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Regulatation of hepatic lipid metabolism by glutaredoxin‐1 and protein glutathione‐adducts
Author(s) -
Shao Di,
Han Jingyan,
Hou Xiuyun,
Fry Jessica,
Behring Jessica,
Yao Chunxiang,
Weng Xiang,
Pimentel David,
Long Michelle,
Roy Hemant,
Seta Francesca,
Cohen Richard,
Matsui Reiko,
Bachschmid Markus
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.570.5
Subject(s) - glutaredoxin , glutathione , biochemistry , chemistry , steatosis , lipid metabolism , microbiology and biotechnology , biology , enzyme , endocrinology
Objective Oxidants can contribute to cellular signaling via glutathione‐(GSH) adducts, which are reversible post‐translational modifications of proteins that alter their function. Glutaredoxin‐1 (Glrx) is an enzyme that specifically removes these GSH‐adducts and modulates enzyme activity. We aimed to study the physiological role of Glrx and protein GSH‐adducts in vivoMethods Whole body Glrx knockout mice (Glrx ‐/‐ ) were created in a C57BL/6J strain and metabolic alterations were monitored over eight months Results Chow fed Glrx ‐/‐ mice developed obesity, hepatic steatosis and hyperlipidemia. The key enzyme in hepatic lipid biosynthesis, fatty acid synthase (FASN), was upregulated by 50% in Glrx ‐/‐ mice. Liver‐specific adenoviral Glrx reconstitution of Glrx‐/‐ mice down‐regulated hepatic FASN and normalized hepatic and plasma lipid levels. The central metabolic regulator sirtuin‐1 (SirT1), regulates FASN expression. Here, we found that elevated GSH‐adducts on SirT1 in Glrx ‐/‐ mice inhibited SirT1 activity leading to increased FASN transcription. Conclusions Our data suggest that Glrx regulates SirT1 activity in vivo through GSH‐adducts thereby modulating hepatic and plasma lipids.