Regulation of lipid metabolism by the unfolded protein response

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.

FIGURE 1

The Unfolded Protein Response (UPR) is controlled by three endoplasmic reticulum (ER) stress sensors: inositol‐requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6) and PKR‐like ER kinase (PERK). Upon activation, IRE1 splices x‐box binding protein 1 (XBP1) mRNA, which is then ligated by RTCB and translated into XBP1s. IRE1 also cleaves cytosolic RNA in the process called regulated IRE1 dependent decay (RIDD), which reduces levels of target transcripts. Activated ATF6 is translocated to the Golgi, where its N‐terminal fragment is released by proteases and translocated to the nucleus. PERK‐mediated phosphorylation of eIF2α inhibits a global expression of genes, like SREBP activity‐regulating Insig, and prompts selective translation of ATF4. The figure shows genes involved in lipid metabolism that are regulated by each of the three transcription factors, XBP1s, ATF6f and ATF4, produced by the UPR

FIGURE 2

Overview of the major lipid metabolic pathways regulated by the UPR: Kennedy pathway, TG synthesis, lipogenesis, mevalonate pathway, fatty acid elongation and desaturation, fatty acid oxidation, tricarboxylic acid cycle, very low‐density lipoprotein formation and low‐density lipoprotein uptake. Only key nodes are shown. For further details, see the main text. Abbreviations: ACC, Acetyl‐CoA carboxylase; ACACB, Acetyl‐CoA carboxylase 2; ACAT, acyl‐CoA:cholesterol acyltransferase; ACLY, ATP‐citrate lyase; ACS, Acetyl‐CoA synthetase; CoA, coenzyme A; AGPAT, Acylglycerol‐P acyltransferase; CHKA, Choline kinase alpha; CHKB, Choline kinase beta; CHPT, Cholinephosphotransferase; CPT, Carnitine palmitoyltransferase; CTPCT, Phosphocholine cytidylyltransferase; DG, Diacylglycerol; DGAT2, DG acyltransferase; ELOVL4, Elongation of very long chain fatty acids‐4; ER, Endoplasmic reticulum; FATP2, Fatty acid transport protein 2; FFA, Free fatty acid; FAO, Fatty acid oxidation; FAS, Fatty acid synthase; G3P, Glycerol‐3 phosphate; GLUT1, Glucose transporter 1; GPAT, Glycerol‐P acyltransferase; HMGCR, HMG‐CoA reductase; HMGCS, HMG‐CoA synthase; Ins, insulin; IR, insulin receptor; LDL, Low‐density lipoprotein; LDLR, LDL receptor; LPIN, Lipin; LPA, Lysophosphatidic acid; MTTP, Microsomal TG‐transfer protein complex; PA, phosphatidic acid; PAP, Phosphatidic acid phosphohydrolase; PCSK9, Proprotein convertase subtilisin/kexin type 9; PECR, Peroxisomal trans‐2‐enoyl‐CoA reductase; PDI, Protein disulphide isomerase; PPAR, Peroxisome proliferator‐activated receptor; SCD1, Stearoyl‐CoA desaturase‐1; SREBP, Sterol regulatory element‐binding protein; TCA, tricarboxylic acid cycle; TG, Triglycerides; VLCFA, Very long chain fatty acids; VLDL, Very low‐density lipoproteins

FIGURE 3

The UPR and lipid metabolism pathways. Overview of how the three arms of the UPR interact with the major pathways involved in lipid metabolism. IRE1 signalling has the most diverse functions in lipid metabolism including lipolysis, triacylglycerol (TG) synthesis, fatty acid (FA) elongation and desaturation, low‐density lipoprotein receptor (LDLR) recycling and lipogenesis. The PERK pathway has been reported to regulate FA elongation and desaturation, LDLR recycling, lipogenesis and mevalonate pathway. ATF6 is mostly linked to lipogenesis, mevalonate pathway and FA oxidation