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Alcohol and HIV Protease Inhibitor‐induced inflammasome activation and hepatic lipotoxicity
Author(s) -
Hinton Michael,
Pandak William,
Hylemon Phillip,
Zhou Huiping
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.947.4
Subject(s) - inflammasome , western blot , caspase 1 , apoptosis , protease , lipotoxicity , liver injury , immunology , chemistry , medicine , pharmacology , endocrinology , inflammation , biochemistry , enzyme , diabetes mellitus , gene , insulin resistance
The development of highly‐active‐antiretroviral therapy (HAART) has allowed management of HIV and extended the lives of those infected. Alcohol abuse, which is very common in HIV‐1 infected patients, is one of the most important co‐morbid risk factors for liver injury and has been associated with the occurrence of serious metabolic syndrome and subsequent discontinuation of HAART in HIV patients. The importance of the NLRP3 inflammasome in liver diseases has been recognized. Kupffer cells (KC) are the major resident macrophages and play a critical role in regulating hepatic inflammatory response. We have shown that HIV protease inhibitors (PI) increase the production of mature IL‐1β production in macrophages suggesting the activation of NLRP3. The aim of this study is to examine the effect of alcohol and HIV PIs on NLRP3 activation in KCs and characterize the impact of inflammasome activation in KCs on alcohol and HIV PI‐induced hepatic lipotoxicity.Methods Primary mouse KCs were isolated from rat and treated with individual HIV PIs with or without alcohol. The mRNA and protein levels of inflammasome components including NLRP3, ASC, and pro‐caspase were measured by real‐time RT‐PCR and Western blot analysis, respectively. The protein levels of IL‐1β and IL‐18 in cell culture medium were measured using ELISA analysis.Results We found both alcohol and HIV PI‐induced activation of NLRP3 in KCs. The expression of mature IL‐1β and IL‐18 were increased by alcohol and HIV PIs. The active form of caspase‐1 was also increased.Conclusions Activation of inflammasome in KCs is a key cellular mechanism underlying alcohol and HIV PI‐induced hepatotoxicity. Support or Funding Information National Institutes of Health (R21 AI068432, R01 AT04148, R01 AI057189, P01 DK38030, P30 CA16059), VA Merit Award, Merck research fund and Jeffress GrantNational Institutes of Health (F31 AA024713‐01)