Endoplasmic reticulum stress and the unfolded protein response in nonalcoholic fatty liver disease

Abstract

The underlying causes of nonalcoholic fatty liver disease (NAFLD) are unclear, although recent evidence has implicated the endoplasmic reticulum (ER) in both the development of steatosis and progression to nonalcoholic steatohepatitis. Disruption of ER homeostasis, often termed "ER stress," has been observed in liver and adipose tissue of humans with NAFLD and/or obesity. Importantly, the signaling pathway activated by disruption of ER homeostasis, the unfolded protein response, has been linked to lipid biosynthesis, insulin action, inflammation, and apoptosis. Therefore, understanding the mechanisms that disrupt ER homeostasis in NAFLD and the role of ER-mediated signaling have become topics of intense investigation. The present review will examine the ER and the unfolded protein response in the context of NAFLD.

FIG. 1.

Overview of the mammalian unfolded protein response (UPR). The presence of unfolded proteins in the endoplasmic reticulum (ER) lumen leads to dimerization and autophosphorylation of protein kinase-like ER kinase (PERK) and (IRE1α), and the release and proteolytic cleavage of activating transcription factor 6 (ATF6) in the Golgi. PERK-mediated phosphorylation of eukaryotic initiation factor 2α (eIF2α) leads to transient attenuation of translation but selective translation of mRNAs containing upstream open reading frames, such as activating transcription factor 4 (ATF4). Increased transcription and translation of GADD34 subsequently leads to dephosphorylation of eIF2α and resumption of translation. Activation of IRE1α leads to the splicing of XBP1. Spliced X-box binding protein 1 (XBP1s), ATF4, and the cleaved form of ATF6 lead to transcriptional activation of a number of gene targets related to protein folding and ER-associated degradation (see text).

FIG. 2.

Protein kinase-mediated phosphorylation of eIF2α and additional downstream targets of p-eIF2α and IRE1α. (A) Phosphorylation of eIF2α can be mediated by four protein kinases: double-stranded RNA-activated protein kinase (PKR), general control nonderepressible 2 kinase (Gcn2), heme-regulated inhibitor kinase (HRI), and PERK. Phosphorylation of eIF2α is linked to the inflammatory response via activation of nuclear factor kappa-β (NFκβ). PERK-mediated phosphorylation of nuclear erythroid 2 p45-related factor 2 (Nrf2) links PERK activation to the regulation of redox balance (see text). (B) Activation of IRE1α can lead to activation of stress kinases, including p38 mitogen-activated protein kinase (MAPK), extracellular-regulated kinase (ERK), c-Jun-NH₂-terminal kinase (JNK), and NFκβ (see text).

FIG. 3.

The UPR is linked to regulation of lipogenesis and hepatic lipid stores. (A) The IRE1α-XBP1 and the PERK-peIF2α pathways can upregulate the lipogenic gene program. In contrast, interactions among ATF6, sterol regulatory element binding protein 2 (SREBP2), and histone deacytelase-1 (HDAC1) can limit lipogenesis. (B) Inability to resolve ER stress may promote hepatic steatosis via upregulation of pathways that contribute to lipid input and downregulation of lipid output pathways.

FIG. 4.

The UPR is linked to insulin action, inflammation, oxidative stress, and apoptosis. The UPR is linked to insulin action via interactions with JNK, to inflammation via PKR, regulated intramembrane proteolysis of CREBH, and interactions with JNK, to protection from oxidative stress via phosphorylation of Nrf2, splicing of XBP1 and selective translation of ATF4, to apoptosis via interactions with JNK, upregulation of C/EBP homologous protein (Chop), activation of caspase-12, and extrusion of luminal calcium (see text).

FIG. 5.

IRE1α can interact with a diverse set of proteins. The activity of IRE1α can be modified by a number of interacting proteins, including B-cell leukemia/lymphoma 2 protein (Bcl-2)-associated X protein (Bax), Bcl-2 antagonist/killer (Bak), Bax inhibitor (BI)-1, protein tyrosine phosphatase-1B (PTP1B), apoptosis signaling-regulating kinase 1 (ASK1)-interacting protein 1 (AIP1), and HSP90. In turn, IRE1α, via interactions with TNFR-associated factor 2 (TRAF2), can modify the activity of ERK, p38, JNK, and NFκβ (see text).

FIG. 6.

Hypothetical model for the UPR in chronic diseases. Signals that lead to ER stress activate the UPR. The ability of the UPR to alleviate ER stress is linked to the magnitude of the UPR (thin line represents a lower magnitude response; thicker line represents higher magnitude response). The UPR is also linked to multiple cell signaling and metabolic pathways. In chronic diseases like obesity and nonalcoholic fatty liver disease (NAFLD) chronic signals induce ER stress, and perhaps activation of the UPR independently of ER stress. In addition, obesity and/or NAFLD may be characterized by signals that impair the UPR, thus dampening the magnitude of the response and the ability to alleviate ER stress (see text).