Pharmacologic activation of the sarco‐endoplasmic reticulum ATPase (SERCA) reduces palmitate‐mediated endoplasmic reticulum stress in liver cells

Abstract

PurposeElevated fatty acids, in particular saturated fatty acids, have been shown to induce endoplasmic reticulum (ER) stress in numerous cell types including hepatocytes. However, the specific mechanisms that link saturated fatty acids to ER stress are poorly understood. Calcium is a critical cofactor for chaperone‐mediated protein folding in the ER. Previous studies have demonstrated that palmitate, a saturated fatty acid, reduces ER lumenal calcium stores, which are maintained by the activities of three ER‐bound proteins: the inositol triphosphate receptor, the ryanodine receptor, and SERCA. In the present study, we examined whether palmitate‐induced ER stress could be mitigated via activation of SERCA.MethodsH4IIE liver cells (n=3) were treated with control media or control media supplemented with palmitate (250μM), a saturated fatty acid that induces ER stress, oleate (250μM), an unsaturated fatty acid that does not induce ER stress, or a combination of both palmitate and oleate that does not induce ER stress. Treatments were administered in the presence or absence of CDN1163 (10μM), a SERCA pump activator, for 6 hours.ResultsOnly palmitate treated cells were characterized by increased ER stress. Co‐incubation with CDN1163 reduced palmitate‐mediated ER stress. These data suggest that palmitate‐mediated ER stress involves a reduction in SERCA activity.Support or Funding InformationNIH: DIK072017