title: UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators.
abstract: The unfolded protein response (UPR) is linked to metabolic dysfunction, yet it is not known how endoplasmic reticulum (ER) disruption might influence metabolic pathways. Using a multilayered genetic approach, we find that mice with genetic ablations of either ER stress-sensing pathways (ATF6alpha, eIF2alpha, IRE1alpha) or of ER quality control (p58(IPK)) share a common dysregulated response to ER stress that includes the development of hepatic microvesicular steatosis. Rescue of ER protein processing capacity by the combined action of UPR pathways during stress prevents the suppression of a subset of metabolic transcription factors that regulate lipid homeostasis. This suppression occurs in part by unresolved ER stress perpetuating expression of the transcriptional repressor CHOP. As a consequence, metabolic gene expression networks are directly responsive to ER homeostasis. These results reveal an unanticipated direct link between ER homeostasis and the transcriptional regulation of metabolism, and suggest mechanisms by which ER stress might underlie fatty liver disease.
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. thomas-rutkowski@uiowa.edu
authors.forename: D Thomas
authors.initials: DT
authors.lastname: Rutkowski
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Back
authors.forename: Michael U
authors.initials: MU
authors.lastname: Callaghan
authors.forename: Sean P
authors.initials: SP
authors.lastname: Ferris
authors.forename: Jahangir
authors.initials: J
authors.lastname: Iqbal
authors.forename: Robert
authors.initials: R
authors.lastname: Clark
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Miao
authors.forename: Justin R
authors.initials: JR
authors.lastname: Hassler
authors.forename: Jamie
authors.initials: J
authors.lastname: Fornek
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
authors.forename: M Mahmood
authors.initials: MM
authors.lastname: Hussain
authors.forename: Benbo
authors.initials: B
authors.lastname: Song
authors.forename: Jayanth
authors.initials: J
authors.lastname: Swathirajan
authors.forename: Junying
authors.initials: J
authors.lastname: Wang
authors.forename: Grace D-Y
authors.initials: GD
authors.lastname: Yau
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D005786:Gene Expression Regulation; D006706:Homeostasis; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D017510:Protein Folding; D051381:Rats; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D008055:Lipids; D051742:Transcription Factor CHOP