin and allopurinol contributes to the reduction in liver inflammation and lipid accumulation under hyperglycaemic conditions. The targeting of hepatic TXNIP by quercetin and allopurinol may have therapeutic implications for prevention of type 1 diabetes‐associated NAFLD.
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.12226