Regulation of lipid metabolism by the unfolded protein response.

Matthieu Moncan,Arnaud Blomme,Aitor Almanza,Adrienne M Gorman,Katarzyna Mnich,Afshin Samali

doi:10.1111/jcmm.16255

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.

Highlights

The endoplasmic reticulum (ER) is one of the largest organelles in the cell
The purpose of this review is to describe the role of the unfolded protein response (UPR) in the regulation of lipid metabolism, in order to introduce this complex field to a new audience
| 1367 human disease models associated with impaired lipid homeostasis have been reported to exhibit UPR activation, including atherosclerosis,[105] type 2 diabetes,[106] liver disease,[107] obesity[108] and cancer.[109]

Summary

Introduction

The endoplasmic reticulum (ER) is one of the largest organelles in the cell It is involved in multiple fundamental biological processes including protein folding and secretion, Ca2+ storage and lipid synthesis. In response to stress (eg accumulation of misfolded proteins), the ER triggers the unfolded protein response (UPR), a complex and conserved signalling pathway that is mediated by three ER transmembrane sensor proteins: inositol-requiring enzyme 1 alpha (IRE1α), protein kinase RNA-like ER kinase (PERK) and activating transcription factor 6 (ATF6). Once active, these sensors induce an elaborate and integrated signalling network that either allows restoration of ER homeostasis or triggers cell death.[1]. We have focussed on primary pathways including the synthesis, function and regulation of fatty acids (FAs), TGs, phospholipids (PLs) and cholesterol, and describe their regulation by the UPR

Objectives

Conclusion