Enhanced synthesis of saturated phospholipids is associated with ER stress and lipotoxicity in palmitate treated hepatic cells

• DOI: 10.1194/jlr.m050237
• Publication Date: 2014-05-24T03:36:24Z
• Authors: Alexandra K. Leamy; Robert A. Egnatchik; Masakazu Shiota; Pavlina T. Ivanova; David S. Myers; H. Alex Brown; Jamey D. Young
• Keywords: nonalcoholic fatty liver disease; 0303 health sciences; Palmitic Acid; phospholipid metabolism; QD415-436; Endoplasmic Reticulum Stress; membrane composition; Biochemistry; lipoapoptosis; Rats; Rats, Sprague-Dawley; 03 medical and health sciences; Liver; Cell Line, Tumor; endoplasmic reticulum stress; Hepatocytes; Animals; saturated fatty acids; Phospholipids

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.