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Nutritional Stress Activates C/EBPb and Induces Hepatic Steatosis In Vivo: Attenuation by AMP Kinase
Author(s) -
Friedman Jacob E,
Rahman Shaikh Mizanoor,
Schroeder Jill M,
Qadri Ishtiaq
Publication year - 2006
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.20.4.a523-b
Subject(s) - ampk , endocrinology , steatosis , medicine , unfolded protein response , fatty liver , protein kinase a , chemistry , amp activated protein kinase , biology , kinase , microbiology and biotechnology , endoplasmic reticulum , disease
CCAAT/Enhancer Binding Protein β plays an important role in transcriptional regulation of metabolic genes in the liver and is induced by ER stress agents, suggesting it may be important for coordinating common metabolic and stress remediation strategies. Here we show that mice deficient in C/EBPβ are protected from hepatic steatosis, while C/EBPβ over‐expression in the liver using adenovirus‐mediated gene delivery triggers ER stress response marker proteins (pPERK, p‐eIF2α, pJNK), down‐regulates pAMPK, and triggers triglyceride accumulation in the liver of normal mice. To investigate the role of AMP Kinase further on these events, FAO hepatoma cells were treated with AICAR, a pharmacological activator of AMPK, or adenovirus expressing a dominant negative subunit of AMPKα1 (adv‐DN‐AMPK). Pretreatment with 0.5 mM AICAR suppressed ER stress‐induced C/EBPβ expression (using either thapsigargin or 0.5 mM glucose) and prevented ER stress protein activation (pPERK, p‐eIF2α), while DN‐AMPKα1 blocked AICAR‐mediated C/EBPβ suppression, suggesting that regulation of C/EBPβ in response to ER stress is AMPK dependent. Finally, a mouse model of non‐alcoholic steatosis (NASH) fed a methionine‐choline deficient diet for 3 weeks induced a 3‐fold increase in liver TG content along with significantly increasing C/EBPβ, PPARγ, p‐PERK and p‐eIF2, while significantly depleting p‐AMPK and levels of the adiponectin receptor. These findings suggest that C/EBPβ plays an important role in ER stress mediated hepatic steatosis, which may be ameliorated by AMPK. Supported by NIH‐DK05967