Heme-Regulated eIF2α Kinase Modulates Hepatic FGF21 and Is Activated by PPARβ/δ Deficiency

Zarei, Mohammad; Barroso, Emma; Leiva, Rosana; Barniol‐Xicota, Marta; Pujol, Eugènia; Escolano, Carmen; Palomer, Xavier; Pardo, Virginia; González-Rodrı́guez, Águeda; Valverde, Ángela M.; Quesada‐López, Tania; Villarroya, Francesc; Wahli, Walter; Vázquez‐Carrera, Manuel

doi:10.2337/db16-0155

Cited by 34 publications

(46 citation statements)

References 48 publications

(60 reference statements)

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“…No target-dependent toxicities have emerged with direct HRI activation [33,34], while there are reports of secondary benefits of HRI activation in models of human disease including beta-thalassemia and fatty liver disease [26,70,71]. Other small-molecule compounds that phosphorylate eIF2α in vivo and reduce tumor growth are known to be well tolerated, such as eicosapentaenoic acid, a main component of fish oils [42].…”

Section: Expert Opinionmentioning

confidence: 99%

“…For example, in mouse hepatocytes, knockout of HRI results in increased ER stress [25], while pharmacologic activation of HRI reduces ER-stress-induced hepatic steatosis and glucose intolerance in mouse models [26]. HRI activation is associated with increased hepatic expression of fibroblast growth factor 21 (FGF21), an important protein for attenuating ER stress [27].…”

Section: Introductionmentioning

confidence: 99%

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The eIF2-alpha kinase HRI: a potential target beyond the red blood cell

Burwick

Aktas

2017

Expert Opinion on Therapeutic Targets

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Introduction The eIF2α kinase heme-regulated inhibitor (HRI) is one of four well-described kinases that phosphorylate eIF2α in response to various cell stressors, resulting in reduced ternary complex formation and attenuation of mRNA translation. Although HRI is well known for its role as a heme sensor in erythroid progenitors, pharmacologic activation of HRI has been demonstrated to have anti-cancer activity across a wide range of tumor sub-types. Here, the potential of HRI activators as novel cancer therapeutics is explored. Areas covered We provide an introduction to eIF2 signaling pathways in general, and specifically review data on the eIF2α kinase HRI in erythroid and non-erythroid cells. We review aspects of targeting eIF2 signaling in cancer and highlight promising data using HRI activators against tumor cells. Expert opinion Pharmacologic activation of HRI inhibits tumor growth as a single agent without appreciable toxicity in vivo. The ability of HRI activators to provide direct and sustained eIF2α phosphorylation without inducing oxidative stress or broad eIF2α kinase activation may be especially advantageous for tolerability. Combination therapy with established therapeutics may further augment anti-cancer activity to overcome disease resistance.

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Section: Expert Opinionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The eIF2-alpha kinase HRI: a potential target beyond the red blood cell

Burwick

Aktas

2017

Expert Opinion on Therapeutic Targets

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“…Moreover, PPAR β / δ inhibits hepatic FGF21 expression [105], while PPAR α is a potent activator of FGF21 [20]. Since FGF21 is known to inhibit SREBP-1c and several other lipogenic genes in the liver [106, 107], the potential cross-talk of different PPAR isotypes on FGF21 may contribute to eliciting context-dependent effects.…”

Section: Ppars and Mitochondrial Dysfunction From Nafld To Hccmentioning

confidence: 99%

PPARs and Mitochondrial Metabolism: From NAFLD to HCC

2016

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Metabolic related diseases, such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD), are widespread threats which bring about a significant burden of deaths worldwide, mainly due to cardiovascular events and cancer. The pathogenesis of these diseases is extremely complex, multifactorial, and only partially understood. As the main metabolic organ, the liver is central to maintain whole body energetic homeostasis. At the cellular level, mitochondria are the metabolic hub connecting and integrating all the main biochemical, hormonal, and inflammatory signaling pathways to fulfill the energetic and biosynthetic demand of the cell. In the liver, mitochondria metabolism needs to cope with the energetic regulation of the whole body. The nuclear receptors PPARs orchestrate lipid and glucose metabolism and are involved in a variety of diseases, from metabolic disorders to cancer. In this review, focus is placed on the roles of PPARs in the regulation of liver mitochondrial metabolism in physiology and pathology, from NAFLD to HCC.

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“…On the other hand, ISR has recently been identified as a potent inducer of a pleiotropic metabolic hormone, fibroblast growth factor 21 (FGF21), in response to various stresses . Notably, it has been shown that GCN2‐ or HRI‐mediated FGF21 induction improves HS and glucose intolerance in mice …”

mentioning

confidence: 99%

Preemptive Activation of the Integrated Stress Response Protects Mice From Diet‐Induced Obesity and Insulin Resistance by Fibroblast Growth Factor 21 Induction

Krumm

et al. 2018

Hepatology

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Integrated stress response (ISR) is a signaling system in which phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) by stress-specific kinases and subsequent activation of activation transcription factor (ATF) 4 help restore cellular homeostasis following exposure to environmental stresses. ISR activation has been observed in metabolic diseases, including hepatic steatosis (HS), steatohepatitis (SH), and insulin resistance (IR), but it remains unclear whether ISR contributes to disease pathogenesis or represents an innate defense mechanism against metabolic stresses. Constitutive repressor of eIF2α phosphorylation (CReP) is a critical regulatory subunit of the eIF2α phosphatase complex. Here, we show that CReP ablation causes constitutive eIF2α phosphorylation in the liver, which leads to activation of the ATF4 transcriptional program including increased fibroblast growth factor 21 (FGF21) production. Liver-specific CReP knockout (CReP ) mice exhibited marked browning of white adipose tissue (WAT) and increased energy expenditure and insulin sensitivity in an FGF21-dependent manner. Furthermore, CReP mice were protected from high-fat diet (HFD)-induced obesity, HS, and IR. Acute CReP ablation in liver of HFD-induced obese mice also reduced adiposity and improved glucose homeostasis. Conclusion: These data suggest that CReP abundance is a critical determinant for eIF2α phosphorylation and ensuing ISR activation in the liver. Constitutive ISR activation in the liver induces FGF21 and confers protection from HFD-induced adiposity, IR, and HS in mice. Augmenting hepatic ISR may represent a therapeutic approach to treat metabolic disorders.

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Heme-Regulated eIF2α Kinase Modulates Hepatic FGF21 and Is Activated by PPARβ/δ Deficiency

Cited by 34 publications

References 48 publications

The eIF2-alpha kinase HRI: a potential target beyond the red blood cell

The eIF2-alpha kinase HRI: a potential target beyond the red blood cell

PPARs and Mitochondrial Metabolism: From NAFLD to HCC

Preemptive Activation of the Integrated Stress Response Protects Mice From Diet‐Induced Obesity and Insulin Resistance by Fibroblast Growth Factor 21 Induction

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