Diabetes Metab J.  2017 Feb;41(1):10-19. 10.4093/dmj.2017.41.1.10.

Nuclear Receptors Resolve Endoplasmic Reticulum Stress to Improve Hepatic Insulin Resistance

• Lee JM

• KMID: 2368524
• DOI: http://doi.org/10.4093/dmj.2017.41.1.10

Abstract

Chronic endoplasmic reticulum (ER) stress culminating in proteotoxicity contributes to the development of insulin resistance and progression to type 2 diabetes mellitus. Pharmacologic interventions targeting several different nuclear receptors have emerged as potential treatments for insulin resistance. The mechanistic basis for these antidiabetic effects has primarily been attributed to multiple metabolic and inflammatory functions. Here we review recent advances in our understanding of the association of ER stress with insulin resistance and the role of nuclear receptors in promoting ER stress resolution and improving insulin resistance in the liver.

Keyword

Diabetes mellitus, type 2; Endoplasmic reticulum stress; Hepatic steatosis; Insulin resistance; Receptors, cytoplasmic and nuclear; Unfolded protein response

MeSH Terms

Diabetes Mellitus, Type 2
Endoplasmic Reticulum Stress*
Endoplasmic Reticulum*
Insulin Resistance*
Insulin*
Liver
Receptors, Cytoplasmic and Nuclear*
Unfolded Protein Response
Insulin
Receptors, Cytoplasmic and Nuclear

Figure

• 

  Fig. 1 Canonical endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) pathways in mammals. Homeostatic perturbations leads to the accumulation of unfolded or misfolded proteins in the ER, which causes the dissociation of binding protein/glucose-regulated protein 78 (BiP/GRP78) from the luminal domain of three ER stress sensors PKR-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6) to exert its chaperone function. BiP/GRP78 dissociation renders PERK to undergo dimerization and transphosphorylation, and activation of its kinase activity, which then phosphorylates Ser51 on eukaryotic initiation factor 2α (eIF2α) to decrease global protein translation but selectively increases translation of ATF4 mRNA. ATF4 acting as a transcription factor induces expression of UPR target genes involved in amino acid (AA) biosynthesis, anti-oxidant response, and apoptosis. C/EBP homologous protein (CHOP) as one of direct ATF4 target genes subsequently activates expression of growth arrest and DNA damage-inducible protein (GADD34), a regulatory subunit of protein phosphatase 1 (PP1), which contributes to dephosphorylation of eIF2α to resume protein translation. ER oxidoreductin 1 (ERO1), another CHOP target gene, is an ER oxidoreductase. IRE1, the most conserved branch of UPR pathways throughout eukaryotes also undergoes dimerization (or oligomerization), transphosphorylation, and activation of endoRNase activity. This RNase function removes a 26-base intron from X-box binding protein 1 (Xbp1) mRNA to generate Xbp1s, a shorter spliced form of Xbp1 mRNA (XBP1s). XBP1s, a basic leucine zipper (bZIP) transcription factor controls a diverse range of UPR target genes including protein fold, ER-associated degradation (ERAD), trafficking, lipogenesis, inflammation, etc. This RNase activity also leads to a regulated IRE1-dependent decay (RIDD) of mRNA to reduce protein loading in the ER. Activation of ATF6 translocates from ER to Golgi apparatus with unknown processes where it is proteolytically cleaved by the Ser protease site 1 and site 2 proteases (S1P/S2P), generating ATF6(n), n-terminal truncated form of bZIP transcription factor. ATF6(n) activates the expression of its target genes involved in protein folding, ERAD, and ER biogenesis. Overall, activation of each sensor generates bZIP transcription factor ATF4, XBP1s, and ATF6(n), respectively that induces the expression of their relevant target genes associated with protein-folding fidelity, ERAD, ER biogenesis, lipogenesis, inflammation, amino acid biosynthesis, anti-oxidant response, etc. Both PERK and IRE1 contribute to reducing protein loading in the ER by suppressing global protein translation via phosphorylation of eIF2α and triggering RIDD of mRNA, respectively. Therefore, ER stress is alleviated by various feedback mechanisms from three branches of UPR pathways at the level of transcription, post-transcription or translation. However, prolonged and unmitigated ER stress induces apoptosis by ATF4-CHOP pathway.

• 

  Fig. 2 The role of nuclear receptor liver receptor homolog-1 (LRH-1) in endoplasmic reticulum (ER) stress resolution. In addition to the activation of three known canonical branches of unfolded protein response (UPR) pathways, LRH-1 is recruited to the promoter of polo-like kinase 3 (Plk3) gene upon ER stress. Moreover, ER stress increases transcription of Lrh-1 gene as well as its transcriptional activity probably via inositol-requiring enzyme 1 (IRE1) and/or activating transcription factor 6 (ATF6) dependent manner. PLK3, an atypical kinase phosphorylates ATF2, which induces the expression of its target genes including beta-1,3 glucuronyltransferase 3 (B3gat3), cysteine rich with EFG like domains 1 (Creld1), and multiple coagulation factor deficiency 2 (Mcfd2). Intriguingly, like liver-specific Lrh-1 knockout (KO) (Lrh-1LKO) mice, Plk3 KO mice or wild-type (WT) mice with hepatic overexpression of dominant negative ATF2 are also defective to resolve ER stress upon tunicamycin challenge. Therefore, identifying other potential ATF2 targeting genes as well as PLK3 substrates in both cytoplasm and nucleus could enrich our understanding of this unexpected but essential nuclear receptor-driven ER stress resolution pathway. BiP/GRP78, binding protein/glucose-regulated protein 78; PERK, PKR-like ER kinase; eIF2, eukaryotic initiation factor 2; XBP1s, shorter spliced form of X-box binding protein 1 (XBP1) mRNA; S1P/S2P, site 1 and site 2 proteases; ERAD, ER-associated degradation.

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