The unfolded protein response in fatty liver disease - PubMed (original) (raw)
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The unfolded protein response in fatty liver disease
Anne Henkel et al. Semin Liver Dis. 2013 Nov.
Abstract
The unfolded protein response (UPR) is a protective cellular response activated under conditions of endoplasmic reticulum (ER) stress. The hepatic UPR is activated in several forms of liver disease including nonalcoholic fatty liver disease (NAFLD). Recent data defining the role of the UPR in hepatic lipid metabolism have identified molecular mechanisms that may underlie the association between UPR activation and NAFLD. It has become increasingly evident that the IRE1α/Xbp1 pathway of the UPR is critical for hepatic lipid homeostasis, and dysregulation of this evolutionarily conserved pathway is associated with human nonalcoholic steatohepatitis (NASH). Although increasing evidence has delineated the importance of UPR pathway signaling in fatty liver disorders, the regulation of the hepatic UPR in normal physiology and fatty liver disorders remains incompletely understood. Understanding the role of the UPR in hepatic lipid metabolism may lead to the identification of novel therapeutic targets for the treatment of NAFLD.
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
Figures
Figure 1. Overview of the Unfolded Protein Response (UPR)
In the unstressed state, IRE1α, PERK, and ATF6α are bound by the ER chaperone Grp78. In response to ER stress, Grp78 dissociates from these receptors to bind to unfolded proteins. IRE1α is activated by dimerization and autophosphorylation. Activated IRE1α induces splicing of XBP1. Spliced (activated) XBP1s translocates to the nucleus where it functions as a potent transcription factor. Upon dissociation from Grp78, PERK forms a dimer leading to its activation by autophosphorylation. Activation of PERK promotes phosphorylation of eIF2α leading to a global attenuation of protein translation. Phosphorylated eIF2α increases the translation of ATF4. Dissociation of Grp78 from ATF6 results in the unmasking of two Golgi localization sequences within ATF6. Upon translocation to the Golgi apparatus, ATF6α is activated by proteolytic cleavage to a 50kDa transcription factor. Activated XBP1s, ATF4, and ATF6α all translocate to the nucleus where they transcriptionally activate numerous genes including ER chaperones, CHOP, and genes associated with ERAD.
Figure 2. Proposed mechanisms of ER stress-induced apoptosis
Activated IRE1α recruits TNFR-associated receptor 2 (TRAF2) leading to activation of the c-Jun N-terminal kinase (JNK). Caspase-12 associates with activated IRE1α, allowing its proteolytic cleavage to active caspase-12. Within the ER membrane, Bak and Bax associate with IRE1α to potentiate its activity. Activated ATF4 increases transcription of CHOP, which functions as a transcriptional activator of numerous pro-apoptotic genes including death receptor 5 (DR5), Bim, and tribbles homolog 3 (TRB3).
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