The novel intracellular protein CREG inhibits hepatic steatosis, obesity, and insulin resistance

Zhang, Quanyu; Zhao, Lei; Tian, Xiaoxiang; Cao, Yan; Yang, Li; Liu, Yanxia; Wang, Pi-Xiao; Zhang, Xiaojing; Han, Yaling

doi:10.1002/hep.29257

Cited by 33 publications

(38 citation statements)

References 42 publications

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“…Hepatocyte‐specific Creg knockout ( Creg ΔHep ) mice and hepatocyte‐specific Creg transgene ( Creg ‐HTG) mice in the C57BL/6J background were generated as previously described . We used albumin‐Cre recombinase transgenic (TG) mice (albumin‐Cre TG mice) and Creg flox/flox mice to intercross and generate mice with the Creg gene specifically deleted in hepatocytes (albumin‐Cre/+ Creg flox/flox mice, abbreviated as Creg ΔHep ).…”

Section: Methodsmentioning

confidence: 99%

“…Interestingly, Creg also exhibits protective properties against heart injury induced by I/R insult through autophagy and anti‐apoptosis . A recent study also suggested that Creg is a suppressor of hepatic steatosis and metabolic disorders through its interaction with MAPK/apoptosis signal‐regulating kinase 1 (ASK1)–c‐Jun N‐terminal kinase 1 (JNK1) signaling . Considering the regulatory effects of Creg on cardiovascular cellular events, in particular of inflammation and cell death, which also directly correlate with the progression of hepatic I/R injury, and the characteristics of Creg in regulating MAPK signaling, we hypothesized that Creg prominently participates in the progression of hepatic I/R‐induced liver injury.…”

mentioning

confidence: 99%

“…Considering the regulatory effects of Creg on cardiovascular cellular events, in particular of inflammation and cell death, which also directly correlate with the progression of hepatic I/R injury, and the characteristics of Creg in regulating MAPK signaling, we hypothesized that Creg prominently participates in the progression of hepatic I/R‐induced liver injury. Nevertheless, in the liver, Creg was only reported to be involved in lipid accumulation and inflammatory response, whereas its potential role in liver I/R injury remains unknown.…”

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confidence: 99%

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Creg in Hepatocytes Ameliorates Liver Ischemia/Reperfusion Injury in a TAK1‐Dependent Manner in Mice

Yang

Wang

et al. 2019

Hepatology

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Hepatic ischemia/reperfusion (I/R) is a major challenge for liver surgery and specific severe conditions of chronic liver disease. Current surgical and pharmacological strategies are limited to improve liver function after hepatic I/R injury. Thus, an in-depth understanding of the liver I/R mechanism is pivotal to develop new therapeutic methods. The cellular repressor of E1A-stimulated genes (CREG), a key regulator of cellular proliferation, exerts protective roles in cardiovascular diseases and participates in lipid accumulation and inflammatory response in the liver. However, the role of CREG in hepatic I/R remains largely unknown. A genetic engineering technique was employed to explore the function of CREG in hepatic I/R injury. Hepatocyte-specific Creg knockout (Creg ) and transgenic (HTG) mice were generated and subjected to hepatic I/R injury, as were the controls. CREG in hepatocytes prevented against liver I/R injury by suppressing cell death and inflammation. In vitro studies were performed using primary hepatocytes isolated from Creg that were challenged by hypoxia/reoxygenation insult. These cells exhibited more cell death and inflammatory cytokines production similar to observations in vivo. Moreover, further molecular experiments showed that CREG suppressed MAPK signaling by inhibiting TAK1 phosphorylation. Inhibiting TAK1 by 5Z-7-ox or mutating the TAK1-binding domain of CREG abolished the protective role of CREG, indicating that CREG binding to TAK1 was required for prevention against hepatic I/R injury. Conclusion These data demonstrated that CREG prevents hepatocytes from liver I/R injury. The CREG-TAK1 interaction inhibited the phosphorylation of TAK1 and the activation of MAPK signaling, which protected against cell death and inflammation during hepatic I/R injury. This article is protected by copyright. All rights reserved.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Creg in Hepatocytes Ameliorates Liver Ischemia/Reperfusion Injury in a TAK1‐Dependent Manner in Mice

Yang

Wang

et al. 2019

Hepatology

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“…ASK1 is normally held in an inactivated state bound to various inhibitors such as thioredoxin or glutathione (GSH) S ‐transferases, which are redox sensitive so that ROS can release ASK1 from inhibition . In addition, CASP8‐ and FADD‐like apoptosis regulator (cFLIP) and cellular repressor of E1A‐stimulated genes (CREG) have been shown to interfere with the dimerization of ASK1, preventing activation . Therefore, conditions in which the expression of cFLIP or CREG is inhibited can lead to enhanced ASK1 activation.…”

Section: The Jnk Signaling Pathway In the Liver: Recent Advancesmentioning

confidence: 99%

New insights into the role and mechanism of c‐Jun‐N‐terminal kinase signaling in the pathobiology of liver diseases

et al. 2018

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The c‐Jun‐N‐terminal‐kinase (JNK) family is highly conserved across species such as Drosophila, C. elegans, zebrafish and mammals, and plays a central role in hepatic physiologic and pathophysiologic responses. These responses range from cell death to cell proliferation and carcinogenesis, as well as metabolism and survival, depending on the specific context and duration of activation of the JNK signaling pathway. Recently, several investigators identified the key molecules in the JNK activation loop which include apoptosis signal‐regulating kinase (ASK1) and SH3‐domain binding protein 5 (Sab) and their involvement in acute or chronic liver disease models. Thus, regulating JNK activation through modulating the JNK activation loop may represent an important new strategy in the prevention and treatment of acute and chronic liver diseases. In this review, we will discuss the molecular pathophysiology of the JNK activation loop and its role in the pathogenesis of liver diseases. (Hepatology 2018;67:2013‐2024).

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“…Many ASK1 regulatory mechanisms have been described previously and could represent potential therapeutic targets for NASH. For instance, TRAF1, DKK3, and CREG modulate hepatic ASK1 phosphorylation and the severity of NASH; CFLAR targeting of ASK1 interrupts its dimerization and activation in NASH; and TNFAIP3 mediates the deubiquitination and inactivation of hepatic ASK1during NASH . Given that Lys63‐, Lys29‐, and Lys11‐linked ubiquitination is critical in activation of ASK1 during NASH progression, identification of a molecule that regulates one or some of these types of ubiquitination in ASK1 could provide an alternative or an adjuvant therapeutic target for NASH.…”

Section: Discussionmentioning

confidence: 99%

F‐box/WD Repeat‐Containing Protein 5 Mediates the Ubiquitination of Apoptosis Signal‐Regulating Kinase 1 and Exacerbates Nonalcoholic Steatohepatitis in Mice

Bai

Chen

et al. 2019

Hepatology

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Inhibition of apoptosis signal‐regulating kinase 1 (ASK1) activation has emerged as a promising target for the treatment of nonalcoholic steatohepatitis (NASH). Multiple forms of posttranslational modifications determine the activity of ASK1. In addition to phosphorylation, recent studies revealed that ubiquitination is essential for ASK1 activation. However, the endogenous factor that regulates ASK1 ubiquitination and activation remains poorly defined. In this study, we identified the E3 ligase Skp1‐Cul1‐F‐box (SCF) protein F‐box/WD repeat‐containing protein 5 (FBXW5) as a key endogenous activator of ASK1 ubiquitination. FBXW5 is the central component of the SCF complex (SCFFbxw5) that directly interacts with and ubiquitinates ASK1 in hepatocytes during NASH development. An in vivo study showed that hepatocyte‐specific overexpression of FBXW5 exacerbated diet‐induced systemic and hepatic metabolic disorders, as well as the activation of ASK1‐related mitogen‐activated protein kinase (MAPK) signaling in the liver. Conversely, hepatocyte‐specific deletion of FBXW5 significantly prevented the progression of these abnormalities. Mechanically, FBXW5 facilitated the addition of Lys63‐linked ubiquitin to ASK1 and thus exacerbated ASK1‐c‐Jun N‐terminal kinase/p38 MAPK signaling, inflammation, and lipid accumulation. Furthermore, we demonstrated that the N‐terminus (S1) and C‐terminus (S3) of FBXW5 respectively and competitively ablate the function of FBXW5 on ASK1 activation and served as effective inhibitors of NASH progression. Conclusion: This evidence strongly suggests that SCFFbxw5 is an important activator of ASK1 ubiquitination in the context of NASH. The development of FBXW5(S1) or FBXW5(S3)‐mimicking drugs and screening of small‐molecular inhibitors specifically abrogating ASK1 ubiquitination‐dependent activation are viable approaches for NASH treatment.

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The novel intracellular protein CREG inhibits hepatic steatosis, obesity, and insulin resistance

Cited by 33 publications

References 42 publications

Creg in Hepatocytes Ameliorates Liver Ischemia/Reperfusion Injury in a TAK1‐Dependent Manner in Mice

Creg in Hepatocytes Ameliorates Liver Ischemia/Reperfusion Injury in a TAK1‐Dependent Manner in Mice

New insights into the role and mechanism of c‐Jun‐N‐terminal kinase signaling in the pathobiology of liver diseases

F‐box/WD Repeat‐Containing Protein 5 Mediates the Ubiquitination of Apoptosis Signal‐Regulating Kinase 1 and Exacerbates Nonalcoholic Steatohepatitis in Mice

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