Regulation of lipid metabolism by the unfolded protein response

J Cell Mol Med. 2021 Feb;25(3):1359-1370. doi: 10.1111/jcmm.16255. Epub 2021 Jan 4.

Abstract

The endoplasmic reticulum (ER) is the site of protein folding and secretion, Ca2+ storage and lipid synthesis in eukaryotic cells. Disruption to protein folding or Ca2+ homeostasis in the ER leads to the accumulation of unfolded proteins, a condition known as ER stress. This leads to activation of the unfolded protein response (UPR) pathway in order to restore protein homeostasis. Three ER membrane proteins, namely inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like ER kinase (PERK) and activating transcription factor 6 (ATF6), sense the accumulation of unfolded/misfolded proteins and are activated, initiating an integrated transcriptional programme. Recent literature demonstrates that activation of these sensors can alter lipid enzymes, thus implicating the UPR in the regulation of lipid metabolism. Given the presence of ER stress and UPR activation in several diseases including cancer and neurodegenerative diseases, as well as the growing recognition of altered lipid metabolism in disease, it is timely to consider the role of the UPR in the regulation of lipid metabolism. This review provides an overview of the current knowledge on the impact of the three arms of the UPR on the synthesis, function and regulation of fatty acids, triglycerides, phospholipids and cholesterol.

Keywords: PRKR-like endoplasmic reticulum kinase; activating transcription factor 6; cholesterol; endoplasmic reticulum; fatty acid; inositol-requiring enzyme 1; lipid metabolism; phospholipid; triglyceride; unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Biomarkers
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress
  • Gene Expression Regulation*
  • Humans
  • Lipid Metabolism*
  • Metabolic Networks and Pathways
  • Unfolded Protein Response*

Substances

  • Biomarkers