title: Enhanced synthesis of saturated phospholipids is associated with ER stress and lipotoxicity in palmitate treated hepatic cells.
abstract: High levels of saturated FAs (SFAs) are acutely toxic to a variety of cell types, including hepatocytes, and have been associated with diseases such as type 2 diabetes and nonalcoholic fatty liver disease. SFA accumulation has been previously shown to degrade endoplasmic reticulum (ER) function leading to other manifestations of the lipoapoptotic cascade. We hypothesized that dysfunctional phospholipid (PL) metabolism is an initiating factor in this ER stress response. Treatment of either primary hepatocytes or H4IIEC3 cells with the SFA palmitate resulted in dramatic dilation of the ER membrane, coinciding with other markers of organelle dysfunction. This was accompanied by increased de novo glycerolipid synthesis, significant elevation of dipalmitoyl phosphatidic acid, diacylglycerol, and total PL content in H4IIEC3 cells. Supplementation with oleate (OA) reversed these markers of palmitate (PA)-induced lipotoxicity. OA/PA cotreatment modulated the distribution of PA between lipid classes, increasing the flux toward triacylglycerols while reducing its incorporation into PLs. Similar trends were demonstrated in both primary hepatocytes and the H4IIEC3 hepatoma cell line. Overall, these findings suggest that modifying the FA composition of structural PLs can protect hepatocytes from PA-induced ER stress and associated lipotoxicity.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235-1604.
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Leamy
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235-1604.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Egnatchik
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37235-1604.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shiota
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37235-1604.
authors.forename: Pavlina T
authors.initials: PT
authors.lastname: Ivanova
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37235-1604.
authors.forename: David S
authors.initials: DS
authors.lastname: Myers
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37235-1604 Department of Biochemistry, Vanderbilt University, Nashville, TN 37235-1604 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37235-1604.
authors.forename: H Alex
authors.initials: HA
authors.lastname: Brown
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235-1604 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37235-1604.
authors.forename: Jamey D
authors.initials: JD
authors.lastname: Young
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D019308:Palmitic Acid / Q000633:toxicity*; D010743:Phospholipids / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D010743:Phospholipids; D019308:Palmitic Acid
keywords: endoplasmic reticulum stress; lipoapoptosis; membrane composition; nonalcoholic fatty liver disease; phospholipid metabolism; saturated fatty acids; triacylglycerol synthesis