Lipid-induced endoplasmic reticulum stress in liver cells results in two distinct outcomes: adaptation with enhanced insulin signaling or insulin resistance

Endocrinology. 2012 May;153(5):2164-77. doi: 10.1210/en.2011-1881. Epub 2012 Feb 28.


Chronically elevated fatty acids contribute to insulin resistance through poorly defined mechanisms. Endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR) have been implicated in lipid-induced insulin resistance. However, the UPR is also a fundamental mechanism required for cell adaptation and survival. We aimed to distinguish the adaptive and deleterious effects of lipid-induced ER stress on hepatic insulin action. Exposure of human hepatoma HepG2 cells or mouse primary hepatocytes to the saturated fatty acid palmitate enhanced ER stress in a dose-dependent manner. Strikingly, exposure of HepG2 cells to prolonged mild ER stress activation induced by low levels of thapsigargin, tunicamycin, or palmitate augmented insulin-stimulated Akt phosphorylation. This chronic mild ER stress subsequently attenuated the acute stress response to high-level palmitate challenge. In contrast, exposure of HepG2 cells or hepatocytes to severe ER stress induced by high levels of palmitate was associated with reduced insulin-stimulated Akt phosphorylation and glycogen synthesis, as well as increased expression of glucose-6-phosphatase. Attenuation of ER stress using chemical chaperones (trimethylamine N-oxide or tauroursodeoxycholic acid) partially protected against the lipid-induced changes in insulin signaling. These findings in liver cells suggest that mild ER stress associated with chronic low-level palmitate exposure induces an adaptive UPR that enhances insulin signaling and protects against the effects of high-level palmitate. However, in the absence of chronic adaptation, severe ER stress induced by high-level palmitate exposure induces deleterious UPR signaling that contributes to insulin resistance and metabolic dysregulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / drug effects
  • Adaptation, Physiological / physiology*
  • Animals
  • Cell Line, Tumor
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / physiology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Humans
  • Insulin / metabolism*
  • Insulin Resistance / physiology*
  • Mice
  • Palmitic Acid / metabolism
  • Palmitic Acid / pharmacology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Unfolded Protein Response / drug effects
  • Unfolded Protein Response / physiology


  • Insulin
  • Palmitic Acid