Genistein upregulates AHR to protect against environmental toxin-induced NASH by inhibiting NLRP3 inflammasome activation and reconstructing antioxidant defense mechanisms.

Abstract

We have previously proven that the environmental toxin could accelerate the development and progression of nonalcoholic steatohepatitis (NASH). However, the underlying mechanism associated with such excessive inflammation hasn't been fully illustrated. Although Genistein has been well accepted for its capability in anti-inflammation and anti-oxidation, its effect in ameliorating contaminants-induced NASH still needs to be identified. In this study, using chickens and primary chicken hepatocytes as models, we found that NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome were over-activated in bromoacetic acid (BAA, one of the typical environmental toxins)-induced NASH, characterized by the infiltration of inflammatory cell, and the increase of NLRP3, Caspase-1 p20, and cytokines (IL-1β, IL-18) expressions. Interestingly, genistein treatment could recover these changes, with the signs of restored activities of anti-oxidases, decreased expressions of NLRP3 inflammasome components, and increased levels of elements in phase I metabolic system. The detailed mechanism was that, via up-regulating aryl hydrocarbon receptor (AHR), genistein lifted mRNA levels of Cyp1-related genes to reconstruct cytochrome P450 (CYP450) systems, and the raised AHR negatively regulated NLRP3 inflammasome activity to relieve inflammation. More important, the interaction and co-localization between AHR and NLRP3 was first proved, and genistein could promote the levels of AHR that interacted with NLRP3, which thereafter blocked the activation of NLRP3 inflammasome. Conclusively, in this research, we confirmed the AHR-dependent protective role of genistein in environmental toxin-linked NASH, which shed light on the potential precautions for contaminants-induced NASH.

• Authors: Shuhui Liu, Jiwen Liu, Yuting Wu, Lei Tan, Yan Luo, Chenchen Ding, Zhihui Tang, Xizhi Shi, Wentao Fan, Suquan Song
• Journal: The Journal of nutritional biochemistry (J Nutr Biochem) Vol. 121 Pg. 109436 (Nov 2023) ISSN: 1873-4847 [Electronic] United States
• PMID: 37666477 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.