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Endoplasmic Reticulum Stress and Lipid Metabolism 1 Mike F ENDOPLASMIC RETICULUM STRESS AND LIPID METABOLISM 1 MIKE F. RENNE ABSTRACT specialized for different functions and Upon endoplasmic reticulum (ER) stress, therefore differ in form. The cisternal ER the unfolded protein response (UPR) is continuous with the nuclear envelope triggers cellular mechanisms to restore and is studded with ribosomes, thus the ER homeostasis. Aberrancies in lipid cisternal sheets are the location of protein homeostasis can cause alterations in synthesis and folding. The tubular ER is biochemical and biophysical properties enriched in tissues specializing in the of the ER membrane, which impair ER biosynthesis of lipids and steroids and the function and induce UPR signaling. The large amount of enzymes required for UPR is also involved in regulation of lipid these processes. In addition to metabolism and membrane biogenesis, anterograde or retrograde vesicular indicating a link between ER-stress and transport, the ER can form membrane lipid homeostasis. In this review, we will junctions, or contact sites, with other discuss how alterations in lipid organelles to facilitate inter-organelle metabolism can activate the UPR, as well trafficking of lipids, enzymes and other as how the UPR alters lipid metabolism compounds. to relieve stress from the ER. When something goes wrong in cellular homeostasis, such as the accumulation of INTRODUCTION unfolded or misfolded proteins due to The endoplasmic reticulum is part of the inherited mutations, calcium- or oxidative endomembrane system, which further flux, the cell can be under (ER) stress. In consists of the nuclear envelope, plasma 1988, a stress response to unfolded membrane (PM), Golgi apparatus, proteins was reported, which we now endosomes, lysosomes, lipid droplets, know as the unfolded protein response peroxisomes and secretory vesicles. The (UPR) (Kozutsumi, Segal, Normington, ER is the entry point to the secretory Gething, & Sambrook, 1988). ER stress is pathway, and plays a central role in the synonymous with the activation of the synthesis of proteins but is also the site of UPR. The key signaling proteins for the phospholipid biosynthesis. It is UPR are ER-localised transmembrane responsible for all de novo synthesis of proteins that communicate perturbations membranes within the cell and has a within the lumen to initiate downstream dynamic membrane structure that allows cytoplasmic signaling cascades that fast expansion to accommodate protein function to resolve stress or, when in and membrane biosynthesis. The ER crisis, signal apoptosis. Chronic ER stress consists of the cisternal ER (historically has therefore been implicated in the referred to as “rough ER”) and tubular ER pathogenesis of many degenerative (historically referred to as “smooth ER”). diseases associated with lipid metabolism, Both compartments of the ER are 1Membrane Biochemistry & Biophysics, Bijvoet Centre for Biomolecular Research and Institute of Biomembranes, Utrecht University, the Netherlands including metabolic diseases (e.g. proper membrane (and membrane diabetes, obesity) and inflammatory protein) function, such as surface charge, diseases (e.g. artherosclerosis). While thickness and fluidity of the membrane cytosolic enzymes execute the synthesis (reviewed by de Kroon, Rijken, and De of fatty acids, the elongation of fatty acids Smet (2013)). De novo synthesis of lipids and the assembly of lipids occur starts with the formation of acetyl- predominantly in the ER. coenzyme A (Acetyl-CoA) in the cytosol. To synthesize of fatty acids, acetyl-CoA is This review will discuss studies from both carboxylated to malonyl-CoA. Fatty acid mammalian systems and the model synthases synthesize (mainly) palmitoyl- eukaryote Saccharomyces cerevisiae CoA from malonyl-CoA and acetyl-CoA; (baker’s yeast or yeast in short). Yeast is a palmitoyl-CoA can be processed widely used model eukoryote in studies (elongation, desaturation) in the ER to on ER-related subjects, such as ER-stress provide different fatty acids bound to CoA and lipid metabolism. Lipid metabolism (Acyl-CoA) (Figure 1). and regulation are highly conserved between yeast and mammals (Nielsen, In the following section we will briefly 2009). Furthermore, the yeast UPR is discuss the synthesis of lipids in mammals conserved in one of the branches of the and yeast. For a more complete coverage mammalian UPR, as well as one of the of these topics, the reader is referred to mammalian UPR branch is highly recent reviews (Henry, Kohlwein, & homologues to the yeast UPR (Mori, Carman, 2012; Holthuis & Menon, 2014; 2009). Nohturfft & Zhang, 2009) and references therein. There is accumulating evidence, from yeast and mammalian model systems, PHOSPHOLIPIDS that loss of lipid homeostasis causes ER The bulk of the lipids of all cellular stress and that the UPR is an important membranes are phospholipids, the main sensor of changes in ER membrane precursor for all phospholipids is homeostasis and is required for lipid phosphatic acid (PA). PA is synthesized biosynthesis. Therefore, this review will from glycerol-3-phosphate (G3P) by discuss the intersection between the UPR covalent binding of two acyl chains from and lipid metabolism. Acyl-CoA to the sn-1 and sn-2 positions of G3P. In mammals, the acetylation of G3P LIPID METABOLISM AT A GLANCE (to monoacyl G3P) occurs in the Membrane lipids can be discriminated on mitochondria and the acetylation of the base of their chemical structure, monoacyl G3P (to PA) occurs in the dividing them into three main families: mitochondria and ER. In yeast the entire glycerophospholipids (phospholipids, PL), process occurs in the ER. PA can undergo glycerosphingolipids (sphingolipids, SL) phosphatase action to form diacylglycerol and sterols. Within these three families, (DAG) or be coupled to there are various different classes in cytidinediphosphate (CDP) to provide which thousands of different molecular CDP-DAG. Both DAG and CDP-DAG are species have been identified. The lipid precursors for different lipids in separate composition of the membrane determines pathways (Figure 1). CDP-DAG provides the biophysical properties essential for Figure 1. Schematic overview of lipid metabolism in yeast and mammals. Conserved pathways are indicated by black arrows, yeast pathways are indicated by green arrows and mammalian pathways are indicated by red arrows. Responsible genes are indicated in red for mammals and green for yeast. For detailed description of biochemical pathways and abbreviations, see text. the lipid backbone for rafts in the plasma membrane. phosphatidylinositol (PI), Sphingolipids are typically elevated 50% in phosphatidylglycerol (PG) and cardiolipin lipid rafts compared to the total PM. (CL). In both mammals and yeast the Synthesis of sphingolipids starts with synthesis of PI takes place in the ER, Palmitoyl-CoA, which is consumed in a whereas the synthesis of PG and CL take condensation reaction with serine, to place in the mitochondria. In yeast, CDP- generate dehydrospringosine that is DAG is also the precursor for subsequently reduced to phosphatidylserine (PS). dihydriosphingosine. Dihydrosphingosine Phosphatidylethanolamine and is oxidized to form sphingosine, which is phosphatidylcholine can be synthesized the backbone for all sphingolipids. In from DAG and CDP-ethanolamine/CDP- mammals, ceramide is formed from choline, via a conserved pathway known sphingosine by the attachment of a as the Kennedy pathway (Figure 1, arrows (second) fatty acid to the free amine from DAG to PE and PC). PS is group and is the precursor for decarboxylated to generate PE and PE is sphingomyelin and the complex methylated to form PC in the Golgi and glycopshingolipids. In yeast, ER, respectively. In mammals however, dihydrosphingosine is hydroxylated to the only pathway generating PS is via the provide phytosphingosine, which is used carboxylation of PE in the ER. to form phytoceramide. Phytoceramide is the precursor for α- SPHINGOLIPIDS hydroxyphytoceramide and inositol- Sphingolipids and ceramide are an phosphoceramides (IPC). Synthesis of important component of the specialized ceramide or phytoceramide takes place in membrane microdomains known as lipid the ER, whereas complex sphingolipids are transcription factors that bind SREs are formed from ceramide in the Golgi. promoters. Phospholipid synthesis is coordinated by an upstream activating STEROLS sequence (UASIno), which is recognized by Sterols are important for membrane a heterodimeric transcription factor of fluidity and are found in all membranes, Ino2p and Ino4p. Opi1p represses the but the highest concentration of sterols is Ino2p/Ino4p pathway by binding directly found in the plasma membrane. Acetyl- to Ino2p and recruiting a transcriptional CoA is also the precursor for sterol repressor (Sin3p) to the promoter. Opi1p synthesis. Acetyl-CoA acetyl transferase activity is, in turn, regulated by ER protein proteins assemble acetoacetyl-CoA out of Scs2p and increased PA concentrations two acetyl-CoA molecules to form 3- that block Opi1p export from the ER. hydroxy-3-methylglutaryl-CoA (HMG-CoA) that is then reduced and released from In mammals, the synthesis of cholesterol CoA to provide mevalonate. Mevalonate and fatty acids is also regulated by the is the precursor for the synthesis of SREBP family of transcription factors. sterols in yeast (ergosterol) and mammals SREBPs are synthesized as inactive (cholesterol), which takes place in the ER. proteins, which become active after forming a complex with SREBP cleavage- Steryl esters and other
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