No abstract

The endoplasmic reticulum (ER) is the cellular organelle responsible for protein folding and assembly, lipid and sterol biosynthesis, and calcium storage. The unfolded protein response (UPR) is an adaptive intracellular stress response to accumulation of unfolded or misfolded proteins in the ER. In this study, we show that the most conserved UPR sensor inositol‐requiring enzyme 1 α (IRE1α), an ER transmembrane protein kinase/endoribonuclease, is required to maintain hepatic lipid homeostasis under ER stress conditions through repressing hepatic lipid accumulation and maintaining lipoprotein secretion. To elucidate physiological roles of IRE1α‐mediated signalling in the liver, we generated hepatocyte‐specific Ire1α‐null mice by utilizing an albumin promoter‐controlled Cre recombinase‐mediated deletion. Deletion of Ire1α caused defective induction of genes encoding functions in ER‐to‐Golgi protein transport, oxidative protein folding, and ER‐associated degradation (ERAD) of misfolded proteins, and led to selective induction of pro‐apoptotic UPR trans‐activators. We show that IRE1α is required to maintain the secretion efficiency of selective proteins. In the absence of ER stress, mice with hepatocyte‐specific Ire1α deletion displayed modest hepatosteatosis that became profound after induction of ER stress. Further investigation revealed that IRE1α represses expression of key metabolic transcriptional regulators, including CCAAT/enhancer‐binding protein (C/EBP) β, C/EBPδ, peroxisome proliferator‐activated receptor γ (PPARγ), and enzymes involved in triglyceride biosynthesis. IRE1α was also found to be required for efficient secretion of apolipoproteins upon disruption of ER homeostasis. Consistent with a role for IRE1α in preventing intracellular lipid accumulation, mice with hepatocyte‐specific deletion of Ire1α developed severe hepatic steatosis after treatment with an ER stress‐inducing anti‐cancer drug Bortezomib, upon expression of a misfolding‐prone human blood clotting factor VIII, or after partial hepatectomy. The identification of IRE1α as a key regulator to prevent hepatic steatosis provides novel insights into ER stress mechanisms in fatty liver diseases associated with toxic liver injuries.

This review presents an overview of mammalian phospholipid synthesis and the cellular locations of the biochemical activities that produce membrane lipid molecular species. The generalized endoplasmic reticulum compartment is a central site for membrane lipid biogenesis, and examples of the emerging relationships between alterations in lipid composition, regulation of membrane lipid biogenesis, and cellular secretory function are discussed.-Fagone, P., and S. Jackowski. BIOLOGICAL MEMBRANESBiological membranes are composed of lipids and proteins that together form hydrophobic barriers that limit the distribution of aqueous macromolecules and metabolites. Cells use membranes for a number of different purposes, including segregation and protection from the environment, compartmentalization of functions, energy production, storage, protein synthesis and secretion, phagocytosis, movement, and cell-cell interaction. Eukaryotic cells contain ordered infrastructures, called organelles, to organize and carry out complex processes and to enable distinct reactions that require a hydrophobic environment. The level and complexity of compartmentalization varies among organisms and among mammalian cells. Some cells also change in size and organelle complexity after biological stimulation. An example of induced membrane biogenesis occurs in naïve B-lymphocytes that are converted to plasma cells (1), and an example of membrane redistribution occurs in macrophages in which the Golgi apparatus is reoriented during transient cytokine synthesis and secretion (2). The versatility of biological membranes is dependent on their structures and biophysical properties, which are dictated by the types of lipids and proteins that compose the membranes. The functions of membranes require a fluid plasticity that is accomplished through alteration in lipid composition. Lipid composition is diverse, not only among different organisms, but also among different compartments within the same cells and between the two leaflets of the same membrane. Lipid composition is determined through regulation of de novo synthesis at designated cellular sites, selective distribution or trafficking to new sites, and by localized remodeling reactions. Understanding the relationships between the dynamic changes in membrane lipid composition and specific cellular events is our current challenge. This review is focused on membrane phospholipid biogenesis in mammalian cells with a particular emphasis on the role played by the endoplasmic reticulum (ER). The ER, together with the Golgi apparatus, is a major site of de novo bulk membrane lipid synthesis, and recent experiments demonstrate a link between phospholipid synthesis and secretion from this compartment. THE ARCHITECTURE OF THE ERThe ER and Golgi apparatus together constitute the endomembrane compartment in the cytoplasm of eukaryotic cells. The endomembrane compartment is a major site of lipid synthesis, and the ER is where not only lipids are synthesized, but membrane-bound proteins and secretory pr...

When the protein folding capacity of the endoplasmic reticulum (ER) is challenged, the unfolded protein response (UPR) maintains ER homeostasis by regulating protein synthesis and enhancing expression of resident ER proteins that facilitate protein maturation and degradation. Here, we report that enforced expression of XBP1(S), the active form of the XBP1 transcription factor generated by UPR-mediated splicing of XBP1 mRNA, is sufficient to induce synthesis of phosphatidylcholine, the primary phospholipid of the ER membrane. Cells overexpressing XBP1(S) exhibit elevated levels of membrane phospholipids, increased surface area and volume of rough ER, and enhanced activity of the cytidine diphosphocholine pathway of phosphatidylcholine biosynthesis. These data suggest that XBP1(S) links the mammalian UPR to phospholipid biosynthesis and ER biogenesis.

No abstract