Reduced Luminal Calcium and Chaperone Function in Response to Elevated Free Fatty Acids in Liver Cells

Abstract

Chronic exposure to elevated free fatty acids, in particular long chain saturated fatty acids, provokes endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR) and cell death in a number of cell types. The perturbations to the ER that instigate ER stress and activation of the unfolded protein response to fatty acids in hepatocytes have not been identified. The present study employed H4IIE liver cells and primary rat hepatocytes to examine the hypothesis that saturated fatty acids induce ER stress via effects on ER luminal calcium stores and reduced chaperone function. Exposure of H4IIE liver cells and primary hepatocytes to palmitate and stearate reduced thapsigargin‐sensitive calcium stores and induced multiple markers of ER stress and UPR activation over similar time courses (6h). Increased cell death was observed following 16h of exposure. Co‐incubation with oleate prevented the reduction in calcium stores, induction of ER stress markers and cell death. Since several ER molecular chaperones function in a calcium‐dependent manner, the effects of chemical chaperones on palmitate‐mediated ER stress and cell death was examined. The chemical chaperones, 4‐phenyl butyric acid and taurine‐conjugated ursodeoxycholic acid, reduced palmitate‐mediated ER stress and cell death. These data suggest that reduced ER luminal calcium and protein folding capacity contribute to long chain saturated fatty acid‐mediated perturbations in the ER.