Fatty liver disease (FLD) has a variety of causes including chronic alcohol consumption, obesity, viral infection, malnutrition, and acute exposure to hepatotoxins. FLD can progress from simple steatosis to steatohepatitis that compromises liver function, leading to inflammation, fibrosis, cirrhosis, and ultimately liver failure. While FLD most likely reflects an imbalance between lipid synthesis, storage, oxidation, and/or secretion, the underlying molecular causes of this imbalance are only partially understood. As FLD of both alcoholic and nonalcoholic origins is very common, identifying its etiologies, which are likely varied, will suggest avenues of treatment to prevent liver failure. This research proposal is based upon strong preliminary data demonstrating that endoplasmic reticulum (ER) stress leads to transcriptional suppression of genes involved in maintaining lipid homeostasis;mice genetically deficient in the ER stress-sensing protein ATF61 fail to overcome ER stress, and become profoundly steatotic upon challenge. These animals, which are otherwise normal in the uninjured state, provide a valuable tool for dissecting the connections between ER stress and liver lipid metabolism. The long-term objective of this work is to understand how ER perturbation contributes to fatty liver disease. This goal will be achieved by three complementary areas of investigation.
The first aim i s to understand how the ER stress response is mechanistically connected to lipid homeostasis at the level of transcription. Gene regulatory events will be placed into a hierarchy based on the ability of in vivo overexpression of key metabolic transcription factors to partially or fully rescue steatosis in Atf61-null mice. In parallel, direct regulation of genes by ER stress-regulated transcription factors will be probed by both unbiased and targeted chromatin immunoprecipitation. Finally, the mechanism that ties metabolic transcriptional regulation to unresolved ER stress will be determined.
The second aim i s to determine how the regulation of lipid metabolism by the ER stress response in turn impacts ER function.
This aim will be achieved by pinpointing the pathways of lipid metabolism that contribute to steatosis during ER stress, and testing how the ability of the ER to fold and process client proteins (i.e., """"""""ER function"""""""") is altered when these pathways are manipulated independent of ER stress.
The third aim i s to determine how chronic ER stress contributes to pathological steatosis, in particular alcoholic fatty liver disease. We will use Atf61-null mice to test whether impairment of ER function sensitizes mice to steatosis during chronic ethanol consumption. We will also determine how chronic ethanol consumption alters cellular homeostasis through ER stress-regulated changes in gene expression. This work provides several independent avenues to address an aspect of the development of steatosis that is currently poorly understood, and will identify novel key regulatory pathways that might represent attractive targets for future therapeutic intervention to prevent liver failure.
Public Health Relevance Steatosis, or fatty liver disease, is the most common liver disease in Western countries, being present in approximately 25 percent of American adults;it can progress to steatohepatitis, fibrosis, cirrhosis, and liver failure. The causes underlying the development of steatosis are not clear, and must be understood for effective therapies to be developed. The identification of endoplasmic reticulum stress as a contributing factor to steatosis suggests that the work proposed here will enhance our understanding of molecular basis for steatosis and suggest means of therapeutically treating it.
|Jo, Fusakazu; Jo, Hiromi; Hilzendeger, Aline M et al. (2015) Brain endoplasmic reticulum stress mechanistically distinguishes the saline-intake and hypertensive response to deoxycorticosterone acetate-salt. Hypertension 65:1341-8|
|Gomez, Javier A; Tyra, Heather M; DeZwaan-McCabe, Diane et al. (2014) Synthetic embryonic lethality upon deletion of the ER cochaperone p58(IPK) and the ER stress sensor ATF6?. Biochem Biophys Res Commun 443:115-9|
|Mao, Hui Z; Ehrhardt, Nicole; Bedoya, Candy et al. (2014) Lipase maturation factor 1 (lmf1) is induced by endoplasmic reticulum stress through activating transcription factor 6? (Atf6?) signaling. J Biol Chem 289:24417-27|
|Hassan, Ihab; Gaines, Kayla S; Hottel, Wesley J et al. (2014) Inositol-requiring enzyme 1 inhibits respiratory syncytial virus replication. J Biol Chem 289:7537-46|
|Arensdorf, Angela M; Diedrichs, Danilo; Rutkowski, D Thomas (2013) Regulation of the transcriptome by ER stress: non-canonical mechanisms and physiological consequences. Front Genet 4:256|
|DeZwaan-McCabe, Diane; Riordan, Jesse D; Arensdorf, Angela M et al. (2013) The stress-regulated transcription factor CHOP promotes hepatic inflammatory gene expression, fibrosis, and oncogenesis. PLoS Genet 9:e1003937|
|Arensdorf, Angela M; Rutkowski, D Thomas (2013) Endoplasmic reticulum stress impairs IL-4/IL-13 signaling through C/EBP?-mediated transcriptional suppression. J Cell Sci 126:4026-36|
|Sadighi Akha, Amir A; Theriot, Casey M; Erb-Downward, John R et al. (2013) Acute infection of mice with Clostridium difficile leads to eIF2? phosphorylation and pro-survival signalling as part of the mucosal inflammatory response. Immunology 140:111-22|
|Arensdorf, Angela M; Dezwaan McCabe, Diane; Kaufman, Randal J et al. (2013) Temporal clustering of gene expression links the metabolic transcription factor HNF4? to the ER stress-dependent gene regulatory network. Front Genet 4:188|
|Chikka, Madhusudana R; McCabe, Diane DeZwaan; Tyra, Heather M et al. (2013) C/EBP homologous protein (CHOP) contributes to suppression of metabolic genes during endoplasmic reticulum stress in the liver. J Biol Chem 288:4405-15|
Showing the most recent 10 out of 17 publications