The role of vitamin D3 in modulating the interplay between NLRP3 inflammasome and autophagy in NASH
Bibliographic Information
Authors: Abdelrahman B.A.; Hammam O.A.; El-Khatib A.S.; Attia Y.M.
Journal: Biochemical and Biophysical Research Communications
Publisher: Elsevier B.V.
Publication Date: December 2023
Volume / Issue: Volume 688
Article No.: 149122
ISSN: 0006291X
DOI: 10.1016/j.bbrc.2023.149122
Scopus: View on Scopus
PubMed: 37951152
Document Type: Article
Access: All Open Access; Hybrid Gold Open Access
Authors and Affiliations
Abdelrahman B.A., Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Hammam O.A., Pathology Department, Theodor Bilharz Research Institute, Cairo, Egypt; El-Khatib A.S., Pharmacology Department, Faculty of Pharmacy, Cairo University, Egypt; Attia Y.M., Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
Abstract
Damage-associated molecular patterns released upon hepatocyte injury ensuing non-alcoholic steatohepatitis (NASH) can stimulate innate immunity by activating NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, thereby triggering pro-inflammatory cascades in the liver. Aberrant NLRP3 activation allied to compromised autophagic clearance of its components contributes to the progression of multiple inflammatory diseases. Such intricate interplay, however, was not fully deciphered in NASH. Prior studies have illuminated the ability of vitamin D3 to temper inflammasome activation in several contexts, prompting us to probe the impact of vitamin D3, particularly its active form, calcitriol (CAL), on NLRP3 overactivation in a high-fat diet (HFD)-based NASH model and its potential dependence on autophagy. Hydroxychloroquine (HCQ), an autophagy inhibitor, was co-administered with CAL to examine the likely modulation of the NLRP3/autophagy crosstalk. Our results showed that treatment with CAL countervailed the histopathological derangement reported in the livers of HFD-fed mice that paralleled a restoration of vitamin D receptor gene expression and reduction in sterol regulatory element binding protein 1c levels. Moreover, p62 was curtailed with CAL treatment indicating autophagy induction. CAL also prompted a reduction in NLRP3, caspase-1, gasdermin D, and IL-18 protein levels along with the apoptosis-associated speck-like protein (ASC) gene expression. Treatment with CAL also reduced IL-1β and caspase-3 immunoreactivities compared to control. Intriguingly, CAL modulatory effects on inflammasome activation were curbed in the group that received HCQ, suggesting a potential autophagy dependency. Accordingly, the current study suggests that CAL was capable of ameliorating NASH via inhibiting NLRP3 inflammasome activation in an autophagy-dependent manner. © 2023 Elsevier Inc.
Keywords
Autophagy; Calcitriol; Hydroxychloroquine; NASH; NLRP3; VDR; Animals; Cholecalciferol; Inflammasomes; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Non-alcoholic Fatty Liver Disease; caspase 3; colecalciferol; cryopyrin; gasdermin; gasdermin D; inflammasome; interleukin 18; interleukin 1beta; interleukin 1beta converting enzyme; sequestosome 1; sterol regulatory element binding protein 1c; unclassified drug; vitamin D receptor; animal cell; animal experiment; animal model; animal tissue; Article; ASC gene; autophagy (cellular); controlled study; down regulation; gene; gene expression; histopathology; immunoreactivity; lipid storage; male; modulation; mouse; nonalcoholic steatohepatitis; nonhuman; protein expression; vitamin D receptor gene; animal; metabolism; nonalcoholic fatty liver
Citation Information
Scopus Citations: 11
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