From sugar to fat: How the transcription factor XBP1 regulates hepatic lipogenesis Abstract Dietary carbohydrates regulate hepatic lipogenesis by controlling the expression of critical enzymes in glycolytic and lipogenic pathways. We have recently discovered that the transcription factor XBP1, best known as a key regulator of the Unfolded Protein Response (UPR) downstream of the ER transmembrane kinase IRE1, is required for de novo fatty acid synthesis in the liver, a function unrelated to its role in the UPR (1). XBP1 protein expression is induced in the liver by a high carbohydrate diet and directly controls the induction of critical genes involved in fatty acid and sterol synthesis. Inducible, selective deletion of XBP1 in liver results in marked hypocholesterolemia and hypotriglyceridaemia secondary to decreased production of lipids from the liver. Notably, this phenotype is not accompanied by hepatic steatosis or significant compromise in protein secretory function. Recent data demonstrate that in vivo administration of liposome encapsulated siXBP1 targeted to liver of wildtype or hypercholesterolemic apolipoproteinE (ApoE) deficient mice results in significant reductions in serum triglycerides and cholesterol within 48 hours that persist for almost 2 weeks. Hence, XBP1 directly regulates lipogenesis in vivo and its function in lipogenesis appears to be highly significant. Our recent discovery that XBP1 directly regulates the expression of PCSK9 may partly explain its effect on serum cholesterol. XBP1 joins an already rich field of transcriptional regulatory proteins in the control of hepatic lipogenesis. Our goal here is to place XBP1 in the context of the extensive existing knowledge of hepatic lipogenesis. How does XBP1 act as a transcriptional regulator of lipogenic genes and is this similar to or different than factors such as SREBPs and ChREBP? Does XBP1 act synergistically with other transcriptional activators or coactivators to regulate the transcription of lipogenic genes? What are the signals that activate IRE1 and induce XBP1 in liver and how do they relate to signals that induce other regulatory proteins? What are the consequences of XBP1 deficiency or XBP1 silencing in the liver for models of atherosclerosis? In this revised proposal, our goals are to 1) further explore the mechanism(s) by which XBP1 induces the transcription of genes encoding lipogenic enzymes;2) Identify the extracellular and intracellular signals that activate IRE11 and induce XBP1 protein in liver in response to carbohydrate feeding and establish by what mechanisms these signals induce XBP1 protein and;3) Examine the role of XBP1 in dietary and genetic models of atherosclerosis. A more complete understanding of the mechanisms by which XBP1 accelerates de novo fatty acid and sterol synthesis in the liver while preserving normal hepatic lipid composition is highly relevant to the treatment of diseases such as atherosclerosis that are associated with dyslipidemia.
We have recently discovered that the transcription factor XBP1, best known as a key regulator of the Unfolded Protein Response, is required for de novo fatty acid synthesis in the liver. Inducible, selective deletion of XBP1 in liver results in profound hypocholesterolemia and hypotriglyceridaemia secondary to decreased production of lipids from the liver. Here we propose to investigate the mechanisms by which XBP1 accelerates de novo fatty acid and sterol synthesis in the liver while preserving normal hepatic lipid composition. This knowledge is highly relevant to the treatment of diseases such as atherosclerosis that are associated with dyslipidemia.
|Cubillos-Ruiz, Juan R; Bettigole, Sarah E; Glimcher, Laurie H (2016) Molecular Pathways: Immunosuppressive Roles of IRE1?-XBP1 Signaling in Dendritic Cells of the Tumor Microenvironment. Clin Cancer Res 22:2121-6|
|Bettigole, Sarah E; Lis, Raphael; Adoro, Stanley et al. (2015) The transcription factor XBP1 is selectively required for eosinophil differentiation. Nat Immunol 16:829-37|
|Cho, Jin A; Lee, Ann-Hwee; Platzer, Barbara et al. (2013) The unfolded protein response element IRE1? senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe 13:558-69|
|So, Jae-Seon; Hur, Kyu Yeon; Tarrio, Margarite et al. (2012) Silencing of lipid metabolism genes through IRE1?-mediated mRNA decay lowers plasma lipids in mice. Cell Metab 16:487-99|
|Hur, Kyu Yeon; So, Jae-Seon; Ruda, Vera et al. (2012) IRE1? activation protects mice against acetaminophen-induced hepatotoxicity. J Exp Med 209:307-18|
|Johansen, Christopher T; Wang, Jian; McIntyre, Adam D et al. (2012) Excess of rare variants in non-genome-wide association study candidate genes in patients with hypertriglyceridemia. Circ Cardiovasc Genet 5:66-72|
|Jurczak, Michael J; Lee, Ann-Hwee; Jornayvaz, Francois R et al. (2012) Dissociation of inositol-requiring enzyme (IRE1?)-mediated c-Jun N-terminal kinase activation from hepatic insulin resistance in conditional X-box-binding protein-1 (XBP1) knock-out mice. J Biol Chem 287:2558-67|
|Lee, Jung Hoon; Giannikopoulos, Petros; Duncan, Stephen A et al. (2011) The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism. Nat Med 17:812-5|
|Lee, Ann-Hwee; Heidtman, Keely; Hotamisligil, Gokhan S et al. (2011) Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion. Proc Natl Acad Sci U S A 108:8885-90|