The role of ER stress in lipid metabolism and lipotoxicity

Abstract

The endoplasmic reticulum (ER) is a cellular organelle important for regulating calcium homeostasis, lipid metabolism, protein synthesis, and posttranslational modification and trafficking. Numerous environmental, physiological, and pathological insults disturb ER homeostasis, referred to as ER stress, in which a collection of conserved intracellular signaling pathways, termed the unfolded protein response (UPR), are activated to maintain ER function for cell survival. However, excessive and/or prolonged UPR activation leads to initiation of self-destruction through apoptosis. Excessive accumulation of lipids and their intermediate products causes metabolic abnormalities and cell death, called lipotoxicity, in peripheral organs, including the pancreatic islets, liver, muscle, and heart. Because accumulating evidence links chronic ER stress and defects in UPR signaling to lipotoxicity in peripheral tissues, understanding the role of ER stress in cell physiology is a topic under intense investigation. In this review, we highlight recent findings that link ER stress and UPR signaling to the pathogenesis of peripheral organs due to lipotoxicity.

Keywords: cell signaling; diabetes; endoplasmic reticulum; fatty acid; lipids.

Fig. 1.

ER stress and the UPR. Numerous environmental, physiological, and pathological insults cause ER stress and activate the UPR. The UPR is signaled by three ER membrane-bound proteins, PERK, IRE1α, and ATF6α, to resolve ER homeostasis through translational and transcriptional changes in response to ER stress. PERK phosphorylates eIF2α to attenuate protein synthesis, which preferentially activates ATF4 mRNA translation to induce its target genes, CHOP and GADD34. Activated IRE1α cleaves XBP1 mRNA to produce a spliced form that translates a novel polypeptide, XBP1s, to upregulate genes involved in ER membrane biogenesis, ER folding and trafficking, and ERAD. ATF6α traffics to Golgi apparatus for cleavage by S1P and S2P, which release p50ATF6α that transcriptionally induces its target genes encoding ER chaperone and ERAD functions.

Fig. 2.

ER stress and lipid metabolism. ER stress and UPR induction alters expression of genes in lipid metabolism. PERK/eIF2α phosphorylation activates SREBP-1c and SREBP-2. ATF4 upregulates expression of SCD1, FAS, ACC, and SREBP-1c. CHOP also negatively regulates the activity of C/EBPα and C/EBPβ. IRE1α is involved in lipid metabolism by suppressing the expression of C/EBPβ, C/EBPδ, and PPARγ. XBP1s regulated expression of SCD1, DGAT2, and ACC. ATF6α interacts with the nuclear form of SREBP-2 to antagonize SREBP-2-mediated transcription of lipogenic genes. ATF6α also upregulates SREBP-1c expression.

Fig. 3.

ER stress and lipotoxicity. SFAs cause ER stress in numerous peripheral tissues, including pancreatic β cells, hepatocytes, skeletal myocytes, and cardiomyocytes, leading to cell dysfunction or death through lipotoxicity. In pancreatic β cells, SFA-mediated ER stress induces protein palmitoylation, alteration in sphingolipid metabolism, and depletion of ER Ca²⁺. In the liver, ER stress induces ROS production, saturation of membrane phospholipid, induction of VLDLR expression, and reduction of PPARα and FXR expression. In skeletal muscle, it is not clear whether ER stress is directly involved in SFA-mediated lipotoxicity. In the heart, ER stress induces expression of VLDLR to cause lipotoxicity. In each organ, inhibition of ER stress can prevent SFA-mediated lipotoxicity.