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Publication
The unfolded protein response transducer IRE1a prevents ER stress-induced
hepatic steatosis.
Authors Zhang K, Wang S, Malhotra J, Hassler JR, Back SH, Wang G, Chang L, Xu W, Miao H,
Leonardi R, Chen YE, Jackowski S, Kaufman RJ
Submitted By Submitted Externally on 7/27/2017
Status Published
Journal The EMBO journal
Year 2011
Date Published
Volume : Pages 30 : 1357 - 75
PubMed Reference 21407177
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 a (IRE1a), 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 IRE1a-mediated signalling in the liver, we generated
hepatocyte-specific Ire1a-null mice by utilizing an albumin promoter-controlled
Cre recombinase-mediated deletion. Deletion of Ire1a 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 IRE1a is
required to maintain the secretion efficiency of selective proteins. In the
absence of ER stress, mice with hepatocyte-specific Ire1a deletion displayed
modest hepatosteatosis that became profound after induction of ER stress.
Further investigation revealed that IRE1a represses expression of key metabolic
transcriptional regulators, including CCAAT/enhancer-binding protein (C/EBP) ß,
C/EBPd, peroxisome proliferator-activated receptor ? (PPAR?), and enzymes
involved in triglyceride biosynthesis. IRE1a was also found to be required for
efficient secretion of apolipoproteins upon disruption of ER homeostasis.
Consistent with a role for IRE1a in preventing intracellular lipid accumulation,
mice with hepatocyte-specific deletion of Ire1a 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 IRE1a as a key
regulator to prevent hepatic steatosis provides novel insights into ER stress
mechanisms in fatty liver diseases associated with toxic liver injuries.






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