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Cellular mechanisms by which alcohol promotes HIV protease inhibitor‐induced liver lipotoxicity
Author(s) -
Hinton Michael,
Pandak William,
Hylemon Phillip,
Zhou Huiping
Publication year - 2015
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.29.1_supplement.715.22
Subject(s) - chop , lipotoxicity , lipid metabolism , liver injury , unfolded protein response , steatosis , fatty liver , biology , apoptosis , medicine , pharmacology , endocrinology , biochemistry , insulin resistance , diabetes mellitus , disease
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. We have identified endoplasmic reticulum (ER) stress‐induced proapoptotic factor CHOP as an important factor underlying HIV PI‐induced inflammation and hepatic lipotoxicity. However, little is known about the mechanistic pathways by which alcohol promotes HIV PI‐induced hepatic lipotoxicity. The aim of this study was to determine if inhibition of CHOP expression prevents alcohol‐ and HIV PI‐induced apoptosis and dysregulation of lipid metabolism. Methods Primary hepatocytes from wild type or CHOP ‐/‐ mice were treated with individual HIV PIs with or without alcohol. Activation of the key genes responsible for lipid metabolism was determined by real time RT‐PCR and Western Blot. Results CHOP ‐/‐ mice prevent ethanol and HIV PI‐induced dysregulation of key genes involved in lipid metabolism in hepatocytes. CHOP ‐/‐ hepatocytes treated with alcohol showed decreased biosynthesis of cholesterol, fatty acid, and bile acid. Conclusions Activation of the ER stress‐induced proapoptotic factor CHOP is a key cellular mechanism underlying alcohol and HIV PI‐induced hepatotoxicity. CHOP expression is key for alcohol and HIV PI‐induced dysregulation of key genes involved in lipid metabolism in hepatocytes.