Downregulation of Connexin 32 Attenuates Hypoxia/Reoxygenation Injury in Liver Cells

Ren, Wei; Huang, Fei; Chen, Zhangyan; Li, Shangrong

doi:10.1002/jbt.21684

Cited by 10 publications

(6 citation statements)

References 55 publications

(57 reference statements)

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“…Furthermore, after establishing the importance of cGAS in ALD, we were able to identify the critical role of Cx32, a known modulator of the intercellular transfer of cGAS-produced 2′3′-cGAMP (15,16). Previous work has established the important role of Cx32 in the inflammatory process of a variety of liver diseases, including drug-induced liver injury, nonalcoholic fatty liver disease, and ischemia-reperfusion injury (17)(18)(19). In the only published study of hepatic gap junctions in ALD, investigators examined the association of Cx32 in alcohol-related hepatocellular carcinoma and did not focus on inflammation (23).…”

Section: Discussionmentioning

confidence: 99%

“…Although these investigations were limited to in vitro models, recent in vivo studies have highlighted the importance of gap junctions in establishing liver injury. For example, deficiency in connexin 32 (Cx32), the predominant hepatic gap junction, attenuates injury in several murine models of liver disease (17)(18)(19). Despite these compelling data, the role of Cx32 in ALD and its ability to modulate IRF3 in vivo have not been studied.…”

Section: Significancementioning

confidence: 99%

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Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation

Luther

Khan

Gala

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Alcohol-related liver disease (ALD) accounts for the majority of cirrhosis and liver-related deaths worldwide. Activation of IFN-regulatory factor (IRF3) initiates alcohol-induced hepatocyte apoptosis, which fuels a robust secondary inflammatory response that drives ALD. The dominant molecular mechanism by which alcohol activates IRF3 and the pathways that amplify inflammatory signals in ALD remains unknown. Here we show that cytoplasmic sensor cyclic guanosine monophosphate-adenosine monophosphate (AMP) synthase (cGAS) drives IRF3 activation in both alcohol-injured hepatocytes and the neighboring parenchyma via a gap junction intercellular communication pathway. Hepatic RNA-seq analysis of patients with a wide spectrum of ALD revealed that expression of the cGAS-IRF3 pathway correlated positively with disease severity. Alcohol-fed mice demonstrated increased hepatic expression of the cGAS-IRF3 pathway. Mice genetically deficient in cGAS and IRF3 were protected against ALD. Ablation of cGAS in hepatocytes only phenocopied this hepatoprotection, highlighting the critical role of hepatocytes in fueling the cGAS-IRF3 response to alcohol. We identified connexin 32 (Cx32), the predominant hepatic gap junction, as a critical regulator of spreading cGAS-driven IRF3 activation through the liver parenchyma. Disruption of Cx32 in ALD impaired IRF3-stimulated gene expression, resulting in decreased hepatic injury despite an increase in hepatic steatosis. Taken together, these results identify cGAS and Cx32 as key factors in ALD pathogenesis and as potential therapeutic targets for hepatoprotection.

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation

Luther

Khan

Gala

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Likewise, nontumorigenic rat liver epithelial WB-F344 cells highly express Cx43, but not Cx32 (Neveu et al, 1994b; Rae et al, 1998). The former also holds true for immortal BRL-3A rat liver cells (Wang et al, 2015). As a result, hepatic cell lines can not be used to address specific toxicological issues, such as effects of strain, species, age and gender of nongenotoxic carcinogens on hepatocellular GJIC (Kamendulis et al, 2002; Klaunig and Ruch, 1987).…”

Section: In Vitro Models To Study Of Liver Gap Junctionsmentioning

confidence: 87%

Models and methods for in vitro testing of hepatic gap junctional communication

Maes¹,

Yanguas²,

Willebrords³

et al. 2015

Toxicology in Vitro

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Inherent to their pivotal roles in controlling all aspects of the liver cell life cycle, hepatocellular gap junctions are frequently disrupted upon impairment of the homeostatic balance, as occurs during liver toxicity. Hepatic gap junctions, which are mainly built up by connexin32, are specifically targeted by tumor promoters and epigenetic carcinogens. This renders inhibition of gap junction functionality a suitable indicator for the in vitro detection of nongenotoxic hepatocarcinogenicity. The establishment of a reliable liver gap junction inhibition assay for routine in vitro testing purposes requires a cellular system in which gap junctions are expressed at an in vivo-like level as well as an appropriate technique to probe gap junction activity. Both these models and methods are discussed in the current paper, thereby focusing on connexin32-based gap junctions.

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“…cell cultures, targeting the Cx32 gene increased cell survival, which was associated with decreased molecular permeability of GJs. 72 An alternative explanation is that a reduction of cell-to-cell communication prevents disruption of cellular metabolism. 73 Ischaemic preconditioning, which attenuates and protects against ischaemia-reperfusion damage, is NO dependent.…”

Section: Key Pointmentioning

confidence: 99%

Gap junctions in liver disease: Implications for pathogenesis and therapy

Hernández‐Guerra

Hadjihambi

Jalan

2019

Journal of Hepatology

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In the normal liver, cells interact closely through gap junctions. By providing a pathway for the trafficking of low molecular mass molecules, these channels contribute to tissue homeostasis and maintenance of hepatic function. Thus, dysfunction of gap junctions affects a wide variety of liver processes, such as differentiation, cell death, inflammation and fibrosis. In fact, dysfunctional gap junctions have been implicated, for more than a decade, in cholestatic disease, hepatic cancer and cirrhosis. Additionally, in recent years there is an increasing body of evidence that these channels are also involved in other relevant and prevalent liver pathological processes, such as non-alcoholic fatty liver disease, acute liver injury and portal hypertension. In parallel to these new clinical implications the available data include controversial observations. Thus, a comprehensive overview is required to better understand the functional complexity of these pores. This paper will review the most recent knowledge concerning gap junction dysfunction, with a special focus on the role of these channels in the pathogenesis of relevant clinical entities and on potential therapeutic targets that are amenable to modification by drugs.

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Downregulation of Connexin 32 Attenuates Hypoxia/Reoxygenation Injury in Liver Cells

Cited by 10 publications

References 55 publications

Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation

Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation

Models and methods for in vitro testing of hepatic gap junctional communication

Gap junctions in liver disease: Implications for pathogenesis and therapy

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