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Palmitate‐induced alterations in phospholipid composition promote ER stress and cellular dysfunction in hepatic lipotoxicity (1001.2)
Author(s) -
Leamy Alexandra,
Egnatchik Robert,
Shiota Masakazu,
Jacobson David,
Young Jamey
Publication year - 2014
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.28.1_supplement.1001.2
Subject(s) - lipotoxicity , endocrinology , unfolded protein response , medicine , chemistry , apoptosis , oxidative stress , reactive oxygen species , saturated fatty acid , microbiology and biotechnology , biology , biochemistry , fatty acid , insulin resistance , insulin
Lipotoxicity induced by saturated fatty acid (SFA) accumulation has been postulated as a contributing factor in the pathogenesis of diseases such as non‐alcoholic fatty liver disease (NAFLD) and type II diabetes. Our central hypothesis is that overexposure to SFAs results in increased saturation of ER membrane phospholipids, which induces ER stress marked by calcium efflux and CHOP overexpression, ultimately culminating in apoptosis. Our objective is to determine how perturbations of pathways involved in lipid metabolism modulate SFA‐induced lipotoxicity, as assessed by measurements of phospholipid (PL) composition, ER stress, reactive oxygen species (ROS) accumulation and apoptotic cell death. Using the calcium chelator BAPTA, we suppressed downstream markers of lipotoxicity such as ROS accumulation and caspase activation, but were unable to prevent ER dysfunction. Interventions designed to reduce PA incorporation into PLs by increasing triglyceride synthesis resulted in elevated levels of lipid accumulation but significantly reversed PA‐induced increases in PL saturation, abnormalities in ER membrane structure and homeostasis, and all other phenotypic markers of hepatic lipotoxicity. Our data indicate that by modulating alternative pathways of hepatic lipid metabolism upstream of PL incorporation, the lipotoxic effects of SFAs can be significantly reduced. Grant Funding Source : Supported by: National Science Foundation Career Award 0955251