Benzyl isothiocyanate ameliorates high-fat/cholesterol/cholic acid diet-induced nonalcoholic steatohepatitis through inhibiting cholesterol crystal-activated NLRP3 inflammasome in Kupffer cells.

Abstract

Incidence of nonalcoholic fatty liver disease is increasing worldwide. Activation of the NLRP3 inflammasome is central to the development of diet-induced nonalcoholic steatohepatitis (NASH). We investigated whether benzyl isothiocyanate (BITC) ameliorates diet-induced NASH and the mechanisms involved. C57BL/6 J mice fed a high-fat diet containing cholesterol and cholic acid (HFCCD) and Kupffer cells stimulated with LPS and cholesterol crystals (CC) were studied. LPS/CC increased the expression of the active form of caspase 1 (p20) and the secretion of IL-1β by Kupffer cells, and these changes were reversed by MCC950, an NLRP3 inflammasome inhibitor. LPS/CC-induced NLRP3 inflammasome activation and IL-1β production were dose-dependently attenuated by BITC. BITC decreased cathepsin B release from lysosomes and binding to NLRP3 induced by LPS/CC. Compared with a normal diet, the HFCCD increased serum levels of ALT, AST, total cholesterol, and IL-1β and hepatic contents of triglycerides and total cholesterol. BITC administration (0.1% in diet) reversed the increase in AST and hepatic triglycerides in the HFCCD group. Moreover, BITC suppressed lipid accumulation, macrophage infiltration, fibrosis, crown-like structure formation, and p20 caspase 1 and p17 IL-1β expression in liver in the HFCCD group. These results suggest that BITC ameliorates HFCCD-induced steatohepatitis by inhibiting the activation of NLRP3 inflammasome in Kupffer cells and may protect against diet-induced NASH.

• Authors: Haw-Wen Chen, Chih-Ching Yen, Li-Li Kuo, Chia-Wen Lo, Chin-Shiu Huang, Chih-Chieh Chen, Chong-Kuei Lii
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 393 Pg. 114941 (04 15 2020) ISSN: 1096-0333 [Electronic] United States
• PMID: 32126212 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Cholesterol, Dietary
• IL1B protein, mouse
• Inflammasomes
• Interleukin-1beta
• Isothiocyanates
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Triglycerides
• benzyl isothiocyanate
• Cholesterol
• Cholic Acid

Topics

• Animals
• Cholesterol (blood, chemistry)
• Cholesterol, Dietary (adverse effects)
• Cholic Acid (adverse effects)
• Diet, High-Fat (adverse effects)
• Dose-Response Relationship, Drug
• Inflammasomes (drug effects)
• Interleukin-1beta (metabolism)
• Isothiocyanates (therapeutic use)
• Kupffer Cells (drug effects)
• Lipid Metabolism (drug effects)
• Liver (metabolism)
• Liver Function Tests
• Male
• Mice
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein (antagonists & inhibitors)
• Non-alcoholic Fatty Liver Disease (drug therapy, etiology)
• Triglycerides (metabolism)